Combining L-Arginine with Vitamin C Improves Long-COVID Symptoms: The Nationwide Multicenter LINCOLN Study, 2022, Izzo et al

Andy

Andy

Retired committee member
HIGHLIGHTS
•We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have beneficial effects in Long-COVID.

•We designed a nationwide multicenter clinical study, in which we administered to COVID-19 survivors a survey assessing several symptoms that have been associated with Long-COVID.

•1390 patients – divided in two groups L-Arginine + Vitamin C vs multivitaminic combinations (alternative treatment) – completed the study.

•After 1-month treatment, patients in the L-Arginine + Vitamin C group had significantly lower scores compared to the alternative treatment group.

ABSTRACT

Introduction
Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms.

Methods
We designed a nationwide multicenter clinical study (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), in which a survey assessing several symptoms that have been associated with Long-COVID was administered to COVID-19 survivors; effort perception was measured using the Borg scale. Patients were divided in two groups, with a 2:1 ratio: the first group included patients treated with L-Arginine + Vitamin C, whereas the second group was treated with a multivitamin combination (alternative treatment). Before administering the survey, patients completed 30 days of treatment.

Results
1590 patients were initially enrolled, of which 1390 completed the study. Following a 30-day treatment with L-Arginine + Vitamin C, the survey revealed that patients in this treatment group had significantly lower scores compared to the other group. There were no other significant differences between the two groups. When examining effort perception, we observed a significantly lower value (p<0.0001) in patients receiving L-Arginine + Vitamin C compared to the alternative-treatment arm.

Conclusions
Taken together, our findings indicate that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of reducing its typical symptoms and improving effort perception.

Open access, https://www.sciencedirect.com/science/article/pii/S104366182200305X
 
I have no idea how this paper was accepted.

- No approval number from an ethical review board specified; did the study even receive ethical approval?

- Randomisation method not detailed

- Participant characteristics not given (not in the appendices either)

- No baseline data, the outcome measures were only measured at outcome

- Error in Fig 1: 108 out of 1408 eligible participants refused to participate, so the number of participants should be 1290 according to this figure, but 1390 patients were actually enrolled

- No blinding, seemingly; the patients knew whether they were given a multivitamin supplement or the L-arginine + vitamin C supplement

- No funding source declared even though the supplement seems to have supplied by a local company: Bioarginina® C (L-Arginine 1.66 g in association with 500 mg of liposomal Vitamin C, Damor, Naples, Italy)

- Trial not registered & protocol not published in advance
 
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I have sent the following mail to Prof Emilio Clementi, Editor-in-Chief of Pharmacological Research.

Dear Professor Clementi,

I am writing to you in your capacity as Editor-in-Chief of Pharmacological Research with regards to the LINCOLN study that was published in your journal on 19 July 2022 (https://doi.org/10.1016/j.phrs.2022.106360).

Most importantly, the authors have not declared:

- whether they received ethical approval for their study from an institutional review board (they only state that the followed the Declaration of Helsinki and that patients provided informed consent)

- whether they received funding, nor the role of the funding source in a separate section, even though a local company (Damor, Naples, Italy) appears to have provided the supplement Bioarginina C that was trialed in the study

Further, the authors have not detailed:

- their method of randomisation, except that it was a 2:1 split (how was the randomisation generated?)

- participant characteristics, which do not appear in a table or in the supplementary material

- whether patients were blinded or not; did they know whether they were taking multivitamins (control intervention) or Bioarginina C? It is not explained if the pills in both arms were similar in shape, colour and taste.

There also is an error in Figure 1: it states that 108 out of 1408 eligible participants refused to participate, thus 1290 participants should have been enrolled, but 1390 participants were actually enrolled.

For these reasons, and also due to the fact that outcome measures were not measured at baseline but only at outcome (30 days), the authors’ conclusion that Bioarginina C ”has beneficial effects in Long-COVID, in terms of reducing its typical symptoms and improving effort perception” is not supported by the data.

Could you please ask the authors to provide all the information above, especially whether they received ethical approval and whether their study was funded by Damor (or if Damor supplied the supplement)?

If the authors cannot provide this key information, especially ethical approval and funding, an immediate retraction of the article is warranted.

Yours sincerely,
Click to expand...
 
The first and senior authors, Raffaele Izzo and Bruno and Valentina Trimarco, from the University of Naples — the city where the supplement manufacturer Damor Pharma is based —, have been churning out papers for them since 2009.

Their papers are listed on Damor’s website on the page for their “Akademy Pharma” (AKP) sub-brand, which explicitly states: “AKADEMY PHARMA develops its products with the support of the team of top academic experts that provide scientific advice and clinical support”. This conflict of interest has not been disclosed by the authors.

AKP01 / LopiGLIK:

AKP02 / Zinutrik: https://doi.org/10.2165/11530420-000000000-00000 Raffaele Izzo, Bruno Trimarco

AKP04 / MOREstril: https://doi.org/10.2147%2FIJWH.S115948 Valentina Trimarco, Raffaele Izzo

AKP05:
 
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608 physicians were recruited for the study but the authors do not mention how they were recruited. I doubt that they were able to find and contact them all, so I suspect Damor was involved in recruiting them (e.g. via a mailing list) despite the authors saying that Damor had no role in conducting the study.

I have informed Prof Clementi of these further findings, before which he replied saying he will contact the authors.

Edit: Prof Clementi’s reply to this point:
“this is not an issue. What they have done and this is clear from the workflow is to recruit the registrars a thing pretty easy in Italy”.

This may be what they have done but it is not clearly indicated in the study, contrary to Prof Clementi’s claim.
 
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