- adverse events
- acute kidney injury Covid‐19, coronavirus disease 2019
- computed tomography
- data and safety monitoring board
- emergency use authorization
- Ebola virus disease
- food and drug administration
- human immunodeficiency virus type 1
- middle east respiratory syndrome coronavirus
- murine hepatitis Virus
- nucleoside analog
- National Institute of Allergy and Infectious Diseases
- nipah virus
- nonstructural proteins
- randomized controlled trial
- RNA‐dependent RNA polymerase
- serious adverse event
- severe acute respiratory syndrome coronavirus 2
- World Health Organization
1 AN OVERVIEW OF REMDESIVIR
The story of remdesivir started in 2016 when it was first developed to combat the Ebola virus disease (EVD) outbreak in Africa, with the development code name of GS‐5734.1 In brief, remdesivir is a nucleoside analog (NA) inhibitor of RNA‐dependent RNA polymerase (RdRp). After the metabolism of remdesivir into its active form (GS‐441524), it interferes with the viral RNA polymerase, limiting viral replication.2
Regarding Ebola virus, although a study in 2016 confirmed the efficacy of remdesivir for suppression of viral replication both in vitro and in vivo (rhesus monkey),1, 3 the only randomized controlled trial (RCT), which was published in 2019, did not show any significant benefit of remdesivir for the treatment of EVD in comparison to other treatments, including Zmapp, MAb114, and REGN‐EB3.4
After reporting the first cluster of cases of coronavirus disease 2019 (Covid‐19) in Wuhan, China, other countries became rapidly affected, and this triggered the World Health Organization (WHO) to declare the outbreak a public health emergency of international concern on 30 January 2020. Pointing to the over 118 000 cases at the time, on 11 March 2020, WHO officially characterized Covid‐19 as a pandemic.5 Covid‐19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2).6 Several therapeutic options have been tried for symptomatic improvement and increased survival of Covid‐19 patients; for instance, anti‐inflammatory drugs such as hydroxychloroquine, tocilizumab, anakinra, and interferon beta‐1b have all shown some signals of benefit, while no effective antiviral agent has been introduced yet.7–10 Remdesivir is one among numerous small molecules that are actually evaluated for their efficacy in treating Covid‐19.11 Based on the previous successful in vivo experiences of using remdesivir for inhibition of Ebola virus and for other coronaviruses,1, 2, 12–14 it is considered as a promising antiviral for the treatment of Covid‐19. Interestingly, in vitro administration of remdesivir led to a reduction of viral loads of SARS‐CoV‐2 in two separate studies.15, 16 Despite the introduction of different therapeutic approaches along with efforts for the development of an effective vaccine against Covid‐19, no medication has received Food and Drug Administration (FDA) approval yet. However, remdesivir was granted an emergency use authorization (EUA) for Covid‐19 on 1 May 2020.17 Meanwhile, several RCTs are currently being conducted to evaluate the benefits and side effects of remdesivir in patients infected by SARS‐CoV‐2.
In this study, we reviewed all the clinical evidence regarding remdesivir, with a special focus on Covid‐19. In addition, we discussed possible road maps for Covid‐19 management. Up to the date of writing this review (19 May 2020), remdesivir had received an EUA for Covid‐19 patients17; there is one finished clinical trial18 and seven active clinical trials, based on the clinicaltrials.gov and isrctn.com websites.
2 GOOD AND BAD MEMORIES FOLLOWING THE EMERGENCE OF REMDESIVIR
The evidence regarding the efficacy of remdesivir in viral infections is somewhat controversial. Following signals of the efficacy of remdesivir in a rhesus monkey model of EVD in 2016, hopes for overcoming this disease flourished.1 Indeed, a 12‐day administration of remdesivir showed significant suppression of Ebola virus and Marburg virus replication, followed by amelioration of the disease.1 This report suggested the potential broad‐spectrum antiviral activity of remdesivir, not only for Ebola virus but also for other RNA viruses, and indicated it was ready to enter human studies. In 2019, an RCT including 681 patients with EVD demonstrated that remdesivir and Zmapp (triple monoclonal antibody cocktail) did not have any mortality benefit in comparison to the two other treatment arms, MAb114 (single monoclonal antibody) and REGN‐EB3 (cocktail of three monoclonal antibodies). In fact, the mortality rate at 28 days in the remdesivir group (53.1%) was significantly higher than that of the REGN‐EB3 and MAb114 groups (33.5% and 35.1%, respectively), and slightly higher than that of the Zmapp group (control group; 49.3%). Moreover, this study indicated that remdesivir exhibited a favorable safety profile in the human population.4
Given the broad‐spectrum antiviral activity of remdesivir13, 14, 19 and in the quest for finding treatments for distinct members of the Coronaviridae family, remdesivir was tested on severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV) in animal models.14, 20 In 2017, early administration of remdesivir in a murine model of SARS and MERS showed reduction in lung viral load and improvement in pulmonary function as of day 4 to 5 after infection.14 Experiments on a rhesus macaque model of MERS showed prevention of clinical disease, inhibition of replication in respiratory tissues, and no formation of pulmonary lesions after prophylactic administration of remdesivir. Initiating remdesivir after inoculation of the infection also showed similar significant clinical benefits.12 Accordingly, researchers and physicians kept the remdesivir option in their minds as a possible treatment for infectious diseases caused by emerging viruses, such as filoviruses, paramyxoviruses, pneumoviruses, and pathogenic coronaviruses.13, 21 Recently, a new pathogen from the Paramyxoviridae family, called Nipah virus (NiV), caused an outbreak of a fatal respiratory and neurological disease in India.22 To assess the efficacy of remdesivir against NiV, an African green monkey model of NiV infection was evaluated. Inoculation of animals with a lethal dose of NiV was performed, and monkeys were treated with remdesivir for 12 days. In the treatment group, two of four cases developed mild symptoms, while all cases of the control group developed severe respiratory symptoms.23 This history of remdesivir in its relatively short life since its introduction and lack of adequate human clinical trials raises hopes for its efficacy in new emerging viruses.
After the initial Covid‐19 outbreak, remdesivir emerged as a possible option when no other truly effective direct antiviral treatment existed, although a few in vitro data on possible efficacy of favipiravir (T‐705), another antiviral drug, exist.15, 24 The timeline of events related to the therapeutic use of remdesivir is depicted in Figure 1.
3 HOW DOES REMDESIVIR WORK IN GENERAL? HOW COULD IT SPECIFICALLY INHIBIT SARS‐COV ‐2 REPLICATION?
Remdesivir is a phosphoramidate prodrug, and like other NAs, is incorporated into the viral RNA.25 It inhibits viral RNA synthesis through delayed chain termination.26 The triphosphate form of remdesivir resembles adenosine triphosphate (ATP) and is, therefore, mistaken by the viral RdRp as a nucleotide.2, 27 The in vitro and in vivo antiviral activity of remdesivir has been confirmed against RNA viruses of the Filoviridae (including Ebola virus)1, 25 and Paramyxoviridae families.23, 28 Inhibition of replication of coronaviruses, including SARS‐CoV‐1 and MERS‐CoV, was revealed in mice and rhesus macaque models.2, 12, 14, 20
Similar to SARS‐Cov‐1, SARS‐CoV‐2 is an enveloped, positive‐sense single‐stranded RNA virus, which shares 82% of its RNA genome with SARS‐CoV‐1. However, their RdRp sequence shares a 96% resemblance,29 which means that inhibitors of SARS‐CoV‐1 RdRp may also work for SARS‐CoV‐2. Of note, both SARS‐CoV‐1 and SARS‐CoV‐2 have an exoribonuclease (ExoN) that is responsible for proofreading and may enable the virus to eliminate incorporated NAs; therefore, potentially conferring degrees of resistance to remdesivir.30 However, remdesivir is capable of eluding the ExoN.1, 31 Two‐thirds of the 5′ end of the coronavirus genome is translated to produce a polyprotein, consisting of 16 nonstructural proteins (nsp).32 The nsp interact together to exert enzymatic functions. The RdRp is known as nsp12,33 and the ExoN is known as nsp14.30
For the development of antiviral agents, it is essential to identify a target with high sequence and structural conservation and minimal homology to host sequences.34 Low conservation leads to rapid changes of sequence and structure in viruses over time, which makes antivirals less efficient.35
In a recent study, Agostini et al observed that in vitro, prolonged passage is needed for a coronavirus (murine hepatitis virus [MHV]) to acquire mutations to reduce sensitivity to remdesivir.2 However, these mutations did make both MHV and SARS‐CoV‐1 less infectious in mouse models. They also reported that no resistance mutation occurred within the ExoN, and confirmed that remdesivir can still efficiently inhibit the coronaviruses in mice not lacking the ExoN. Besides, previous evaluations of RdRp demonstrate high selectivity of NAs in favor of ATP.36–38 The high selectivity of NAs, the delayed chain termination mechanism, and the low likelihood of achieving resistance to remdesivir are all features that make remdesivir a promising candidate for inhibition of SARS‐CoV‐2.
4 OTHER POSSIBLE TREATMENTS FOR COVID‐19
One of the first options suggested for treating Covid‐19‐related pneumonia was chloroquine (anti‐malarial) with reported potent in vitro activity against SARS‐CoV‐2.15 Previously, in vitro efficacy of chloroquine for inhibiting SARS‐CoV‐1 and MERS‐CoV was seen.39–41 Satisfactory in vitro findings were the rationale behind running clinical trials of chloroquine and hydroxychloroquine in Covid‐19. A non‐randomized clinical trial conducted by Gautret et al7 showed that hydroxychloroquine significantly reduced viral load compared with controls. Hydroxychloroquine was associated with 50%, 60%, 65%, and 70% viral load reduction on days 3, 4, 5, and 6, respectively. Adding azithromycin led to a 100% viral load reduction on day 6 compared with 70% viral load decrease with hydroxychloroquine alone. In contrast, there are reports that reject the beneficial role of hydroxychloroquine in Covid‐19. An observational study by Geleris et al42 on 1376 patients reported that there was no association between hydroxychloroquine administration and the composite outcome of death or intubation. Still, data on safety and efficacy of these agents in SARS‐CoV‐2 infected patients are not sufficient. The results of ongoing clinical trials are awaited for making a more definite conclusion.
In an RCT conducted by Cao et al, lopinavir/ritonavir, an inhibitor of human immunodeficiency virus type 1 (HIV‐1) protease, showed no difference compared with standard of care in patients hospitalized for Covid‐19 regarding clinical response, mortality rate, and viral RNA load.43 Favipiravir, an anti‐influenza drug previously used in Japan, was tested in multiple studies. A report showed faster negative viral test (4 vs 11 days) and significantly better pneumonia resolution in patients receiving favipiravir compared with controls.44 In a randomized superiority trial comparing favipiravir to umifenovir in Covid‐19, the rate of 7‐day clinical recovery was significantly higher in the favipiravir arm (71.43% vs 55.86%, respectively).45, 10 Combination of darunavir and cobicistat (HIV‐1 protease inhibitors) reported inhibition of SARS‐CoV‐2 in preclinical studies.46, 47 Sofosbuvir (hepatitis C virus RNA polymerase inhibitor), tenofovir (NA with DNA chain termination activity), and galidesivir (NA; RdRp inhibitor) have also shown possible efficacy against SARS‐CoV‐2.11, 48 Other antivirals including ribavirin, acyclovir, ganciclovir, zanamivir, peramivir, and oseltamivir have been excluded from recommendations of treatment for Covid‐19.49 Camostat mesylate and nafamostat (serine protease inhibitors), and meplazumab (anti‐CD147 monoclonal antibody) are under investigation for their possible efficacy in the treatment of Covid‐19.50 Ivermectin, an anti‐parasitic agent, reduced SARS‐CoV‐2 RNA by 93% and 99.8% after 24 and 48 hours, respectively.51 It should be noted that clinical doses needed to exert the same effect would be at least 17 times more than the highest dose ever used in humans (17× 2000 micrograms/kg), which would probably cause significant toxicity.52 Clinical trials are running to determine the clinical efficacy of this agent in patients with Covid‐19.
Tocilizumab, originally developed for rheumatoid arthritis, is a monoclonal antibody that inhibits IL‐6 receptors.53 Disturbances in cytokine levels and high levels of inflammation have been reported in severe Covid‐19 cases.54 A study on 21 patients under treatment with tocilizumab reported reduction in oxygen requirements, improvements of lung lesions on computed tomography (CT), and fast decline of fever and c‐reactive protein levels.55 Evaluation of ongoing clinical trials for a more definitive verdict on tocilizumab is needed.
Corticosteroids are another option present in debates around Covid‐19 treatments. In a study on Covid‐19 and acute respiratory distress syndrome (ARDS), patients who developed ARDS and received corticosteroids were less likely to die in comparison to Covid‐19 patients with ARDS who did not receive corticosteroids (mortality rate: 46% vs 62%).56 Still, the available literature cannot recommend for or against the use of corticosteroids in Covid‐19 patients, but side effects are likely.
Another potential treatment is convalescent plasma. A small preliminary study on five patients who received convalescent plasma showed rapid decline of fever, reductions in sequential organ failure assessment score, increases in PaO2/FiO2, reductions in viral load, and increases in antibody titers. Resolution of ARDS occurred in four patients 12 days after treatment.57 This potential therapy is currently under investigation in multiple clinical trials around the world.
5 CLINICAL EVIDENCE FOR REMDESIVIR EFFICACY FOR COVID‐19 TREATMENT
Initially, remdesivir was administered for compassionate‐use in Covid‐19 patients. Evidence of possible efficacy first emerged from two case reports that showed satisfactory results from relatively late treatment with intravenous (IV) remdesivir due to the worsening clinical status of the patient. The first case who had a history of traveling to Wuhan was a 35‐year‐old man, diagnosed in Washington State on 19 January 2020. Remdesivir was initiated on day 11, and improvement was seen on the next day. It should be noted that the patient received other treatments, including nasal high‐flow oxygen, cefepime, ibuprofen, guaifenesin, and vancomycin, which make interpretation of remdesivir efficacy more difficult.58 In the other case, who was a Covid‐19 patient with ventilatory support, successful extubation occurred 60 hours after remdesivir initiation on day 13 post‐symptom onset.59 In addition, successful treatment of a critically ill pregnant woman with Covid‐19 by combination of convalescent plasma and remdesivir signaled some positive therapeutic effects, possibly related to remdesivir.60
Following the compassionate‐use program for remdesivir in Covid‐19 patients, Grein et al61 reported 68% clinical improvement in 53 severe Covid‐19 patients in a retrospective study. Included patients were given a 10‐day course of remdesivir; clinical improvement, which was defined as at least two points decreasing on the modified ordinal scale, was achieved in 20 of 34 (57%) patients receiving invasive ventilation, and 17 of 19 (89%) patients who were under noninvasive ventilation care. The observed clinical improvement rate in the invasive ventilation group was significantly lower than that of the noninvasive ventilation group at any particular time of the study. This finding was consistent with those observed in other studies of severe and critical Covid‐19 patients.62–65 In addition, the study reported the hospital discharge and mortality rates as 23.5% and 17.6%, respectively, in patients who were ventilated compared with 89.5% and 5.2% in those who did not receive invasive ventilation care at a median follow‐up of 18 days since the first dose of remdesivir was administered. Their results have shown a surprisingly lower mortality rate (17.6%) in the patients who received invasive mechanical ventilation as compared with the 65.7% proportion reported in the Wuhan cohort study.56 It is worth noting that all the above studies were observational studies without control groups. Moreover, different combination therapies and lack of clear inclusion and exclusion criteria might affect the validity of these studies as compared with the RCTs.
Another recently published randomized, double‐blind, placebo‐controlled trial, which was conducted from 6 February to 20 March 2020, reported a statistically non‐significant benefit in terms of the primary outcome in Covid‐19 patients treated with remdesivir vs placebo.18 The study was carried out in 10 hospitals of Wuhan, China, to determine the safety and efficacy of remdesivir in severe Covid‐19 patients, who were within their first 12 days of disease onset. The remdesivir group achieved clinical improvement, defined similarly as the Grein et al study, at a median of 21 days vs 23 days in the placebo group.61 Although the duration of invasive ventilation was shorter, and the mortality rate was higher in the remdesivir group, both differences were found to be insignificant between the two study arms. During the treatment period, results of the viral load, measured by quantitative reverse transcriptase‐polymerase chain reaction and based on upper and lower respiratory tract specimens, were not significantly different between the two groups. However, capability of remdesivir to make the SARS‐CoV‐2 undetectable in nasopharyngeal and nasal swab samplings was shown in two Italian studies, with a time to negativity of 12 and 3 days, respectively.65, 66 Of note, although the Wuhan RCT did not show any significant difference between the remdesivir and placebo group, some serious concerns regarding the methodology and study design had been suggested, such as an insufficient sample size and several baseline differences between the two groups, which may have affected the final results.67
The first and most rigorous clinical trial in the United States started on 21 February 2020 by the National Institute of Allergy and Infectious Diseases (NIAID). The study (NCT04280705) sought to evaluate the efficacy and safety of remdesivir in adult patients with a confirmed diagnosis of Covid‐19 through a randomized, double‐blind, multicenter, placebo‐controlled design. So far, a total of 1063 participants have been assigned to the remdesivir or placebo groups. Participants in the treatment arm were initially started with 200 mg IV remdesivir once, daily, on day1, followed by 100 mg/IV/daily on days 2 to 10. On April 27, an independent data and safety monitoring board (DSMB) announced the initial results of their interim analysis to the study team.68 Two main findings were shared with the public on the NIAID website; the DSMB found a 31% faster time to recovery in the remdesivir group patients than those who received placebo (median: 11 vs 15; P < 0.001). In this study, recovery was defined as discharge from the hospital or reaching normal activity. The mortality rate in the remdesivir group was 8.0%, which was numerically but not significantly lower than the 11.6% mortality rate in the placebo group (P = 0.059). More data from the study have not been published yet (11 May 2020). On May 22, the preliminary report of first stage of the study was officially released.69
On April 29, Gilead Sciences, Inc. reported the primary results of an open‐label, phase 3 RCT, which had been conducted over 181 medical centers in 15 countries (NCT04292899).70 The efficacy and safety of two regimens of remdesivir on 6000 severe Covid‐19 patients were evaluated in this RCT to reach the optimal remdesivir dose. According to the seven‐point scale,71 clinical improvement was defined as at least a two‐point improvement compared with baseline. Results of the initial phase of the study with 397 participants with a 1:1 allocation ratio showed similar effectiveness of 5‐day and 10‐day dosing regimens (200 mg IV remdesivir once daily on the first day, followed by 100 mg/IV/daily for 4 or 9 days). The results suggest that decreasing the duration of remdesivir treatment does not have a significant impact on patient outcome. More precisely, 65% of patients who were treated with a 5‐day dosing regimen achieved clinical improvement at day 14 compared with 54% in the 10‐day treatment group. Numerically, 5‐day remdesivir therapy has been associated with a one‐day shorter time to clinical improvement (a median of 11 days in the 10‐day group vs 10 days in the 5‐day group). More patients in the 5‐day treatment group achieved clinical recovery and discharge compared with the 10‐day treatment group. Moreover, those using the 5‐day regimen had a better survival rate on day 14 than those on the 10‐day regimen.72 Lack of a control group treated with placebo in this study makes the interpretation about the remdesivir treatment benefits difficult (Figure 2).
Although findings related to remdesivir studies in the past few weeks, of which most were sponsored by Gilead Sciences, have rendered researchers and physicians more optimistic, longer follow up durations in a higher number of patients and high protocol adherence are required for proper adjudication.
6 SAFETY CONCERNS AND REPORTED SIDE‐EFFECTS
Remdesivir is a relatively new medication, and there is a lack of necessary data about its safety. Based on the previous experiences of remdesivir in the treatment of MERS and EVD, it is considered to have a relatively good safety profile.4, 20 In an RCT, comparing the effectiveness of four therapeutics for EVD among 725 patients, those in the remdesivir group (n = 175) received 200 mg/IV on day 1 as the loading dose, followed by 100 mg/IV/daily for the next 9 to 13 days.4 The patients who were treated with remdesivir did not experience any serious adverse event (SAE) related to remdesivir, except for one who experienced hypotension and finally died due to cardiac arrest despite remdesivir discontinuation.4 Site causality assessment deemed this SAE as definitely related to remdesivir, while the pharmacovigilance working group adjudicated the SAE to be possibly related to remdesivir. Eight other SAEs occurred in the remdesivir group (urinary tract infection, brain edema, diabetic hyperosmolar coma, sepsis, stroke, cerebral malaria, diabetes mellitus, pyogenic arthritis in shoulder region) of which none were attributed to remdesivir by the two adjudication committees.
An increasing number of surveys focusing on remdesivir’s safety profile is being made available. The compassionate use study of 53 Covid‐19 patients, who were injected with 200 mg IV remdesivir on the first day and 100 mg/IV/daily for the remaining 9 days, has outlined increased hepatic enzymes (23%), diarrhea (9%), rash (8%), renal impairment (8%), and hypotension (8%) as the most common side effects. Twelve patients (23%) experienced SAEs in this study, the most frequent being multiple organ dysfunction syndrome, septic shock, acute kidney injury (AKI), and hypotension that were only experienced by patients intubated at baseline.61 In another study of 35 Covid‐19 patients, hypertransaminasemia (43%), AKI (23%), increased total bilirubin level (20%), and rash (6%) were observed after treatment with remdesivir‐containing regimens.65 In the recently published RCT, with 155 patients, the most common adverse events (AEs) in the remdesivir group were reported as constipation (14%), hypoalbuminemia (13%), hypokalemia (12%), anemia (12%), thrombocytopenia (10%), and increased total bilirubin (10%) at the same dose as previously mentioned for 10 days.18 Although no new safety concerns were identified and the proportion of patients experiencing SAEs was lower in the remdesivir group compared with the placebo group [28/155 (18%) vs 20/78 (26%)], a higher proportion of patients in the remdesivir group had to discontinue its use due to SAEs compared with the placebo group [18/155 (12%) vs 4/78 (5%)]. No deaths in this RCT were attributed to the use of remdesivir by trial adjudicators. According to the Gilead preliminary results from the Phase 3 investigational trial on April 29, remdesivir appears to be tolerated well, whereas nausea was reported in 20/200 (10%) in the 5‐day regimen and in 17/197 (8.6%) in the 10‐day regimen groups; acute respiratory failure was also reported in 12/200 (6%) and 21/197 (10.7%) in the 5‐day and 10‐day regimen groups, respectively.70 Another study reported skin rashes as the only cutaneous adverse event of remdesivir.73 Considering the myriad of signs and symptoms of Covid‐19 (including hepatotoxicity), assigning all these reported AEs and SAEs to remdesivir is controversial. Furthermore, the preliminary report of first stage of the NIAID study showed 114 adverse events among 541 Covid‐19 patients, who recieved IV remdesivir for 10 days.69 The reported side effects are provided in Table 1.
|Concern||Virus||Number of events/ total treated‐patients (%)||Reference|
|Elevated hepatic enzymes||SARS‐CoV2||12/53 (22.6)||61
|28/197 (14.2) a||72, 87|
|26/541 (4.8)||69, 86|
|Acute kidney injury||SARS‐CoV2||3/53 (5.7)||61|
|4/200 (2.0)c||72, 87|
|4/541 (0.7)||69, 86|
|9/200 (4.5)c||72, 87|
|2/541 (0.4)||69, 86|
|Ebola virus||1/175 (1.0)||4
|13/200 (6.5)c||72, 87|
|4/541 (0.7)||69, 86|
|10/200 (5.0)c||72, 87|
|22/541 (4.1)||69, 86|
|Increased total bilirubin||SARS‐CoV2||15/155 (9.7)||18|
|7/541 (1.3)||69, 86|
|Respiratory failure or acute respiratoty distress syndrome||SARS‐CoV2||16/155 (10.3)||18|
|46/541 (8.5)||69, 86|
The administration of 200 mg intravenous remdesivir in the first day following 100 mg of remdesivir up to 10 days.
The administration of 200 mg intravenous remdesivir in the first day followed by a maintenance dose of 100 mg for 9 to 13 days.
The administration of 200 mg intravenous remdesivir in the first day following 100 mg of remdesivir up to 5 days.
In addition, there is also lack of data about the possible side‐effects and safety of remdesivir in specific sub‐populations, such as children, patients with a specific underlying disease (including but not limited to active malignancy, immunosuppression, cardiac disorder, chronic liver and kidney disease, morbid obesity, chronic respiratory disease), and pregnant and breastfeeding patients.74, 75
7 ACTIVE CLINICAL TRIALS
In the literature review for studies of Covid‐19 and remdesivir, some small uncontrolled studies and a few registered and controlled studies are available. In view of the efficacy and safety of remdesivir, we searched for ongoing trials and studies submitted to the ClinicalTrials.gov, EU Clinical Trials Register, UMIN Clinical Trials, ANZCTR, CHICTR, and ISRCTN registries up to 11 May 2020 by using the keyword “remdesivir.” We found 12 studies that are currently underway to assess the efficacy and/or safety of remdesivir as a treatment agent in Covid‐19; seven clinical trials, three observational studies, and two expanded access studies. Details of these studies are presented in Table 2. Among the seven identified RCTs, all are designed to be multicenter, six are in phase 3, and one is in phase 2. For most trials, the anticipated number of recruited participants is more than 1000. Following the preliminary and partial study results showing possible signals of efficacy of remdesivir for treatment of Covid‐19, some studies are emerging for the assessment of the possible efficacy of adding anti‐inflammatory drugs (Figure 2). On 8 May 2020, NIH announced a new trial for evaluating the efficacy and safety of remdesivir combined with baricitinib, a JAK inhibitor (developed by Eli Lilly and Company), in the treatment of Covid‐19 with ARDS. The first arm will receive a 10‐day remdesivir course plus 4 mg oral baricitinib for up to 14 days, and the second will be treated with remdesivir plus placebo. The study is a double‐blind RCT conducted at approximately 100 medical centers.76
|ID||Study type||Participant no.||Age||Start date (month‐year)||Estimated end (month‐year)||Primary outcome(s)/Follow‐up duration (day)||Arms||Primary goal||Status|
|NCT04292899||Parallel randomized clinical trial (Phase 3), open‐label/multicenter||6000a||≥12||Mar‐20||May‐20||Clinical improvement (on a seven‐point ordinal scale)/14||1) 5‐day RDV (not MV)||Efficacy/safety||Recruiting|
|2) 10‐day RDV (not MV)|
|3) 5‐ or 10‐day RDV (Extension)|
|4) 10‐day RDV (MV)|
|NCT04292730||Parallel Randomized clinical trial (Phase 3), open label/Multicenter||1600b||≥12||Mar‐20||May‐20||Clinical improvement (on a seven‐point ordinal scale)/11||1) 5‐day RDV||Efficacy/safety||Recruiting|
|2) 10‐day RDV|
|3) continued SOC|
|3) 5‐ or 10‐day RDV (Extension)|
|NCT04302766||Expanded access, intermediate‐size population, treatment IND/protocol||NAc||Child, Adult, Older Adult||NA||NA||NA/NA||NA||NA||Available|
|NCT04323761||Expanded access, treatment IND/protocol/ multicenter||NAd||≥12||NA||NA||NA/NA||NA||NA||Available|
|NCT04330690||Adaptive parallel randomized clinical trial (Phase 2), open‐label/multicenter||440||≥18||Mar‐20||May‐22||Efficacy of Interventions on 10‐point ordinal scale/29||1) SOC||Efficacy/safety||Recruiting|
|2) 14‐day lopinavir/ritonavir|
|3) 11‐day HCQ|
|4) 10‐day RDV|
|NCT04280705||Adaptive parallel randomized clinical trial (Phase 3), double‐blind/multicenter||800a||≥18||Feb‐20||Apr‐23||Time to recovery on three‐point ordinal scale/29||1) Placebo||Efficacy/safety||Recruiting|
|2) 10‐day RDV|
|NCT04321616||Adaptive parallel randomized clinical trial (Phase 3), open label/multicenter||700||≥18||Mar‐20||Aug‐20||In‐hospital mortality/21||1) 10‐day RDV||Efficacy/safety||Recruiting|
|2) 10‐day HCQ|
|3) 10‐day HCQ plus RDV|
|NCT04315948||Adaptive parallel randomized clinical trial (Phase 3), open label/multicenter||3100a||≥18||Mar‐20||Mar‐23||Efficacy of Interventions on seven‐point ordinal scale/15||1) 10‐day RDV||Efficacy/safety||Recruiting|
|2) 14‐day lopinavir/ritonavir|
|3) 14‐day lopinavir/ritonavir plus six‐day Interferon ß‐1a|
|NCT04314817||Cross‐sectional, observational (case only)/single center||1000||Child, Adult, Older Adult||Mar‐20||Jan‐21||Adverse event of interventions||NA||Safety||Recruiting|
|NCT04365764||Cross‐sectional (cohort), observational (case‐control)/multicenter||400||Child, Adult, Older Adult||Mar‐20||Dec‐20||Composite of death and MV/14||NA||Efficacy/safety||Recruiting|
|NCT04365725||Retrospective (cohort), observational, compassionate use/multicenter||200||≥18||Apr‐20||May‐20||Clinical improvement (on a seven‐point ordinal scale)/15||RDV||Efficacy/safety||Not yet recruiting|
|ISRCTN83971151||Parallel randomized clinical trial (Phase 3), open‐label/multicenter||Anticipated at least several thousand patients||≥18||Mar‐20||Mar‐21||All‐cause mortality according to the severity of disease||1) SOC||Efficacy||Recruiting|
|2) 14‐day lopinavir/ritonavir|
|3) 14‐day lopinavir/ritonavir plus 6‐day Interferon ß|
|4) 11‐day HCQ|
|5) 10‐day RDV|
- Abbreviations: HCQ, hydroxychloroquine; MV, mechanical ventilated;NA, not available; RDV, remdesivir; SOC, standard of care Covid‐19 treatment.
Patients with severe Covid‐19(SpO2 ≤ 94%).
Patients with moderate Covid‐19(SpO2 > 94%).
Patients require invasive mechanical ventilation.
7.1 This is not the end of the battle against SARS‐CoV ‐2
SARS‐CoV‐2 has caused a global disaster, and there is no approved effective treatment and/or vaccine for Covid‐19 yet. There is still no clear prediction about the future of this new virus, and there is much concern about the next wave of the pandemic, especially in the autumn and winter.77 One optimistic possibility is that similar to other coronaviruses (eg, SARS‐CoV‐1 and MERS‐CoV), SARS‐CoV‐2 disappears in the upcoming summer.78 However, none of the former coronaviruses made such a widespread global pandemic, and a recent prospective cohort study showed that temperature is not associated with the epidemic growth of Covid‐19.79 Therefore, many epidemiologists are warning about the next pandemic waves in the colder seasons of the year.80 Some scientists believe that SARS‐CoV‐2 will circulate at a low, regular level in the human community, similar to the influenza A and B viruses, and cause seasonal outbreaks.81 On the other hand, some scientists believe that SARS‐CoV‐2 is going to become endemic/hyperendemic in many regions of the world, and the pandemic will die out only when the “magic percentage” of population infected is reached (1‐1/R0, that is, herd immunity is achieved).82 Therefore, controlling such a contagious and widespread disease without a highly effective and freely available vaccine and/or treatment seems to be impossible.83 Several vaccine studies have been conducted so far.84–86 However, first, it seems that none of them can be approved until mid‐2021, and second, there are some concerns about the efficacy of vaccines in inducing immunity against SARS‐CoV‐2,87 with a wide knowledge gap regarding Covid‐19 pathophysiology. This highlights the importance of effective antiviral treatments for controlling this pandemic.
In summary, we are in the first steps of dealing with SARS‐CoV‐2, and the battle against this deadly virus seems “to be continued” for the unforeseeable future. Non‐pharmaceutical interventions such as social distancing, identification, and isolation of Covid‐19 cases, plus tracing and quarantining of their contacts and adherence to hand hygiene are still of utmost importance in this battle and must prevail alongside pharmaceutical interventions.
CONFLICT OF INTEREST
The authors declare no potential conflict of interest.
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