Protocol Effects of Pycnogenol® in people with post-COVID-19 condition (PYCNOVID): study protocol for a single-center, placebo controlled, quadruple-blind, RCT

forestglip

forestglip

Senior Member (Voting Rights)
Staff member
Effects of Pycnogenol® in people with post-COVID-19 condition (PYCNOVID): study protocol for a single-center, placebo controlled, quadruple-blind, randomized trial

Thomas Radtke, Lisa Künzi, Julia Kopp, Manuela Rasi, Julia Braun, Kyra D. Zens, Babette Winter, Alexia Anagnostopoulos, Milo A. Puhan, Jan S. Fehr

15 June 2024

Abstract
Background
A significant proportion of the global population has been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at some point since the onset of the pandemic. Although most individuals who develop coronavirus disease 2019 (COVID-19) recover without complications, about 6% have persistent symptoms, referred to as post-COVID-19 condition (PCC). Intervention studies investigating treatments that potentially alleviate PCC-related symptoms and thus aim to mitigate the global public health burden and healthcare costs linked to PCC are desperately needed. The PYCNOVID trial investigates the effects of Pycnogenol®, a French maritime pine bark extract with anti-inflammatory and antioxidative properties, versus placebo on patient-reported health status in people with PCC.

Methods
This is a single-center, placebo-controlled, quadruple blind, randomized trial. We aim to randomly assign 150 individuals with PCC (1:1 ratio) to receive either 200 mg Pycnogenol® or placebo daily for 12 weeks. Randomization is stratified for duration of PCC symptoms (≤ 6 months versus > 6 months) and presence of symptomatic chronic disease(s). The primary endpoint is perceived health status at 12 weeks (EuroQol—Visual Analogue Scale) adjusted for baseline values and stratification factors. Secondary endpoints include change in self-reported PCC symptoms, health-related quality of life, symptoms of depression and anxiety, cognitive function, functional exercise capacity, physical activity measured with accelerometry, and blood biomarkers for endothelial health, inflammation, coagulation, platelet function, and oxidative stress. Investigators, study participants, outcome assessors, and data analysts are blinded regarding the intervention assignment. Individuals with PCC were involved in the design of this study.

Discussion
This is the first trial to investigate the effects of Pycnogenol® versus placebo on patient-reported health status in people with PCC. Should the trial proof clinical effectiveness, Pycnogenol® may serve as a therapeutic approach to mitigate symptoms associated with PCC.

Protocol | ClinicalTrials.gov
 
Protocol said:
Pycnogenol® may be an attractive treatment option since it is on the market for a long time with few side effects reported to date [20, 21] and some promising results in patients with PCC [20]. Pycnogenol® is a French maritime pine bark extract and primarily consists of procyanidins and their individual components, namely catechin and epicatechin, alongside phenolic acids [22]. It exerts antioxidative, anti-inflammatory, and antiproliferative properties and has been shown to improve vascular endothelial function, most likely due to an upregulation of endothelial nitric oxide synthase activity [21,22,23,24,25]. In people recovering from COVID-19, daily intake of 150 mg Pycnogenol® over a period of 12 weeks improved endothelial function and inflammatory and antioxidative biomarkers compared to control (usual treatment) [20]. Considering the potential beneficial effects of Pycnogenol® on disease characteristics of COVID-19 and PCC, it may improve the health status and alleviate symptoms in people with PCC.
Click to expand...

This is the study they cite for promising results in post-COVID condition:

Preventive effects of Pycnogenol® on cardiovascular risk factors (including endothelial function) and microcirculation in subjects recovering from coronavirus disease 2019 (COVID-19)

"BACKGROUND: The aim of this open supplement study was to evaluate the effects of Pycnogenol® in comparison with controls on symptoms of post-COVID-19 syndrome and in improving endothelial function, microcirculation, inflammatory markers and oxidative stress over 3 months in symptomatic subjects recovering from COVID-19.

METHODS: Sixty subjects recovering from symptomatic COVID-19 were included. One group of 30 followed a standard recovery management while 30 comparable subjects received a supplement of 150 mg Pycnogenol® daily (in 3 doses of 50 mg) in addition to standard management.

RESULTS: Two groups of selected subjects were comparable at baseline. The groups progressively improved both with the SM (standard management) and with the SM in combination with the supplement. Patients, supplemented with Pycnogenol® showed significantly better improvement compared to the control group patients. No side effects from the supplementation were observed; tolerability was optimal. The progressive evolution over time was visible in all target measurements. Physiological tests: endothelial function, low in all subjects at inclusion was assessed by flow mediated dilation (FMD) and finger reactive hyperemia in the microcirculation (laser Doppler measurements) after the release of an occluding suprasystolic cuff. It was significantly improved in the Pycnogenol® group after one month and after 3 months (P<0.05 vs. controls). The rate of ankle swelling (RAS) by strain gauge decreased significantly in the supplemented group (P<0.05) in comparison with controls showing an improvement of the capillary filtration rate. At inclusion, the kidney cortical flow velocity indicated a decrease in perfusion (lower systolic and diastolic flow velocity) in all patients. Kidney cortical flow velocity increased significantly with the supplement (P<0.05) in comparison with controls with improvement in systolic velocity and in diastolic component. High sensitivity CRP (hs-CRP) and Il-6 plasma levels decreased progressively over 3 months with a significant more pronounced decrease in the supplement group (P<0.05). The number of patients with normal plasma IL-6 levels at the end of the study was higher (P<0.05) with the supplement. ESR followed the same pattern with a progressive and a more significant decrease in the supplemented subjects (P<0.02). Oxidative stress decreased significantly in the supplemented group (P<0.05) compared with the control group. Systolic blood pressure was significantly lower in the supplemented group (P<0.05) at the end of the study. Finally, the scores of Quality-of-life, mood and fatigue questionnaire and the Karnofsky Scale Performance Index significantly improved in the supplement group (P<0.05) compared to controls after 1 and 3 months. All other blood parameters (including platelets and clotting factors) were within normal values at the end of the study.

CONCLUSIONS: In conclusion, Pycnogenol® may offer a significant option for managing some of the signs and symptoms associated with post-COVID-19 syndrome. This pilot evaluation offers some potential rationale for the use of Pycnogenol® in this condition that will have significant importance in the coming years."

Link
 
Last edited:
Swiss study, no declaration of conflicts of interest, which is surprising given the proprietary product being tested.

The study plan looks good - lots of blinding and both objective and subjective outcomes. Some of the measures will be interesting to see, even just in the placebo group.

I haven't checked the criteria for inclusion beyond what is said in the abstract:
Randomization is stratified for duration of PCC symptoms (≤ 6 months versus > 6 months) and presence of symptomatic chronic disease(s).
Click to expand...

Does anyone know this organisation? All the authors are part of it
Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich (UZH), Zurich, Switzerland
It seems a slightly odd group to do a treatment trial.
 
Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich (UZH), Zurich, Switzerland
Click to expand...
Looks like a credible organisation, with a commitment to doing and teaching good research methodology. They have a track record in a lot of research related to chronic conditions:
https://www.ebpi.uzh.ch/en/translational_research/chronic_conditions_health.html

They appear to run an MS registry. I don't know, but perhaps they would be a good partner to make an ME/CFS registry.
 
Mij said:
I took pycnogenol early in my illness for several months with no effects. Is this study done with their own proprietary brand?
Click to expand...

I think "Pycnogenol" is a single specific formulation of pine bark extract, with the name trademarked by a company.
Pycnogenol® is a proprietary French maritime pine bark extract (Pinus pinaster subsp., atlantica, Pinaceae) produced by Horphag Research, Geneva, Switzerland. Pycnogenol® is standardized to contain 70 ± 5% procyanidins in compliance with the United States Pharmacopeia.
Click to expand...
 
Yann04 said:
Would be interesting to see results in of this trial, but I wouldn’t put much hope into it.
Click to expand...
Same.

I very much hope this study isn't paid for by the Pycnogenol producers (Horphag Research) with nod and a wink, and a study confirming how wonderful pycnogenol is produced in due course. The study design seems good, so it would probably take either outright fraud or at least some obvious cherry picking of individual results to produce a positive result. It looks as though the institute has a reputation that would be worth more than a 'payment for endorsement' from Horphag, but, who knows.
 
Shame that it will take at the very least 12-18 months to find out whether they are standing by their product (their investment) or how much placebo effect there will be.
 
alex3619 said:
I tried pycnogenol. At low dose it does nothing. At high dose ... wham, amazing, but only happened once. It was not repeatable.
Click to expand...

Anecdotally we quite often hear about interventions that seems to work at first but then very quickly no longer works. Does this happen often enough to warrant study itself as a phenomenon? Could it have itself inform our understanding of ME as a physiological process?
 
Yann04 said:
Is this not a common manifestation of the placebo effect?
Click to expand...
It definitely can be with minor results. Was it working, was it not? Expectation can lead us to think it was working when it was not. However the placebo effect is limited in at least two ways. First, it applies mostly to pain perception, not a range of other things. Other effects are less proven. Two, a major change is blatantly obvious.

My pycnogenol result was limited by availability. I had only a small bottle. The exact formula I was on is very hard to buy now. This was sourced from red grape skins, which also contain other substances I respond to. At some point they moved to pine bark, if I recall correctly, as it was far cheaper, and it was less effective.

Second, I took a large dose after a small test dose did not work. Here is what happened. I was aching all over and exhausted. I took the dose, which I think was at least four capsules or tablets, I do not recall which. Recommendation is one, again if I recall correctly. This was when pycnogenol first became available in Australia.

First thing is my stomach fizzed. The sensation was very strong. Then it moved out down my legs and up by body and arms, finally in my head. Fizzing. It was painful. Then after a half hour the fizzing stopped. Suddenly I felt better than I can ever recall feeling. I felt amazing. There was no pain, no exhaustion, and I probably could have exercised but I didn't test that.

I plan on rebuilding my old shotgun protocol using everything I have learned, a cocktail of every supplement that has ever helped me at moderate and not high doses. In 1999 that put me in remission for many days, and suddenly I could go for brisk five hour walks, instead of shuffling across a room. But get this, I still felt great at the end of the walk, I just ran out of time. Pycnogenol should be one of those substances. However at about five days the side effects set in. Intense headaches, possibly migraines, every day. I had to stop. I was also running out of money for further experimentation. The next year I went back to university to finish my biochemistry degree.

Part of the idea is substances stop working because they interact with other things, and those things get depleted then the first substance stops working.

ME has maladaptive processes. PEM is an example. We push the body, we crash, and then we can no longer push. I suspect this involves a complex interplay of deep biochemistry. We just don't have the details.

Early this year I realized something. In the early 2000s I had many short remissions, lasting about six hours each. During remissions my brain and memory worked, and my slow walk went away and I could run kilometres. So I did on at least one occasion. I never even notice them starting, but I sure notice them going away. All of these stopped in a few years. What if my shotgun protocol was actually nearly a cure, but I was not doing something right and then stopped too soon? I hope to test this in the next year or two. It might not work. Or it might only be a suppression. But if it suppresses PEM and I can exercise it is a game changer.

PS One of my remissions was hours before one of my major biochemistry exams. Suddenly my memory worked, and it was so easy, I finished the exam in a bit over an hour I think.
 
alex3619 said:
First, it applies mostly to pain perception, not a range of other things.
Click to expand...
Wow, I had learnt in class that the placebo effect could improve disease process and even outcome in cancer patients. Seems that was a load of mind-body bs. Glad you brought my attention to it.

They can affect how patients perceive their condition and encourage the body's chemical processes for relieving pain[10] and a few other symptoms,[12] but have no impact on the disease itself.[9][10]
Click to expand...
https://en.m.wikipedia.org/wiki/Placebo
 
You must log in or register to reply here.
Back
Top Bottom