Folic acid as placebo in controlled clinical trials of hydroxychloroquine prophylaxis in COVID-19: Is it scientifically justifiable?

Abstract

Using folic acid (FA) as placebo complicates the interpretation of the findings of few RCTs evaluating safety and efficacy of hydroxychloroquine prophylaxis in COVID-19. FA is found to bind to furin-protease and spike: ACE2 interface of SARS-CoV-2. In clinical studies, FA level was lowest among severe patients compared to mild and moderate disease. A single controlled study reported the benefit of combination of folic acid with Pyridoxine & cyanocobalamin in terms of clinical and laboratory cure parameters. One hypothesis associates the differences in geographical variation of disease severity with prevalence of methyl tertahydrofolic acid reductase (MTHFR) C677T polymorphism. Other possible domains, where FA is hypothesized to be beneficial are COVID-19 associated pulmonary hypertension and hyper-homocystinemia. So, scientific justification of using folic acid as placebo in COVID-19 trials seems scientifically not credible and this may be one of the major factors for failure of many agents. We need to be more careful in choosing our placebo especially when conducting a placebo controlled trial.

Efficacy and safety of dihydroorotate dehydrogenase (DHODH) inhibitors “leflunomide” and “teriflunomide” in Covid-19: A narrative review

“… Kaur et al, 2021 ; Kaur et al, 2021 ; Smith et al, 2020 ; Li et al, 2020; Jia et al, 2020b; Li et al, 2020 ; NHC 2020; Ke et al, 2020; Wang et al, 2020b; University of Chicago, 2020; City of Hope Medical Center, 2021; Abdallah, 2021; .…”

“…Various virus and host directed therapeutic measures are being tried e.g. favipiravir ( Prajapat et al, 2020b , p. 2; Vm et al, 2020 ), tocilizumab ( Gupta et al, 2021 , p. 19), ivermectin (Harpinder Kaur et al, 2021 ) etc. The questionable efficacy of hydroxychloroquine (Sarma et al, n.d.) and Lopinavir/Ritonavir is under scanner now ( Bhattacharyya et al, 2020 ).…”

“…Role of povidone iodine is also coming up as a prophylactic agent ( Khan et al, 2020 ; Sarma et al, 2020b , 2020c , p. 2). Other agents under evaluation are remdesivir ( Rezagholizadeh et al, 2021 ) folic acid ( Bhattacharyya et al, 2021 , p. 19; Hardeep Kaur et al, 2021 ) etc. Various vaccine candidates are also under clinical trials for the same.…”

Comparative Safety and Efficacy of Remdesivir Versus Remdesivir Plus Convalescent Plasma Therapy (CPT) and the Effect of Timing of Initiation of Remdesivir in COVID-19 Patients: An Observational Study From North East India

“…Presently used therapeutic agents for the management of COVID-19 include steroid therapy [ 8 ]; remdesivir [ 9 ]; chloroquine; hydroxychloroquine [ 10 - 12 ]; favipiravir [ 13 ]; ivermectin [ 14 ]; convalescent plasma therapy (CPT) [ 15 ]; and adjunctive agents including zinc, vitamin D [ 16 ], folic acid [ 17 ], and anticoagulants [ 18 ].…”

Yogic Neti-Kriya Using Povidone Iodine: Can it have a Preventive Role Against SARS-CoV-2 Infection Gateway?

“…In this current scenario, scientists are trying their best to cope up with the situation with all possible way e.g. drug repurposing [ 1 – 8 ], identification of newer drug target [ 9 – 11 ], development of various diagnostic modalities [ 12 ], vaccine development [ 13 ], investigation of newer drug, virtual counseling/tele-medicine [ 14 ], maintaining social distancing, use of personal protective equipment (PPE), lifestyle modification (use of sanitizer, hand washing etc.) etc.…”