4. Discussion
death
ADVERSE EVENTS, DISEASE, DISEASES
During the first phases of the pandemic, the use of over-the-counter nutritional supplements to treat COVID-19 grew in popularity in Italy. In particular, bovine lactoferrin soon became one of the most sought-after supplements despite only a few pilot studies suggesting a potential beneficial effect on the clinical course of COVID-19, regardless of pharmacological formulation and disease severity [Thus, the aim of our study was to shed light on this issue by using a methodologically sound approach. For this purpose, we conducted a prospective, placebo-controlled, multicenter, double-blind clinical trial on a cohort of patients with COVID-19 hospitalized in non-ICU wards. Our results show that a daily 800 mg dose of bovine lactoferrin vs. placebo administered in combination with standard COVID-19 therapy could neither mitigate disease evolution (i.e., the prevention of death or ICU transfer) nor support clinical recovery. Furthermore, we did not observe any significant lactoferrin effects in modifying clinical variables, such as NEWS2 score and the need for oxygen supplementation, or pro-inflammatory biomarkers (e.g., CRP, IL-6, and ferritin). Similar results were also obtained in the elderly patient subgroup treated in the late stage (6-day median) of COVID-19 or after gender stratification.Altogether, our findings do not support the use of bovine lactoferrin in hospitalized patients with moderate-to-severe COVID-19. As our study population consists of a homogeneous cohort of patients, in terms of both clinical features and therapeutic regimen, equally distributed between the two study arms, it provides a simpler framework with which to interpret the efficacy of lactoferrin as an adjuvant in the late phase of COVID-19 treatment. Notably, a recent Egyptian randomized, prospective, interventional study in a few hospitalized patients with mild-to-moderate COVID-19 also obtained similar results [The lack of clinical efficacy of lactoferrin may be due to several factors, with one being a suboptimal bioavailability of bovine lactoferrin. However, despite the paucity of pharmacokinetic studies on its absorption in humans, lactoferrin is known to be well absorbed by the intestine in both mice and pigs [Another possible reason for the poor efficacy may be ascribed to the timing of lactoferrin administration. Indeed, in the three pilot studies where a clinical course improvement was observed [Another important observation of our study is the lack of modulation of pro-inflammatory markers by lactoferrin despite its well-established role as an immunomodulator [Finally, it is worth pointing out that, in our study, we did not record any relevant adverse events related to lactoferrin treatment. This highlights the good safety and tolerability profile of this compound, thus supporting the design of future clinical trials to assess the adjuvant role of lactoferrin in the early phases of the disease.Even though our trial protocol was designed to minimize the potential risk of biases, as it was conducted in clinical practice settings during the third pandemic wave, we cannot rule out that some slight differences in the treatment of individual patients may have occurred due to several different coexisting diseases. However, it is unlikely that these variables would have biased our results.