Effectiveness of Fortified Garlic Extract Oral Capsules as Adjuvant Therapy in Hospitalized Patients with Coronavirus Disease 2019: A Triple-Blind Randomized Controlled Clinical Trial

Background Herbal medicines have been extensively used to treat coronavirus disease 2019 (COVID-19). Garlic, known to exert antiviral and anti-inflammatory effects, can be coadministered with standard treatments to combat COVID-19. Objectives The aim of the study was to evaluate the efficacy and safety profile of Gallecina oral capsules (Samisaz Pharmaceutical Company, Mashhad, Iran), a fortified garlic extract, as adjunctive therapy to improve the clinical status and symptoms in noncritically ill patients hospitalized for COVID-19. Methods This triple-blind randomized, placebo-controlled clinical trial was conducted on noncritically ill patients with COVID-19 hospitalized in the nonintensive care wards of Imam Hassan Hospital. Patients received remdesivir plus 90 mg Gallecina capsule or a placebo every 8 hours for 5 days or until discharge. The clinical status, respiratory symptoms, and laboratory parameters were recorded during the study period. Results Patients were enrolled between April 24 and July 18, 2021. Data from 72 patients in the Gallecina group and 69 patients in the placebo group were analyzed. Oxygen saturation, C-reactive protein levels, and the distribution of respiratory distress and cough were similar between groups on the day of discharge. Although body temperature was significantly lower in the Gallecina group than that in the placebo group on the day of discharge (P = 0.04), it was within the normal range for both groups. The proportion of patients requiring supplemental oxygen for at least 1 day during the study was significantly reduced in the Gallecina group on days 3 and 4 and the day of discharge (P < 0.05). Gastrointestinal complaints were more prevalent in the Gallecina group than in the placebo group but the difference was not statistically significant (P = 0.12). Conclusions There was no significant effect on the primary outcome of clinical status on study day 6. Although the proportion of Gallecina-treated patients who needed supplemental oxygen significantly decreased on days 3 and 4 and the day of discharge, there was no significant difference between the groups on other days. The possible beneficial effects on oxygen requirements in noncritically ill COVID-19 patients may warrant further investigation. (Curr Ther Res Clin Exp. 2023; 84:XXX–XXX). Clinical trial registration: IRCT20201111049347N1.


Introduction
In January 2020, the World Health Organization officially declared the new coronavirus-borne coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as an international public health crisis. During the initial stages of the pandemic, antiviral medications used to combat COVID-19 were mainly known for treating other known viruses, including HIV, influenza, hepatitis, and Ebola virus disease. 1 , 2 The use of many of these treatments, such as favipiravir, 3 lopinavir-ritonavir, 4 , 5 ribavirin, and hydroxychloroquine, 6 , 7 has gradually decreased based on their failure to provide any proven clinical benefits in the treatment of SARS-CoV-2 infections. 3 In contrast, growing evidence supports the Food and Drug Administration-approved therapeutic use of remdesivir. [8][9][10] In addition, herbal medicines have been widely employed as complementary treatments for COVID-19. [11][12][13] The bioactive components of certain herbal medicines can exert antiviral and anti-inflammatory properties, 14 rendering them eligible to treat SARS-CoV-2 infections. 13 , 15 In line with this, evidence suggests that herbal medicines combined with standard treatments could be clinically more effective than standard therapeutic strategies alone. 11 , 16 Traditional Chinese medicines have been extensively evaluated in clinical studies, 11 , 15 and a literature review has indicated the potential therapeutic effects of curcumin, 17 , 18 cinnamon, 19 ginger, 20 , 21 and garlic. 22 , 23 The antiviral potential of garlic ( Allium sativum L) has been demonstrated against certain viruses, including influenza B, HIV (type 1), vesicular stomatitis virus, herpes simplex virus (types 1 and 2), Coxsackie virus, and gammaretrovirus. 24 , 25 Garlic-derived active organosulfur compounds (OSCs) prevent the virus from entering host cells and inhibit virus integration, resulting in the blockage of virus replication and reduced cellular viral loads. 24 Furthermore, sulfur-containing compounds in garlic can exert beneficial effects such as immunomodulatory, anti-inflammatory, anticancer, antitumor, antidiabetes, antiatherosclerosis, and cardioprotective effects. 22 Essential components of garlic that contain sulfur include thiosulfinate (allicin), S-allyl cysteine sulfoxide (alliin), ajoenes, vinyldithiin, and diallyl sulfide. Garlic alliinderived OSCs include S-allyl-cysteine, S-mercaptocysteine, and Nacetylcysteine. 22 Garlic products can be administered as an adjuvant therapy with other effective treatments against COVID-19. 23 , 25 Therefore, the aim of this study was to evaluate whether or not Gallecina oral capsules (Samisaz Pharmaceutical Company, Mashhad, Iran), a fortified garlic extract, can be an effective adjunctive therapy to improve clinical outcomes and symptoms in noncritically ill patients hospitalized for COVID-19.

Study population
The present study was a triple-blind, randomized, placebocontrolled clinical trial in noncritically ill patients with COVID-19 hospitalized in the nonintensive care wards of Imam Hassan Hospital, affiliated with North Khorasan University of Medical Sciences, Bojnurd, Iran. At the time of admission, a diagnosis of COVID-19 was confirmed by polymerase chain reaction or lung highresolution computed tomography (CT) imaging.

Inclusion and exclusion criteria
Eligible participants were patients aged 18 to 65 years who were conclusively diagnosed with SARS-CoV-2 infection and had to be hospitalized in nonintensive care wards. Hospitalization indications were determined based on the latest version of the instructions from the Scientific Committee of the National Staff for COVID-19 Disease Management as follows: respiratory symptoms, including shortness of breath, pain, and chest discomfort with or without fever; oxygen saturation level ˂90%, accompanied by the need for respiratory support; decreased level of consciousness; hypotension (systolic pressure ˂90 mm Hg); persistence of dehydration and oral intolerance after outpatient supportive care; and pulmonary involvement ˂50% based on chest CT imaging.
Exclusion criteria were defined as a history of allergies to garlic and its derivatives based on patient self-report, pregnancy or lactation, malignancies, immune deficiency, Alzheimer disease, multiple organ failure, encephalopathy, active heart disease, diabetes, liver disease, diarrhea or active gastrointestinal (GI) disease, hypo-or hyperthyroidism, and acute or chronic kidney complications. Additionally, patients with low blood pressure at the beginning of the study ( < 120/80 mm Hg) were excluded.

Drug and placebo formulations
A fortified extract was obtained from garlic cloves, formulated as capsules containing immediate-release pellets under the brand name Gallecina. The stability of formulated capsules was markedly enhanced against moisture under storage conditions. Before conducting the study, the company had released Gallecina as an antilipid and antihypertension product in a white polyethylene pocket containing 2 × 10-digit Alu-Alu blisters. Gallecina and its placebo counterpart were packed in identical packaging. The capsules were to be taken with a glass of water after a meal because of their immediate release following dissolution in water. 26 Moreover, the patient was requested to avoid lying down for 30 minutes after consuming capsules to prevent potential digestive tract irritation. 27 , 28 Gallecina is typically produced as 30-, 60-, and 90-mg oral capsules; however, in the current study, 90-mg oral capsules were used to evaluate the maximum possible effectiveness of this product.

Randomization and blinding
Eligible patients were randomly assigned using permuted blocked randomization (1:1) with a block size of 4 into 2 groups: an intervention group receiving remdesivir plus Gallecina oral capsules (group A) and a placebo group receiving remdesivir plus placebo (group B). The order of blocks was also randomized. According to the permuted blocked randomization scheme of the study, the whole randomization list was created before a single patient was enrolled. Then, the prepared list was numbered from the beginning of the list. The assignment of numbers to the study groups was kept confidential and not shared with the research team. Therefore, with this numbering, the research team involved in the intervention process was blinded to the allocated treatment.
These numbers were also included in the pockets of Gallecina and its placebo. Upon randomization into the trial, patients received the next sequential assignment based on the randomization list.
The patient, physician, nurse, researcher, and data analyzer were blinded to the group allocation. The number assigned to each patient in the prepared list was considered as the patient code. Analyses were performed based on codes provided for the groups.
It is well established that allicin and other sulfur-containing volatile compounds in garlic are responsible for its pungent smell. 29 Masking this unpleasant smell is essential for increasing patient adherence and maintaining blinding in randomized studies. 30 Gallecina and its placebo pellets were coated with hydroxypropyl methylcellulose (or hypromellose) to eliminate the malodorous and unpalatable characteristics of garlic. 31

Study procedure
Considering patients in both groups, remdesivir was administered at a 200-mg loading dose as an intravenous infusion on day 1 of hospitalization, followed by a maximum maintenance dose of 100 mg/day from day 2 to 5. If the patient was discharged earlier than 5 days, remdesivir was discontinued. Both groups received standard treatments comprising subcutaneous enoxaparin 40 mg daily, oral bromhexine syrup 5 mL thrice daily, oral multivitamin syrup 5 mL daily, oral zinc sulfate syrup 10 mg daily, and oral acetaminophen tablets 500 mg every 6 hours as needed. Standard treatments were prescribed based on the patient's clinical condition, according to the last version of the COVID -19 treatment guidelines. 10 In both groups, the drug or placebo was to be taken thrice daily (every 8 hours) from day 1 of receiving remdesivir for 5 days or until discharge. To maintain the study's blinding instructions and randomization method, the allocation was concealed, and the treating physicians did not intervene in assigning the patients to study groups. All patients received other required and supportive treatments based on the hospital protocol, and none were deprived of treatment.
The primary outcome was assessing clinical status on a 7-point ordinal scale on day 6 (as described below). Demographic characteristics were recorded at study initiation. Respiratory status (ie, blood oxygen saturation and respiratory rate) and laboratory parameters were assessed based on the hospital protocol. Respiratory symptoms (eg, cough and respiratory distress), type of oxygen supplementation, and vital signs were evaluated daily.
Clinical status was assessed daily from day 1 until hospital discharge on a 7-point ordinal scale as previously mentioned in landmark studies: 8 , 32-34 1 = death; 2 = hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation; 3 = hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices; 4 = hospitalized, requiring low-flow supplemental oxygen; 5 = hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related or not to COVID-19); 6 = hospitalized, not requiring supplemental oxygen or no longer requiring ongoing medical care (used if hospitalization was protracted for infection-control or other nonmedical reasons); 7 = not hospitalized (discharged). The worst score (ie, the lowest) was recorded if the clinical status changed on a particular day; if a patient was discharged, the ordinal score was considered 7 on all ensuing days.

Study outcomes
The primary outcome was the distribution of the clinical status of patients based on a 7-point ordinal scale on study day 6. The secondary outcome was the proportion of patients who experienced adverse effects following Gallecina/placebo consumption.
Other end points were the distribution of the clinical status of patients based on the 7-point ordinal scale on discharge day; time to recovery (an improvement from a baseline score of 2-5 to 6 or 7); differences in the oxygen saturation level, degree of body temperature, and C-reactive protein (CRP) level between the 2 groups on the day of discharge; the proportion of patients with respiratory distress or cough on the day of discharge; and the proportion of days with respiratory distress, cough, or supplemental oxygen requirement during the study period.

Ethical approval and consent to participate
Ethical clearance and approval were obtained from the Biomedical Research Ethics Committee of the North Khorasan University of Medical Sciences under the reference number IR.NKUMS.REC.1399.127. This study is a doctoral degree thesis, which was defended by Erfan Tavana on March 13, 2022, and supported by the Samisaz Pharmaceutical Company. The study protocol was approved by the institution and sponsor. The institutional review board approved the final protocol according to Good Clinical Practice guidelines. All project steps were performed in accordance with the Declaration of Helsinki, University Research Ethics Committee guidelines, and Office of Industrial Affairs requirements. All patients provided written informed consent before study participation. The participation of all patients who met the inclusion criteria was entirely voluntary, and patients could withdraw from the study at any time.
The Iran Food and Drug Administration granted licenses to produce, package, and supply the final products following the certification of Gallecina oral capsules in compliance with safety profile, efficiency, purity, and quality standards. For the 90-mg oral capsule, the license was issued under Iran Registration Code 2417944045143933. In addition, these licenses confirm and support that the property rights and pharmaceutical patents of Gallecina oral capsules belong to the Samisaz Pharmaceutical Company.

Statistical Analysis
Data analysis was performed using SPSS version 20.0 (SPSS for Windows, IBM-SPSS Inc, Armonk, NY). Descriptive statistics are presented as mean (SD) or median (interquartile range [IQR]) for continuous variables and frequency (percentage) for discrete variables. To compare the continuous variables among treatment groups, the Student t test was performed for variables with a normal distribution and the Mann-Whitney U test for variables with nonparametric distribution. In addition, the χ 2 test was applied to discrete variables to compare distributions. A P value < 0.05 was considered statistically significant.
To determine the biological efficacy 35 of Gallecina/placebo, which was added to remdesivir, patients who stayed for ≤2 days in the study with medication adherence < 50% were excluded from the final analysis. However, all randomized patients who received 1 dose of Gallecina/placebo were subjected to the safety profile assessment (intention-to-treat analysis).
Data analysis showed that scores 1, 2, 3, and 6 had no reported frequency. Additionally, this study was performed on hospitalized patients without follow-up after discharge. Therefore, the time to discharge, also known as the duration of hospitalization, was also the time to recovery.

Characteristics of the study population
From April 24 to July 18, 2021, 1741 patients were admitted to the hospital over a 3-month recruitment period and were di- agnosed with COVID-19. Of these 1741 patients, 1177 were under observation for ≤6 hours and were not hospitalized. Of 564 other patients, 152 required intensive treatment and close monitoring. Among those 564 patients, 412 were assessed for eligibility. Before randomization, 216 patients were excluded from the study. Another 196 patients were randomly assigned to the Gallecina (101 patients) and placebo (95 patients) groups. During the intervention, 25 ( ∼13%) patients discontinued their Gallecina/placebo capsules owing to intervention-related GI side effects (n = 23) and a lack of willingness to continue the intervention (n = 2 withdrew consent and did not provide permission to analyze their data). Finally, data from 72 patients in the Gallecina group and 69 in the placebo group were analyzed. The Figure summarizes the enrollment process.
The groups were similar in age, sex, body mass index, and baseline clinical characteristics ( Table 1 ). In addition, the median (IQR) duration of remdesivir administration did not significantly differ between the Gallecina and placebo groups (5 days; IQR, 4-5 days vs 5 days; IQR, 4-5 days, respectively; P = 0.315). In addition, there was no significant difference between the study groups in terms of median (IQR) duration of treatment with Gallecina (5 days; IQR, 4-6 days) or placebo (5 days; IQR, 4-5 days); P = 0.235.

Efficacy Outcomes
As shown in Table 2 , the clinical status distribution on day 6 and at discharge was not statistically significant between the 2 groups. On the day of discharge, the degree of body temperature significantly differed between the Gallecina (36.92 °C) and placebo (36.98 °C) groups (P = 0.04); however, this difference did not seem clinically significant, given that it was in the normal range, and the calculated difference (ie, 0.06 °C) between the 2 groups was less than a value that could be measured. The CRP level on the day of discharge was below the normal range ( < 7 mg/L) in both groups, making it clinically nonsignificant. Although levels in the 2 groups did not differ significantly (P = 0.051), a higher level was noted in the placebo group.
Regarding the other study outcomes, no significant differences were observed between the 2 groups ( Table 2 ). According to the 7-point ordinal scale of clinical status, data analysis revealed that scores 1 (death), 2, 3, and 6 had zero frequency. Moreover, no patient required intensive care unit admission. In addition, the proportion of patients discharged (ie, not hospitalized clinical status) before day 6 (ie, days 3 to 5; no frequency on days 1 and 2) did not significantly differ between the Gallecina and placebo groups (20 [28%] vs 24 [35%] patients, respectively; P = 0.370).
A subgroup analysis of oxygen delivery status was performed among patients needing supplemental oxygen for at least 1 day during the study, detecting a significant difference between the 2 groups on days 3 and 4 and the day of discharge ( Table 3 ). The proportion of patients needing supplemental oxygen was lower in the Gallecina group than that in the placebo group on the aforementioned days.

Safety profile outcome
GI side effects were documented in 18 ( ∼20%) patients in the Gallecina group when compared with 9 ( ∼12%) patients in the placebo group ( Table 4 ). The most frequent complications were abdominal pain, nausea, vomiting, and diarrhea. Furthermore, most patients with GI complications began experiencing complications from days 1 and 2 of Gallecina or placebo treatment. Although  The mean body temperature for each patient was calculated separately during the middle days (excluding the first and last days of the study), and then it was included in calculating the body temperature on the middle days of the study. ¶ The number of days each patient had respiratory distress, cough, or required supplemental oxygen was divided by the total number of his/her hospitalized days.  the distribution of GI complications did not differ significantly between the 2 groups ( P = 0.12), GI complications in the Gallecina group were approximately double when compared with those in the placebo group.

Discussion
COVID-19 remains a crucial health challenge worldwide. Natural compounds have been used as adjuvants to standard treatment protocols to overcome COVID-19 infection. 13 Therefore, the present clinical trial was designed to assess the efficacy and safety profile of Gallecina oral capsules containing immediate-release pellets of fortified garlic extract as an add-on therapy to remdesivir in hospitalized patients with COVID-19.
Our findings revealed no significant differences in primary and secondary outcomes between the Gallecina and placebo groups. Regarding other outcomes, only body temperature was significantly lower in the Gallecina group than that in the placebo group. Nevertheless, this difference appears insignificant, given that it is within the normal temperature range. There were no significant differences in other clinical outcomes between the 2 study groups. However, in a subgroup analysis of oxygen delivery status among patients who needed supplemental oxygen for at least 1 day during the study, the proportion of patients who needed supplemental oxygen was found to be significantly lower in the Gallecina group than that in the placebo group on days 3 and 4, as well as the day of discharge.
Herbal medicines, diets, and food nutrients have been widely employed as complementary therapies for COVID-19. Supplementation with these agents (eg, vitamin D, zinc, vitamin C, traditional Chinese medicines, and curcumin) may alleviate the severity and duration of symptoms, boost immune system function, and improve other clinical outcomes of COVID-19. 11 , 14 , 15 , 36 However, the established positive conclusions are insufficient to support their beneficial effects. 11 , 37 Moreover, the disease burden has resulted in some studies with poor methodology design 11 and no adherence to defining appropriate outcomes for clinical trials 38 on COVID-19, thereby influencing the achievement of reliable results. A systematic review has shown that supplementing traditional Chinese medicines with standard treatments could improve clinical symptoms, blood tests, and virological outcomes better than standard treatment alone. 15 In addition, adjuvant therapy with curcumin can decrease symptoms, duration of hospitalization, and mortality in hospitalized patients with COVID-19 exhibiting different levels of disease severity. 39 In addition, a randomized study has shown that adjuvant therapy with allicin oral capsules, a bioactive component of garlic, improved clinical symptoms, chest CT scores, and laboratory findings within 2 weeks of treatment. 40 Despite the proven antiviral and anti-inflammatory effects of garlic extracts and isolated OSCs, 24 apart from one report, 40 no clinical studies have been conducted to assess the potential benefits against COVID-19.
Therefore, the results of the present study can be compared with those of studies conducted of other herbal medicines. Contrary to the results of the abovementioned clinical studies, our study showed negative results. Co-supplementation with remdesivir and oral Gallecina capsules did not positively influence the clinical outcomes of the present study; this finding could be attributed to several factors. The types of supplements and duration of studies differed. Additionally, the disease severity (ie, mild, moderate, and severe) and variation in the selected population (outpatient vs inpatient) might have led to inconsistent results.
Garlic contains sulfur-containing (eg, allicin, diallyl disulfide, and diallyl trisulfide) and flavonoid (eg, quercetin) phytocomponents exerting antiviral activity. 22 , 24 , 41-44 The interaction of OSCs with a serine-type Mpro (3-chymotrypsin-like protease), the main protease of SARS-CoV-2, via H-bonds inhibits Mpro, which is re-sponsible for viral replication and generation of functional proteins. Furthermore, garlic exerts a strong inhibitory effect on the host angiotensin-converting enzyme 2 protein, with allyl disulfide and allyl trisulfide exhibiting the most potent activities. 44 Because garlic polysulfides (eg, diallyl disulfide and diallyl trisulfide) have been identified as natural hydrogen sulfide donors, 45 they may play a therapeutic role and reduce COVID-19-related symptoms. 45 , 46 The administration of hydrogen sulfide has proven beneficial in various preclinical models of lung damage. 47 , 48 Based on recent findings, pre-perfusion with hydrogen sulfide can reduce oxidative stress, resulting in decreased lung injury. 49 , 50 Recently, the assessment of serum hydrogen sulfide in 74 patients with COVID-19 revealed an inverse association between hydrogen sulfide levels from day 1 to day 7 and mortality, and serum hydrogen sulfide on day 1 negatively correlated with interleukin 6 and CRP levels. The authors concluded that hydrogen sulfide is a potential marker for the severity and outcome of pneumonia caused by SARS-CoV-2 infection. 51 In addition, hydrogen sulfide can elevate circulating levels of endothelial nitric oxide synthase and nitric oxide. 52 In addition to the established antiviral activity of nitric oxide, 53 elevated nitric oxide levels may improve oxidative stress and endothelial dysfunction in patients with COVID-19. 53 , 54 Therefore, hydrogen sulfidebased therapeutics may be considered desirable options for drug development.
Consistent with these mechanisms, in a subgroup analysis of oxygen delivery status among patients needing supplemental oxygen, the Gallecina group had a lower proportion of patients requiring supplemental oxygen on days 3 and 4 and the day of discharge than the placebo group. This improvement in the respiratory status may be related to mechanisms involving hydrogen sulfide production. Although traditional Chinese medicine has been suggested to be effective in mild and moderate cases of COVID-19, 15 garlic extract may be more effective in treating moderate and severe cases that require supplemental oxygen. However, further studies are required to establish this application.
Most effects of any garlic preparation are likely to be dependent on the bioavailability of its active component(s), especially allicin. 24 , 55 However, in several clinical studies, 24 , 55 including ours, the bioavailability and standardization of allicin or any garlic component were not determined before study initiation. Based on in vivo tests, 1 study has recommended that the allicin bioavailability of garlic supplements should be at least 65%. 55 Determining the bioavailability of allicin (and even its bioequivalence) allows the reproducibility of the results in a new set of participants.
Although garlic was highly tolerable in all trials, as indicated by minimal side effects, and has been identified as a safe complementary medication, some concerns regarding the use of garlic and related compounds persist, including GI effects, changes in blood pressure, drug interactions, and uncontrolled bleeding. [56][57][58] In the present study, GI complications were twice as common in the Gallecina group than in the placebo group. Although this difference was not statistically significant, the incidence of GI complications was clinically more significant than expected following a prescription of Gallecina capsules. Consistent with our findings, previous studies have also reported GI symptoms as the most adverse effect of garlic extract. 59 The incidence of GI complications may be related to hydrogen sulfide release, 60 , 61 which was not measured in our study.
Nevertheless, studies assessing sustained-release garlic extract tablets 62 and lipid garlic extracts 63 in patients other than COVID-19 showed no adverse effects. Although clinical studies did not provide sufficient evidence on the adverse effects of Chinese herbal medicines in COVID-19, their supplementation was associated with more adverse effects than treatment with Western medicine alone. 64 However, adverse effects of curcumin 39 and allicin 40 have not been reported in COVID-19 studies.
This study has some strengths. In addition to a randomized, double-blind study that evaluated the therapeutic effects of allicin on patients with COVID-19, 40 the current randomized clinical trial with triple-blinding characteristics also assessed a garlic extract in hospitalized patients with COVID-19. Remdesivir, a Food and Drug Administration-approved drug with established effects on COVID-19, was used in the present study. However, in most studies where herbal medicines were assessed as supplementation, standard treatments involved drugs that were considered standard treatment at the time of the study but were later withdrawn from COVID-19 treatment (eg, lopinavir/ritonavir) owing to poor efficacy. 13 , 29 , 64 Although the relative effects of Gallecina capsules in the presence of remdesivir may be unclear, mild effects were observed in patients who needed supplemental oxygen.
This clinical trial encountered a few limitations: First, the criteria for blinding and concealment were considered in the study design and in preparing the dosage form. However, some patients experienced a pungent smell after taking Gallecina caused by the smell of released hydrogen sulfide. Patients were not excluded from the study because of this unpleasant smell. In addition, none of the patients reported the unpleasant smell of garlic in their skin and secretions. Nevertheless, possible unblinding by this unpleasant smell could be a study limitation. Second, the small sample size of patients receiving supplemental oxygen, which probably underpowered the statistical findings in those patients and obscured the possibility of distribution of findings on other treatment days (ie, days other than 3, 4, and the day of discharge). Third, the sample size was insufficient to adjust for the effects of certain variables (eg, the number of days since the onset of COVID-19) on clinical outcomes. Fourth, the generalizability of the study decreased owing to the extended exclusion criteria and exclusive administration of Gallecina capsules in hospitalized patients. Fifth, the precise time to initiate treatment and the duration of treatment with Gallecina capsules remain unknown. Finally, this study was limited to hospital stays, and the long-term outcomes of patients with COVID-19 could not be evaluated. Further studies are needed to achieve an appropriate duration and dose of treatment with Gallecina capsules to overcome the above-mentioned issues.

Conclusions
The effectiveness of Gallecina oral capsules, a fortified garlic extract, was examined as adjuvant therapy for remdesivir in a randomized, triple-blind, placebo-controlled study assessing hospitalized patients with COVID-19 in nonintensive care wards. Based on our findings, there were no significant differences in study outcomes between the 2 examined groups. However, a subgroup analysis of oxygen delivery status among patients who needed supplemental oxygen revealed that the proportion of patients who needed supplemental oxygen was lower on days 3 and 4 and the day of discharge in the Gallecina group than that in the placebo group. Nevertheless, future studies focused on determining allicin bioavailability before conducting the study and measuring nitric oxide, hydrogen sulfide, and inflammatory biomarkers such as interleukin 6, across different disease severities, especially in patients with severe respiratory distress, should be designed to comprehensively elucidate the efficacy of Gallecina capsules.

Declaration of Competing Interest
The implementation of this study was funded by Samisaz Pharmaceutical Company, Mashhad, Iran. This company covered the costs of patient care (patient recruitment, patient retention, physician visits and consults, treatments other than standard of care, laboratory tests, and lung high-resolution computed tomography imaging tests), administrative and nursing staff involved in the treatment of the study patients, trial-specific training, trial start-up meeting, and quality assurance monitoring. Also, this company formulated, packaged, and supplied Gallecina and its placebo to use in this study free of charge. This funding does not apply to the study design and its approval by the institutional review board. None of the authors received any financial support for this article's authorship and publication.
Mohammad Ansari Mohseni and Sina Rezaei are employed at Samisaz Pharmaceutical Company, Mashhad, Iran. Mohammad Ansari Mohseni and Sina Rezaei have commercial and financial involvements by holding stocks in this company and holding patents, producing, and formulation of Gallecina and its placebo. The authors have indicated that they have no other conflicts of interest regarding the content of this article.