Baricitinib in the Treatment of COVID-19

Abstract

Baricitinib is a novel Janus kinase (JAK) inhibitor which has recently been included in recommendations for treatment of COVID-19. This chapter is focused on discussing the evidence available regarding the safety and efficacy of use of baricitinib alone or in combination with other therapies for treatment of patients with COVID-19. A systematic literature search was conducted for this purpose to find all clinical studies on baricitinib in treatment of COVID-19. A total of 30 studies, including both clinical trials and observational studies were identified, and they have been described briefly. Collation of the results from these observational and interventional studies shows that baricitinib either alone or in combination with other drugs, when used as an add-on to standard therapy, was found to have favorable outcomes in hospitalized patients with moderate to severe COVID-19. Furthermore, ongoing clinical trials indicate that the drug is still under evaluation across the world for its safety and efficacy in COVID-19. The recent approval of baricitinib by the US FDA for treatment of hospitalized adults with COVID-19 accurately reflects the role of the drug in COVID-19. Baricitinib improves clinical outcomes in hospitalized COVID-19 patients, and additional evidence may establish the drug as a standard treatment in such patients.

1. Introduction

Since causing an outbreak of a cluster of cases of pneumonia in Wuhan, China, the novel corona virus, named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has spread globally to become one of the worst pandemics ever seen by humankind [1, 2]. With multiple ‘waves’ of the Corona Virus Disease known as COVID-2019 engulfing the world, the medical and scientific communities have focused their efforts on developing effective management strategies especially for hospitalized patients. These efforts have mostly been concentrated on evaluating the antiviral and anti-inflammatory properties of novel or repurposed medications. COVID-19 treatment guidelines from the World health Organization (WHO), the National Institutes of Health (NIH), U.S., the National Institute for Health and Care Excellence (NICE), UK, and regional healthcare authorities such as Indian Council of Medical Research (ICMR) focus on the management of complications, the prevention of progression, and the provision of supportive care with symptomatic treatment based on evidence-based recommendations. A wide variety of clinical trials and observational studies have been conducted worldwide to evaluate treatment effects on survival rates in various severities of COVID-19 patients, as well as to reduction in morbidity in terms of hospitalization, time to recovery, and symptomatic or virological response in patients with less severe illness. COVID-19 treatments still remain limited; include antiviral therapies such as remdesivir, nirmatrelvir-ritonavir, molupiravir, immunomodulators such as corticosteroids, IL-6 inhibitors, and, more recently, specific monoclonal antibodies such as REGN-COV2 (casirivimab and imdevimab combination), regdanvimab, and sotrovimab among others [3, 4, 5].

The FDA granted emergency use authorization (EUA) to baricitinib, a novel Janus kinase (JAK) inhibitor, to be used in combination with remdesivir in November 2020 [6], which was later revised to a standalone therapy in adults and children above 2 years of age hospitalized for COVID-19 [7]. Finally, in May 2022, baricitinib has received approval from the FDA for the treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) [8]. At present, European Medicines Agency (EMA) is evaluating the marketing authorization application for baricitinib to be used in COVID-19 treatment protocol for patients above the age of 10 years of age who require supplemental oxygen therapy [9]. In May 2021, the Central Drugs Standard Control Organization (CDSCO), drug regulatory authority of India also granted emergency use approval to baricitinib for the treatment of confirmed COVID-19 hospitalized adults requiring supplemental oxygen in combination with remdesivir [10]. Baricitinib is an oral JAK 1 and 2 inhibitor that was approved for rheumatoid arthritis in the United States and Japan in 2017 [11]. JAKs are a family of enzyme involved in the inflammatory pathway that helps regulate the signaling cascade, activating signal transducers and activators of transcription (STATs) for cytokines such as IL-2, 6, 10, 12, IFN- etc. JAK inhibitors (JAK i’s) have been shown to be clinically useful in immune, inflammatory, and hematopoietic diseases by preventing the dysregulated production of proinflammatory cytokines involved in cellular survival, proliferation, differentiation, and immigration [12, 13]. As a result, baricitinib has been studied in the treatment of COVID-19 with the goal of suppressing the hyperinflammatory state of cytokine release syndrome (CRS) or hypercytokinemia (cytokine storm) associated with COVID-19 [14].

Systematic/living reviews of COVID-19 therapies [15, 16] and JAK inhibitors [17, 18] are available. This chapter solely focuses on a comprehensive synthesis of the evidence available regarding use of baricitinib in treatment of COVID-19. For this purpose, we have used a systematic search strategy as recommended per the Cochrane methodology.

Figure 1 provides a schematic representation of the mechanism of action of Baricitinib, mainly on three different aspects of Corona Virus Disease, inhibits viral entry, inhibits Inflammation by blocking JAK–STAT signal transduction pathways and alters the immune status via JAK–STAT inhibition.

Figure 1.

Schematic representation of the mechanism of action of Baricitinib. [1] Interleukins (IL-2, IL-4, IL-7, IL-g, IL-15, IL-21, IL-6) are the most common. Baricitinib inhibits IL-2, IL-4, IL-7, IL-15, IL-21 via JAK1/3 STAT1/3/5 to regulate hemostasis and lymphocyte I proliferation, whereas IL6 acts via tyrosine kinase JAKl/2 STAT3 to regulate T cell differentiation and inflammation. [2] Angiotensin-ACE-2 receptor converting enzyme-2 functions as a docking receptor for SARS C0V-2 attachment. [3] AAKl-adaptor-associated protein I (AAKl-API). [4] Kinase I (AP2-associated protein kinase 1) is a transmembrane enzyme that participates in clathrin-mediated endocytosis. Baricitinib inhibits enzyme activation and thus prevents SARS-CoV 2 endocytosis. [4] Cytokine, type I and type II receptors. [5] Janus activated kinases are intracellular non-receptor tyrosine kinases that regulate cytokine signaling via the JAK–STAT pathway. Baricitinib is a JAK inhibitor that is not selective. [6] Tyrosine residues that aid in the binding of SH2 domain proteins like STAT. [7] Signal transduction activated transcription (STAT) is a downstream transducer of the JAK enzyme that exists intracellularly in an inactivated hypophosporylated state in association with JAK. [8] STAT phosphorylated active form. [9] Specific gene transcription activation. [10] Transcription is followed by protein translation, which results in the regulated effects.

1.1 Search methodology

Literature search was conducted to identify studies which assess the efficacy and safety of baricitinib therapy in COVID-19, either alone or in combination with other therapies. This included interventional studies (Randomized Controlled Trials i.e., RCTs and non RCTs) as well as observational studies assessing the efficacy and/or safety of baricitinib in COVID-19, published or pre-published (in English language) after December 2019. Case reports, review articles, conference proceedings, editorial/comments, author response or book chapter were not included.

The WHO COVID-19 Database (WHO COVID-19 Global literature on Coronavirus Disease) was used which is a comprehensive database of COVID-19 research articles [19] containing global literature from all major standard electronic databases of published, pre-published and gray literature sources such as MEDLINE, Scopus, ProQuest Central, ELSEVIER, Web of Science, EMBASE, ScienceDirect, CINAHL, CAB Abstracts, APA PsycInfo, ChemRxiv, BioMed Central, Oxford Academic, medRxiv, BMC, bioRxiv, etc. Furthermore, a manual search was performed using the bibliography of selected articles, and any studies that satisfied eligibility criteria were added. We searched all information sources up to May 31, 2022.

The list of keywords searched in the Titles, Abstracts and Authors, using Boolean operators consisted of Baricitinib, Janus Kinase, JAK–STAT, Therapy, Treatment, 2019 novel Coronavirus disease, COVID-19, SARS-CoV-2, novel Coronavirus infection, 2019-ncov infection, Coronavirus disease 2019, Coronavirus disease-19, 2019-ncov disease, COV, Coronavirus. After removing the duplicate results, the titles and abstracts were independently screened by two sets of reviewers based on the eligibility criteria and then assessed for availability of full texts. Data was then extracted from eligible studies related to pre-decided data items—study characteristics, patient characteristics, interventions studied, and outcomes reported. Standard definitions were used for the severity of disease and various outcome parameters [20].

We used the Cochrane tool for randomized trials (RoB 2.0) [21] to categorize the published RCTs as either low risk of bias, some concerns—probably low risk of bias, more concerns—probably high risk of bias, or high risk of bias. The “Study Quality Assessment tool” [22] was used for critical appraisal of internal validity and bias in observational studies (Non-Randomized Studies of Intervention, NRSIs).

2. Evidence from published studies

After careful consideration, 30 studies were chosen to be described in this chapter. Among these, there are 24 observational studies and 6 interventional studies. Table 1 summarizes the details of these published/pre-published studies, as well as the assessment of study quality/risk of bias.

S.; N.	Title of study	Authors	Study location	Study design	Bias assessment
Observational studies
1	Impact of high dose of baricitinib in severe COVID-19 pneumonia: a prospective cohort study in Bangladesh.	Hasan MJ, Rabbani R, Anam AM, Huq SM, Polish MM, Nessa SS, et al.	Bangladesh	Prospective Cohort	Good
2	Additional baricitinib loading dose improves clinical outcome in COVID-19	Hasan MJ, Rabbani R, Anam AM, Huq SM, Polash MM, Nessa SS, et al.	Bangladesh	Case Control	Good
3	Use of baricitinib in patients with moderate to severe Coronavirus Disease 2019	Titanji BK, Farley MM, Mehta A, Connor-Schuler R, Moanna A Cribbs SK, et al.	United States	Retrospective Cohort	Fair
4	Baricitinib restrains the immune dysregulation in patients with severe COVID-19.	Bronte V, Ugel S, Tinazzi E, Vella A, Sanctis FD, Canè S, et al.	Italy	Prospective Cohort	Fair
5	Role of Low-Molecular-Weight Heparin in hospitalized patients with Severe Acute Respiratory Syndrome Coronavirus 2 pneumonia: A prospective observational study	Falcone M, Tiseo G, Barbieri G, Russo A, Virdis A, Forfori F, et al.	Italy	Prospective Cohort	Good
6	Experience with the use of baricitinib and tocilizumab monotherapy or combined, in patients with interstitial pneumonia secondary to coronavirus COVID19: A real-world study.	Rosas J, Liaño FP, Cantó ML, Barea JM, Beser AR, Rabasa JT, et al.	Spain	Case Control	Fair
7	Clinical outcomes in a cohort of non-ventilated COVID-19 patients with progressive hypoxemia and hyper-inflammatory response treated with baricitinib	Milligan PS, Amsden J, Norris SA, Baker RL, Myers J, Preston F, et al.	United States	Retrospective Cohort	Fair
8	Beneficial impact of baricitinib in COVID-19 moderate pneumonia; multicenter study.	Cantini F, Niccoli L, Nannini C, Matarrese D, Natale M Lotti P, et al.	Italy	Retrospective Cohort	Fair
9	Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact.	Cantini F, Niccoli L, Nannini C, Matarrese D, Natale M Lotti P, et al.	Italy	Retrospective Cohort	Fair
10	Biological agents for rheumatic diseases in the outbreak of COVID-19: friend or foe?	Santos CS, Férnandez XC, Moriano CM, Álvarez ED, Castro CA, Robles AL, et al.	Spain	Retrospective Cohort	Good
11	Baricitinib plus dexamethasone compared to dexamethasone for the treatment of severe COVID-19 pneumonia: A retrospective analysis	Pérez-Alba E, Nuzzolo-Shihadeh L, Aguirre-García G, Espinosa-Mora J, Lecona-Garcia J, Flores-Pérez R, et al.	Mexico	Retrospective Cohort	Good
12	The effect of baricitinib usage on the clinical and biochemical profiles of COVID-19 patients- A retrospective observational study	Amarnath A, Das A, Mutya VSS, Ibrahim I	India	Retrospective Cohort	Fair
13	Anakinra vs baricitinib: Different strategies for patients hospitalized with COVID-19	García-García J, Pérez-Quintana M, Ramos-Giráldez C, Cebrián-González I, Martín-Ponce M, del Valle-Villagrán J, et al	Spain	Retrospective Cohort	Good
14	Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study	Rodriguez-Garcia J, Sanchez-Nievas G, Arevalo-Serrano J, Garcia-Gomez C, Jimenez-Vizuete J, Martinez-Alfaro E.	Spain	Prospective Cohort	Good
15	Baricitinib against severe COVID-19: effectiveness and safety in hospitalized pretreated patients	Iglesias Gómez R, Méndez R, Palanques-Pastor T, Ballesta-López O, Borrás Almenar C, Megías Vericat J, et al.	Spain	Retrospective Cohort	Fair
16	Baricitinib reduces 30-day mortality in older adults with moderate-to-severe COVID-19 pneumonia	Abizanda P, Calbo Mayo J, Mas Romero M, Cortés Zamora E, Tabernero Sahuquillo M, Romero Rizos L, et al.	Spain	Retrospective Cohort	Good
17	Efficacy of combination therapy with the JAK inhibitor baricitinib in the treatment of COVID-19	Thomas BL, Gosselin J, Libman B, Littenberg B, Budd R C.	United States	Retrospective Cohort	Good
18	Combination of baricitinib plus remdesivir and dexamethasone improves time to recovery and mortality among hospitalized patients with severe COVID-19 infection (preprint)	Perez-Gutierrez V, Shah V, Afsheen A, Khalid A, Yangco A, Ocrospoma S, et al.	United States	Case Control	Good
19	Effect of baricitinib in patients with coronavirus disease 2019 and respiratory failure: A propensity score-matched retrospective cohort study.	Tanimoto T, Tada S, Fujita S, Hirakawa T, Matsumura M, Isoyama S, et al.	Japan	Retrospective Cohort	Good
20	Efficacy of the combination of baricitinib, remdesivir, and dexamethasone in hypoxic adults with COVID-19: A retrospective study.	Yasuda Y, Hirayama Y, Uemasu K, Arasawa S, Iwashima D, Takahashi K	Japan	Retrospective Cohort	Fair
21	Use of baricitinib in combination with remdesivir and steroid in COVID-19 treatment: A multicenter retrospective study.	So, JM, Umeh C, Noriega S, Stratton E, Aseri M, Gupta R C	United States	Retrospective Cohort	Good
22	Tocilizumab, netakimab, and baricitinib in patients with mild-to-moderate COVID-19: a retrospective cohort study	Bryushkova EA, Skatova VD, Mutovina ZY, Zagrebneva AI, Fomina DS, Kruglova TS, et al.	Japan	Retrospective Cohort	Fair
23	Real-life effectiveness and safety of baricitinib as adjunctive to standard-of-care treatment in hospitalized patients with severe coronavirus disease 2019.	Tziolos N, Karofylakis E, Grigoropoulos I, Kazakou P, Koullias E, Savva A, et al.	Greece	Retrospective Cohort	Good
24	Therapeutic safety and efficacy of triple-immunosuppressants vs dual-immunosuppressants in severe-to-critical COVID-19: A prospective cohort study in Bangladesh.	Hasan MJ, Rabbani R, Anam AM, Huq SMR	Bangladesh	Prospective Cohort	Fair
Interventional studies
25	Efficacy and safety of baricitinib in patients with COVID-19 infection: Results from the randomized, double-blind, placebo-controlled, parallel-group COV-BARRIER phase 3 trial.	Marconi VC, Ramanan AV, Bono S, Kartman CE, Krishnan V, Liao R, et al.	South and North America, Europe, Asia.	Double-blinded RCT	Low
26	Baricitinib plus remdesivir for hospitalized adults with Covid-19.	Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, et al.	U.S., Singapore, South Korea, Mexico, Japan, Spain, U.K., Denmark	Double-blinded RCT	Low
27	Clinical impact of combination therapy with baricitinib, remdesivir, and dexamethasone in patients with severe COVID-19	Izumo T, Kuse N, Awano N, Tone M, Sakamoto K, Takada K, et al.	Japan	Double-blinded RCT	Low
28	Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure	Gavriilidis E, Antoniadou C, Chrysanthopoulou A, Ntinopoulou M, Smyrlis A, Fotiadou I, et al.	Greece	Non-Randomized Open label	Probably high risk
29	Baricitinib plus Standard of care for hospitalized adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: Results of a randomized, placebo-controlled trial.	Ely EW, Ramanan AV, Cynthia EK, Bono S, Liao R, Piruzeli MLB, et al	Argentina, Brazil, Mexico, U.S.	Double-blinded RCT	Low
30	Baricitinib vs dexamethasone for adults hospitalized with COVID-19 (ACTT-4): A randomized, double-blind, double placebo-controlled trial	Wolfe CR, Tomashek KM, Patterson TF, Gomez CA, Marconi VC, Jain MK, et al.	United States	Double-blinded RCT	Low

Table 1.

Summary of the observational and interventional studies.

2.1 Observational studies

In a prospective cohort study conducted in Bangladesh, Hasan et al. [23] included 238 patients with severe COVID-19 pneumonia, 122 of whom received baricitinib 8 mg (high dose) and 116 patients received 4 mg (usual dose) orally for 14 days, along with dexamethasone, remdesivir, and enoxaparin/dalteparin. The time to achieve ≥94% oxygen saturation (5 vs 8 days; IQR: 4–5 and 6–9 days respectively, P < 0.05) and the need for supplemental oxygen were significantly shorter in the high dose group. Similarly, the need for intensive care unit (ICU) and intubation support was significantly lower in patients receiving the high dose of baricitinib compared to those receiving the usual dose (9 vs 17.2%, P = 0.02; 4.1 vs 9%, P = 0.001, respectively), as was the 30-day all-cause mortality (3.3 vs 6%, P = 0.001). The median duration of hospitalization in the high dose group was also shorter (11 vs 13 days; IQR: 9.5–14 and 10–17.5 days, respectively, P = 0.072). Thrombocytopenia and mouth sores were also significantly higher in the high dose group (9.8 vs 2.6% and 2.4 vs 0.8%, respectively). High-dose baricitinib treatment provided significant benefits in terms of survival and other clinical outcomes among patients with severe COVID-19, albeit at a higher risk of thrombocytopenia and mouth sores. The study participants, however, differed in clinical and biochemical parameters at baseline.

The same investigators conducted another prospective study involving 37 adult patients; 17 were assigned to the ‘control’ (No Loading Dose, NLD) group, while 20 were assigned to the ‘case’ (Loading Dose, LD) group, where they received an additional 8 mg loading dose of baricitinib orally before receiving 4 mg daily oral baricitinib for 14 days. Tolerability was good in both groups and there were no significant differences in mortality. However, the median time (in days) to reach SpO₂ > 95% was relatively shorter in the LD group as compared to NLD [3 (IQR:2–8) vs 4 (IQR:4–5) respectively, P = 0.180]. A similar trend was observed for the median time to return to normal breathing [(LD 5(4–5) vs NLD 8 (7–10) days] and the median time spent in the hospital (LD 12 vs NLD 15 days). The NLD group required greater ICU support and mechanical ventilation (29.4% NLD vs 10% LD, P < 0.05 and 11.8% NLD vs 5% LD, P = 0.141, respectively) [24].

Titanji et al. [25] conducted a retrospective cohort study in 15 patients with moderate–severe COVID-19 pneumonia, treated with oral baricitinib (2–4 mg OD for a maximum of 7 days) and oral hydroxychloroquine (200–400 mg OD) with standard prophylactic treatment of DVT with unfractionated heparin or lower molecular weight heparin (LMWH). The combination therapy showed improved clinical status in 73% of patients in terms of fever and other presenting symptoms, oxygen requirement, and C-reactive protein (CRP) levels, with 80% survival (12/15); three patients died due to underlying pre-existing conditions. With no comparator and concurrent administration of hydroxychloroquine. With a very small study and no comparator, this study could not establish a cause-effect relationship between baricitinib treatment and outcomes.

In Verona, Italy, Bronte et al. [26] observed 76 patients with COVID-19 pneumonia prospectively, 20 of whom received 4 mg BD baricitinib for 2 days as an initial loading dose, followed by 4 mg OD for 5 days as maintenance dose, in addition to standard therapy of hydroxychloroquine and/or antivirals (ritonavir/lopinavir), along with supportive therapy with antimicrobials and anticoagulants. The mortality rate in the baricitinib cohort was significantly lower than in the standard therapy cohort [1(5%) vs 25(45%), respectively]. Similarly, the need for oxygen flow therapy was reduced (P < 0.001), as were serum/plasma levels of CRP (P < 0.001), p-STAT3 (P < 0.001), as well as T lymphocytes, NK cells, monocytes, IL-1, IL-6, and TNF-α concentrations in the baricitinib group. The baricitinib group also showed an absolute increase in circulating lymphocytes, IL-8 serum levels, CD4⁺ T cells, and an increase in the PaO₂/FiO₂ ratio (P = 0.02). However, both cohorts faired the same with regards to acute respiratory distress syndrome (ARDS) incidence, hospitalization duration, fever resolution, lung involvement as on HR-CT/Chest X ray, CD8⁺ T cells, the absolute number of NK (Natural Killer) cells, and expansion of monocytes.

In a prospective cohort study (with 1:1 matching) in Pisa, Italy, Falcone et al. [27] primarily evaluated the effect of LMWH treatment in 244 patients with COVID-19 pneumonia, as along with assessment of treatment effects of many drugs like hydroxychloroquine, proteases inhibitors, doxycycline, corticosteroids, macrolides, tocilizumab and remdesivir including baricitinib (n = 40 patients). Only 21 of these 40 patients, who received baricitinib along with one or more additional drugs, had matched controls and were evaluated for outcome. The univariate and multivariate regression analysis for the association between interventions and mortality revealed a hazards ratio of 0.14 (P = 0.006) and an aHR of 0.69 (P = 0.45), with a mortality of 9% with baricitinib. The hazards ratio for death/severe ARDS was 0.53 (P = 0.12). When baricitinib intervention was matched with mortality and severe ARDS, and regression analysis was performed, the HRs were 1.35 (0.32–5.96) and 1.38 (0.48–4.01), respectively, with P values of 0.678 and 0.54. The study found no significant beneficial (or harmful) effect of baricitinib on the clinical recovery of COVID-19 pneumonia patients, but it was clearly underpowered to evaluate the effect of baricitinib.

In a retrospective observational study, Rosas et al. [28] compared the effect of baricitinib and tocilizumab as monotherapies or in combination with the standard of care therapy used for COVID-19 in Spain among 60 patients. The baricitinib group (n = 12) received 2 or 4 mg orally, tocilizumab group (n = 20) received weight adjusted dose of 400–600 mg, combination group (n = 11) received both baricitinib and tocilizumab and a fourth group (n = 17) received neither of the therapies. The patients received drugs such as antivirals, azithromycin, hydroxychloroquine, interferon, corticosteroid apart from the above therapies. More than 50% of patients were over the age of 70 years. The study revealed no significant mortality benefits of either of the treatment regimens. When compared to the standard of care group (neither tocilizumab or baricitinib), the baricitinib monotherapy group showed a significant reduction in temperature, CRP, D-Dimer, oxygen saturation, and respiratory rate (P < 0.05), and the combination group (tocilizumab + baricitinib) showed a similar but more significant difference (P < 0.01). When baricitinib was compared to tocilizumab monotherapy, it showed greater reductions in CRP, D-Dimer, respiratory rate, lymphocytosis, LDH, and temperature. During the study, no relevant side effects were recorded with either of the therapies. Baseline comparison revealed that the patients receiving baricitinib/tocilizumab presented with a more serious (worsened) disease in comparison to those who received neither drug.

Milligan et al. [29] conducted a retrospective longitudinal study in 22 patients with COVID-19 pneumonia and compared the effect of baricitinib (2 mg OD orally for 7 days) to the standard of care (hydroxychloroquine ± ribavirin ± corticosteroids and anticoagulant treatment). The baseline characteristics of the participants differed significantly. The study found clinical improvement in patients receiving baricitinib therapy; 16 patients did not experience disease progression, while the remaining patients died (n = 3) or required mechanical ventilation. Prior to the completion of the baricitinib regimen, the oxygen demands of the majority of the patients (77.3%) improved by at least one WHO oxygenation criteria. Ferritin and CRP levels fell significantly from a median of 885 to 326.5 ng/ml and 20.35 ng/ml to 17.3 mg/dl, respectively. Baricitinib caused mild adverse effects such as thrombocytosis (n = 22), transaminase elevation (n = 5), while acute kidney injury, AKI (n = 2), lymphopenia (n = 1) led to treatment discontinuations.

Cantini et al. [15] conducted a pilot ambivalent cohort study in Italy, enrolling 12 patients with moderate COVID-19 who received baricitinib in addition to standard antiviral and hydroxychloroquine therapy. Another 12 patients were matched from previous hospital records to serve as controls, who had received the then-standard of care therapy. Overall, clinical characteristics and respiratory function parameters improved significantly in the baricitinib-treated group. CRP levels decreased significantly after 14 days, whereas no significant changes were observed in the controls. While none of the baricitinib-treated patients requested ICU transfer, 33% (4/12) of the controls did (P = 0.093). In comparison to 8% (1/12) of the controls, 58% (7/12) of the baricitinib-treated patients were discharged at 14 days (P = 0.027). Fever, SpO₂, PaO₂/FiO₂, CRP, and the Modified Early Warning Score (MEWS) all improved significantly when compared to controls.

The same team of researchers also conducted a retrospective longitudinal multicentric study in patients who had previously been hospitalized with moderate COVID-19 to compare the effectiveness of standard therapy (n = 78) and baricitinib (n = 113) administered over the course of 2 weeks as an add-on to lopinavir/ritonavir and LMWH. The 2-week case-fatality rate was found to be significantly lower in the baricitinib group as compared to the control group (0 vs 6.4% in baricitinib vs control, P = 0.01), along with lesser ICU admissions (0.88 vs 17.9%). SpO₂, PaO₂/FiO₂, transaminase levels, and lymphocyte counts were significantly increased in the baricitinib group, while CRP and IL-6 levels were significantly decreased. At discharge, the baricitinib group had a significantly lower proportion of patients who tested positive for COVID-19 on pharyngeal swabs (2.5 vs 40% in controls) [16].

Santol et al. [30] studied the incidence of COVID-19 pneumonia in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) retrospectively. COVID was contracted by 40 of 820 rheumatic disease patients. Among the three patients were being treated with baricitinib, none developed COVID, indicating that the drug may have a protective effect. The study’s major limitations were the very low number of COVID-19 cases and patients receiving baricitinib.

In a Mexican retrospective cohort study [31], Alba et al. compared baricitinib in combination with dexamethasone (n = 123) to dexamethasone alone (n = 74) among hospitalized patients with severe COVID-19. Overall 30-day mortality was significantly lower in the combination therapy group (20.3%) than in the dexamethasone monotherapy group (40.5%); P < 0.05. Combination therapy did not increase the risk of hospital acquired infections.

Another retrospective study from India [32] described the clinical and biochemical parameters of 31 patients with moderate-to-severe COVID-19 who were treated with a combination of baricitinib and remdesivir. At baseline, over 50% of patients were males, diabetic, had at least one comorbidity, and all of them received steroids along with baricitinib and remdesivir. The treatment reduced oxygen requirement over the course of hospitalization (P < 0.05), reduced CRP levels from an average of 93.9 to 32.3 (P = 0.0001), IL-6 values from an average of 47.5 to 20.8 (P = 0.004), and the neutrophil lymphocyte ratio (NLR), with no significant changes in ferritin or D-dimer. The study also performed a subgroup analysis, which showed that oxygen requirement was higher in older age groups, reduced in individuals with comorbidities, absent in those with no comorbidities, and showed a decrease in all survivors. The CRP value, IL-6, NLR, D-dimer and ferritin all showed a similar trend of reduction with treatment in older age groups and comorbidities.

Garcia-Garcia et al. [33] carried out a retrospective cohort study in Spain to compare the effect of IL-1 inhibitor anakinra (n = 125) vs baricitinib (n = 217) as an add-on to corticosteroid and standard care therapy in hospitalized patients with COVID-19 pneumonia, and found no differences in mortality (17.6 vs 16.6%). However, a significantly lower proportion of patients receiving baricitinib required invasive mechanical ventilation than those receiving anakinra (4.6 vs 10.4%; P = 0.039).

Garcia-Rodriguez et al. [34] in a prospective cohort study, compared improvement in pulmonary function in patients with moderate to severe COVID-19 pneumonia treated with corticosteroids (n = 50) vs combination of corticosteroids and baricitinib (n = 62), both in addition to lopinavir/ritonavir and hydroxychloroquine. The combination group improved SpO₂/FiO₂ significantly more than the corticosteroid alone group (mean difference 49; 95% CI 22–77, P < 0.001). Similarly, a significantly lower proportion of patients in the combination group required supplemental oxygen at discharge and 1 month (25.8%, 12.9%) compared to those in the corticosteroid alone group (62%, 28%), with ORs of 0.18 and 0.31 respectively.

In a retrospective analysis by Gómez et al. in Spain [35], 43 hospitalized severe COVID-19 patients (SpO₂ < 92%) received barictinib 4 mg orally for 5–7 days; Majority (84%) of these patients were additionally administered corticosteroids. On an 8-category ordinal scale, a substantial median clinical improvement of 3 points (IQR 1–4) was noted from day 1 to day 15 (P < 0.01). There was no mortality by days 30 and 60, and all participants were discharged with clinical improvement. The median recovery time was 12 days. All clinical measures associated with poor prognosis in COVID-19 showed a substantial improvement (P < 0.05), and no noteworthy adverse effects were reported.

In a retrospective cohort study, Abizanda et al. [36] enrolled 328 older adults with moderate to severe COVID-19 pneumonia (n = 164 each on baricitinib and propensity score matched controls). They were divided into two groups: <70 years old (n = 86) and ≥70 years old (n = 78), receiving a mean total dose of 17.6 ± 10.2 mg baricitinib for a mean 5.9 days of treatment. A few participants were also given tocilizumab, anakinra, and corticosteroids. When using Cox proportional hazard models adjusted for important covariates, patients in the ≥70 age group had a significantly lower 30-day fatality rate with baricitinib (HR 0.21; 95% CI 0.09–0.47; P < 0.001). Despite a higher disease severity in the baricitinib group, similar results were found in those <70 (HR 0.14; 95% CI 0.03–0.64; P = 0.011). This study demonstrated baricitinib’s clinical utility and safety in the important subset of elderly patients.

Thoms et al. [37], in their retrospective longitudinal study in the U.S., observed the impact of short course baricitinib therapy (4 mg daily either as single dose or two divided doses) in 45 COVID-19 positive in-patients in addition to IV remdesivir with a loading dose of 200 mg and 100 mg maintenance dose for 4 days along with dexamethasone 6 mg IV for 10 days. The patients had an average age of 65 years with a predominance of female gender. The average treatment duration was 6 days. Results showed a 4.4% mortality over the first 7 days of admission and 13.3% over the entire duration of hospitalization among patients, with oxygen supplementation in some format required for all participants. There was a reversal in the downward trend of hemoglobin levels post commencement of treatment along with CRP, D-dimer, and ferritin, and along with increased platelet counts. The Adaptive COVID-19 Treatment Trial—Clinical Status (ACTT-CS) scores also showed a significant statistical improvement in response to therapy. Four patients were reported to have experienced a hemodynamic shock requiring a vasopressor.

Gutierrez et al. [38] conducted a case control study in New York city consisting of 139 COVID patients, and compared the effect of dexamethasone 6 mg OD with remdesivir 200 mg IV followed by 100 mg daily IV for 10 days (Standard of Care, SOC) and a combination of baricitinib 4 mg OD with remdesivir for 10 days. The SOC group consisted of 51 individuals serving as controls, and 88 patients who received SOC plus baricitinib were considered as cases. The groups displayed similar baseline characteristics. Thirty-three patients received mechanical ventilation overall, of which 14 were in standard therapy (27.45%) and 19 (21.59%) in the baricitinib group. There was an increased need for antibiotics in the controls over the cases (76.5 vs 53.4%, P = 0.007). The individuals who received baricitinib displayed a reduction in median time to recovery by 3 days compared to the control group, but this difference was not statistically significant. The study also performed stratification based on oxygen requirement, and those with low flow oxygen (OS5) and high flow nasal cannula (OS6) both showed significant reductions in median time to recovery (OS 5: 3 days lesser, rate ratio of recovery of 2.95 in 95% CI, 1.03–8.42, P = 0.04, OS 6: 2 days lesser, Rate Ratio 1.80, 95% CI, 1.09–2.98, P = 0.02).

Tanimoto et al. [39], in their propensity score-matched retrospective cohort study, recruited 229 patients in Hiroshima, Japan, to study the effect of baricitinib in comparison to standard of care on 30 and 60 day survival after admission. Other drugs such as favipiravir, corticosteroids, remdesivir, heparin and tocilizumab were also administered to both groups in similar proportions. A logistic regression model was used to designate two propensity matched cohorts of similar age, sex, severity of disease, BMI, comorbidities, and usage of other drugs. The 30-day survival was significantly higher in the baricitinib propensity score-matched cohort (P = 0.03) whereas there was no significant statistical difference in the 60-day survival. Other outcomes of significance were the need for oxygen therapy in the cohorts where a smaller proportion of individuals in the baricitinib group required oxygen (P < 0.001), and a better outcome at discharge in the baricitinib cohort (P = 0.02). There were no significant differences in the adverse events reported in either group.

Yasuda et al. [40] carried out a single centre retrospective study in Osaka, Japan, where they recruited 108 COVID-19 positive patients. Of them, 16 were treated with dexamethasone only (6 mg daily for 10 days), 2 with standard of care, 30 received the combination of 3 drugs (baricitinib 4 mg or 2 mg for 2 weeks or until no more requirement of oxygen therapy with dexamethasone and remdesivir IV with a loading dose of 200 mg and maintenance dose of 100 mg for 5 days), and 60 with only remdesivir and dexamethasone (controls). At baseline, the baricitinib group had significantly younger individuals (P = 0.006), as well as significantly more severe chest X ray abnormalities (P = 0.0248). Patients in the baricitinib group experienced a faster recovery (3 days less, P < 0.001), with a recovery rate of 90% in the baricitinib group and 63.3% in the control group (P = 0.011). All-cause mortality was also significantly lower in baricitinib (6.7 vs 28.3%, P = 0.0263), with a ratio of recovery at 5.26 (95% CI, 1.99–13.9, P < 0.001). Among the 39 patients receiving oral anticoagulants, the recovery rate was 90 vs 44.4% (baricitinib vs control, P = 0.0089). The study identified age and anticoagulants to be significantly associated with recovery time. Baricitinib showed an accelerated recovery in patients aged 65 years or above (P = 0.039) but no such difference in those below 65 years of age (P = 0.307).

So et al. [41], in their retrospective cohort study, included 100 COVID-19 diagnosed patients in Southern California, U.S., to compare the efficacy of baricitinib in comparison to other treatment regimens used in the hospital. Those who received baricitinib were less likely to be in the intensive care units as compared to those who did not (45.8% of ICU patients took baricitinib and 56.2% did not, P = 0.017). Kaplan–Meier analysis revealed that patients who received baricitinib have an increased survival as compared to those who did not (26 days, 95% CI 11.7–40.3, vs 14 days, 95% CI 12.4–15.6, P = 0.045). The study also revealed that 33% of patients on baricitinib showed an elevation of liver enzymes post commencement of drug administration but not severe enough to indicate an abrupt discontinuation of treatment and returned to normal after stopping treatment.

Bryushkova et al. [42], in their retrospective cohort study on 154 COVID-19 patients in Moscow, Russia, compared the effects of three drugs namely baricitinib, netakimab and tocilizumab along with the standard of care including hydroxychloroquine (400 mg BD on day 1 and 200 mg BD on days 5–10), azithromycin (500 mg once per day for 5 days), lopinavir–ritonavir (400/100 mg twice per day for 14 days), and low molecular-weight heparin according to indications. The cohorts consisted of 38 individuals who received baricitinib, 48 received netakimab, 34 received tocilizumab and 34 received only the standard of care, and showed significant baseline differences in neutrophil lymphocyte ratio, lactate dehydrogenase (LDH) and NEWS-2 median score among the cohorts. The CRP and LDH levels showed significant reduction in the tocilizumab group and netakimab group but not in baricitinib and SOC after 72 h; reduced in all groups majorly after 120 h. In similar trends, NEWS-2 score improved in 72 h for tocilizumab and netakimab, and in 120 h for tocilizumab, netakimab and baricitinib. The NLR showed a decrease in the baricitinib group but an improvement in netakimab and tocilizumab groups. In comparison to the baricitinib (31.6%) and SOC (23.5%) groups, the proportion of patients who were discharged 5–7 days after the initiation of therapy was greater in the tocilizumab (44.1%) and netakimab (41.7%) groups. The SOC (9%) and baricitinib (3%) groups had greater mortality rates than tocilizumab (0%) and netakimab (0%) groups.

A retrospective cohort study conducted by Tziolos et al. [43] in Athens, Greece assessed the role of baricitinib (4 mg/day for 14 days or discharge) as an add-on therapy to the standard of care in 369 hospitalized patients with COVID-19 which included dexamethasone (6 mg/day), remdesivir (200 mg/day on day 1 followed by 100 mg/day for subsequent days) and low molecular weight heparin for thromboprophylaxis apart from antimicrobials as per the physicians discretion. The standard of care regimen was provided to 47.7% of the patients and the remaining received baricitinib as an add-on. At baseline, patients in the standard of care group showed increase comorbidities of hypertension, CVD, heart failure, end stage renal disease (ESRD) and active neoplastic or inflammatory disease and those in the baricitinib group were significantly younger (61.6 ± 12.7 vs 69.1 ± 13.5 years, P < 0.001), received remdesivir more often, and an intermediate dose of LMWH and oxygen by high flow nasal cannula (P < 0.05 for both). The baricitinib combination showed a reduced overall mortality (14.7 vs 26.6%, P = 0.005), achieved a lower composite outcome of ICU admission and all-cause mortality (22.3 vs 36.9%, P = 0.002). When subgroup analysis as per ARDS severity was performed, the mortality, and the composite outcome was statistically significant in favor of the combination group for both subgroups. No significant difference in thromboembolic events were seen in either group.

Hasan et al. [44], in their third published study on use of baricitinib in COVID-19, conducted a prospective cohort study in 103 adult patients who were divided into two groups by simple random sampling as 49 participants in group A (receiving baricitinib 4 mg OD PO for 14 days plus secukinumab two doses 48 h apart 300 mg IV) and 54 participants in group B (baricitinib plus secukinumab single dose in similar doses as A plus tocilizumab 8 mg/Kg single dose IV). All patients received dexamethasone 0.25 mg/Kg in divided doses, remdesivir 200 mg IV loading plus 100 mg maintenance for 10 days IV, LMWH, and antimicrobials for infections. The number of male patients in both groups was higher and the median time of hospitalization was 7 and 9 days in group A and B respectively. Group B showed a quicker median day to achieve normal SpO₂, lower requirement of ICU and mechanical ventilation (N = 54) 28.6%/16.7% (P = 004); 18.4%/11.1% (P = 038), lower risk of ARDS (OR = 0.43, P = 0.045) and a lower 60 day all-cause mortality 14.29% (N 1/4 49) vs 7.41% (N 1/4 54); OR 0.35 (0.08–1.44), 95% CI). However, group B also showed a higher rate of adverse events.

2.2 Interventional studies

Marconi et al. [45] published the findings of the phase 3 COV BARRIER trial, a randomized placebo-controlled double blind study that enrolled adult hospitalized symptomatic COVID-19 patients who required low flow oxygen and had atleast one elevated inflammatory marker (CRP, D-dimer, LDH, ferritin). This trial was carried out at 101 sites in 12 countries across South and North America, Europe, and Asia. It enrolled a total of 1525 participants who received either oral baricitinib 4 mg (n = 764) or placebo once daily for 14 days (1:1), in addition to standard of care (SOC), which included low dose systemic corticosteroids (79.3%, mostly dexamethasone), remdesivir (18.9%), and anticoagulants. All patients were monitored for disease progression and mortality until day 28 and then again until day 60. No significant difference was seen in the proportion of patients who progressed (requiring high flow oxygen, non-invasive/invasive ventilation, or death) after treatment with baricitinib vs placebo [27.8 vs 30.5%; OR 0.85, 95% CI 0.67–1.08; P = 0.18] on day 28. However, in a prespecified secondary endpoint analysis, baricitinib significantly reduced the all-cause mortality on day 28 compared to placebo (8.1 vs 13.1%, HR 0.57, 95% CI 0.41–0.78, P = 0.0018). On day 60 also, mortality was reduced significantly (HR 0.62, 95% CI 0.47–0.83, P = 0.005). The survival benefits were more pronounced in patients with more severe disease at baseline. There were no appreciable differences in treatment-emergent adverse events (44.5 vs 44.4%), serious adverse events (14.7 vs 18%), serious infections, or venous thromboembolic events between baricitinib vs placebo. The trial showed that the combination of baricitinib and corticosteroid therapy significantly lowers mortality among patients of moderate—severe COVID-19 who are hospitalized.

The results of the first stage of the Adaptive COVID-19 Treatment Trial (ACTT-1) demonstrating the efficacy of remdesivir treatment in hospitalized COVID-19 patients with pneumonia were released in May 2020 [46]. In ACTT-2 [47], the efficacy of treatment with remdesivir in combination with baricitinib was compared to remdesivir plus placebo (control) in 1033 hospitalized adults with COVID-19. The combination group patients (n = 515) were given oral baricitinib at a daily dose of 4 mg for 14 days, or until hospital discharge/death along with IV remdesivir in a loading dose of 200 mg on day one, followed by a maintenance dose of 100 mg from day 2 to day 10, or until hospital discharge/death Patients who got remdesivir in combination with baricitinib had quicker recovery than those who received only remdesivir (median 7 vs 8 days; RR for recovery 1.16; 95% CI 1.01–1.32; P = 0.03). The combination group had a faster median time to recovery of 10 days compared to 18 days among patients getting high flow oxygen or non-invasive ventilation (RR 1.51; 95% CI 1.10–2.08). The RR of recovery was 0.88 (95% CI 0.63–1.23), 1.17 (95% CI 0.98–1.39) and 1.08 (95% CI 0.59–1.97) for patients who received no oxygen, supplemental oxygen, and mechanical ventilation respectively. After 28 days, the overall mortality rate was relatively lower in the combination group (5.1 vs 7.8%, HR 0.65; 95% CI 0.39–1.09). Patients who received supplemental oxygen had a relatively lower mortality rate than those who received high flow oxygen (1.9 vs 4.7%; HR 0.40; 95% CI 0.14–1.14 or non-invasive ventilation (7.5 vs 12.9%; HR 0.55; 95% CI 0.22–1.38), but results were not statistically significant. Patients in the combination group recovered in 6 days on an average compared to 8 days in the control group (RR 1.21; 95% CI 1.06–1.39). In the combination group, 40.7% (n = 207) patients experienced grade 3 or 4 adverse events (anemia, hyperglycemia, decreased lymphocyte count, and acute kidney injury), compared to 46.8% (n = 238) patients in the remdesivir group. Among these, a significantly higher proportion of patients experienced serious adverse events in the remdesivir group (21%) compared to the combination group (16%); a difference of −5.0% (95% CI, −9.8 to −0.3; P = 0.03). This trial concluded that baricitinib in combination with remdesivir is superior and safer than remdesivir alone, with fewer serious adverse events. Combination therapy also helps patients recover faster and accelerates improvements in clinical status, especially among those who require high flow oxygen or non-invasive ventilation.

A small interventional study was conducted by Izumo et al. [48] in Tokyo, Japan, on COVID-19 patients with severe or critical disease without renal dysfunction. A total of 44 patients were given a triple combination therapy of oral baricitinib 4 mg (up to 14 days), standard IV remdesivir regimen (up to 10 days), and IV dexamethasone 6 mg (up to 10 days). Overall, the results demonstrated that mortality was low (2.3%), with no need for invasive mechanical breathing in majority of patients (90%). The median length of hospitalization was 11 days whereas ICU stay was 6 days on an average, with a 9-day median recovery time. Adverse events were reported in 34% (15/44) patients. This was the first trial to demonstrate the safety and efficacy of a triple combination of baricitinib, remdesivir and corticosteroids in hospitalized COVID-19 patients. However, its primary weakness was the lack of a comparison group.

Through a non-randomized open label study in Greece, Gavriilidis et al. [49] analyzed the effect of various treatment modalities in the reduction of in-hospital mortality in 78 RT-PCR diagnosed COVID-19 patients. Participants were categorized into four groups: 26 patients received standard of Care (SOC) that included dexamethasone 6–8 mg OD, LMWH, antibiotic prophylaxis and supportive care, 11 patients received SOC and tocilizumab intravenously at a single dose of 8 mg/kg body weight (TOCI), 19 patients received SOC plus anakinra at a dosage of 200 mg BD for 3–6 days followed by 100 mg BD up to 10 days (ANA) and the COMBI group of 22 patients received a combination of tocilizumab, anakinra, dornase alfa (2500 IU/BD for 2 weeks) with budesonide (800 ug/BD) and salbutamol, and baricitinib at 4 mg OD if GFR >60 ml/min or 2 mg OD for 2 weeks. The baseline characteristics of all groups were similar. The SOC group observed 9 deaths (34.6%) and 10 intubations (38.5%) with a mean duration of hospital stay of 19.4 days, the ANA group had 6 deaths and intubations (31.6%) with an average duration of hospital stay of 23.9 days, the TOCI group showed 7 deaths (63.6%) and an average duration of 19.4 days of hospital stay and the COMBI group showed the lowest mortality of 2 deaths (9.1%, P = 0.014), lowest intubation rate (P = 0.013) and the lowest average hospital stay of 15.6 days (P = 0.019). Apart from these outcomes, the COMBI group also showed a prolonged survival (P = 0.003) after a median follow up of 110 days, an increase in ALC count (P = 0.021), and reduction in CRP levels (P = 0.002). Though the study demonstrates a reduction in mortality with the combination therapy including baricitinib, the lack of randomization and unequal group sizes are important limitations.

Wesley et al. [50] have published the results of an exploratory trial following the phase 3 COV-BARRIER trial which was a multicentric (18 centers across Argentina, Brazil, Mexico and the U.S.A.), randomized, double-blinded placebo controlled parallel group trial to compare the effect of baricitinib on all-cause mortality at day 28 and 60, overall improvement of clinical status, duration of hospitalization or time to recovery in COVID-19 patients. This study recruited 101 participants randomized 1:1 into baricitinib 4 mg or 2 mg if GFR < 60, l/min/1.73 m² (n = 51) and placebo (n = 50) for 14 days or up to discharge. All participants received the standard of care which included medications such as corticosteroids, antivirals, vasopressors, and prophylaxis for venous thromboembolic events as per local practice. All participants had at least one underlying comorbid condition. The median duration of treatment exposure was 12 days in the placebo group and 11 in the baricitinib group. The baricitinib group significantly reduced all-cause mortality by day 28 (39% in baricitinib vs 58% in placebo, HR 0.54, 95% CI 0.31–0.94., P = 0.03) with a 46% relative reduction and 19% absolute risk reduction, with a similar significant reduction at day 60 also (23 [45%] events vs 31 [62%]; HR 0.56 [95% CI 0.33–0.97]; P = 0.027; 44% relative reduction; absolute risk reduction 17%). The study revealed no significant differences in the number of ventilator free days or mean duration of hospitalization. Both groups showed a high proportion of treatment-emergent adverse events where 44 of 50 participants (88%) in the baricitinib group and 47 out of 49 (96%) in the placebo group reported at least one event, while 50% in the baricitinib arm and 71% of the placebo arm reported at least one serious adverse event, causing 28 and 35% of the patients to discontinue treatment in the baricitinib and placebo group respectively. There were five (10%) and three (6%) deaths due to adverse events in the baricitinib and placebo arm respectively. Overall, the study supported the results of the COV BARRIER trial by showing consistent results in reducing mortality in critically ill hospitalized patients with COVID-19 for baricitinib compared with placebo (plus standard of care, including corticosteroids), albeit in a small sample size.

Most recently, the results of ACTT-4 have been published (May 2022) [51], in which 1010 hospitalized patients with COVID-19 requiring supplemental oxygen or non-invasive mechanical ventilation were randomized to receive either baricitinib plus remdesivir (51%, n = 503) or dexamethasone plus remdesivir (49%, n = 482) at 67 sites across the world. All patients received remdesivir (≤10 days) and either baricitinib for a maximum of 14 days or dexamethasone for a maximum of 10 days. There was no difference between the two groups in the primary outcome of mechanical ventilation-free survival by day 29 [87.0% in the baricitinib plus remdesivir vs 87.6% in the dexamethasone plus remdesivir group; risk difference 0.6 (95% CI −3.6 to 4.8 and P = 0.91)]. Similar results were seen with odds ratio for improved clinical status at day 15 which was similar between the two groups. Outcomes were statistically similar for mortality at 29 days (2.9 vs 4.7% for baricitinib vs dexamethasone combination groups) or 60 days (6.8 vs 8%). Outcomes were consistently similar among different geographical regions, gender, race, and ethnicity as well. The safety analysis showed that 4% of patients in the baricitinib plus remdesivir group and 10% of patients in the dexamethasone plus remdesivir group experienced at least one treatment-related adverse event (risk difference: 60%; P = 000041). So, when combined with remdesivir, baricitinib is a significantly safer treatment option than dexamethasone, with severe or life-threatening grade 3 or 4 adverse events occurring in 28% of patients in the baricitinib plus remdesivir group compared to 36% of patients in the dexamethasone plus remdesivir group (P = 0012).

3. Summary of evidence

The COVID-19 pandemic has presented extremely challenging conditions for clinicians across the globe due to its infectivity, morbidity and mortality, characterized by the spread of lethal pneumonia in up to 15–20% of the cases [11]. The current therapeutic strategies for hospitalized patients are focused on the use of anti-inflammatory agents like corticosteroids, IL-6 inhibitors, antivirals agents like remdesivir, molnupiravir or a few monoclonal antibodies in combination with standard supportive care. There is still a need for more therapeutic alternatives for the hospitalized COVID-19 patients who are at risk of developing life-threatening complications such as ARDS and multiorgan dysfunction. In this context, the US FDA granted a EUA in November 2020 for baricitinib, an oral Janus Kinase inhibitor that inhibits cytokine release, to be used at a dose of 4 mg once daily in hospitalized adult patients with moderate to severe COVID-19 pneumonia in combination with remdesivir.. The FDA revised this EUA in July 2021 to allow the use of baricitinib alone (without remdesivir) for the treatment of COVID-19 in hospitalized adults and children ≥2 years of age who require supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO [6]. Finally, in May 2022, the FDA has given full approval to baricitinib to be used for hospitalized COVID-19 adult patients as per the same conditions laid out in the EUA, while the use in children is still under the EUA.

In this chapter, we have attempted to meticulously unearth the evidence regarding the use of baricitinib as an anti-inflammatory drug for the treatment of COVID-19. Data from published observational and interventional studies reveal promising immunomodulatory and anti-inflammatory effects of baricitinib as monotherapy or in combination with other drugs in improving clinical and biochemical parameters, and other relevant disease markers in patients hospitalized with moderate to severe COVID-19. A lot of the initial evidence has come from observational studies on different drugs being tried in patients admitted in hospitals due to COVID-19, rather than the conventional gold standard RCTs; the published observational studies of different types outnumber the published interventional trials. Though the quality of evidence from observational studies (or NRSIs) may be relatively lower, the sheer number of parallel conclusions, supported by the evidence from the limited RCTs point to substantial benefits of using baricitinib in the treatment of COVID-19.

Among the multiple studies attempted to investigate clinical benefits of baricitinib in hospitalized COVID patients, some have compared the efficacy of baricitinib alone to the standard of care (antivirals, immunomodulators, protease inhibitors etc.), with different dosing regimens or loading dosages, and others have studied baricitinib as a part of a multi-drug pharmacological treatment regimens with different comparators. Despite the considerable heterogeneity in terms of study populations, sites, study designs, treatment regimens, significant study limitations, as well as the differences in summary measures, the evidence available is largely in favor of utility of the drug in COVID-19 in improving key clinical outcomes and/or biochemical or laboratory parameters, supported by an acceptable/satisfactory safety profile.

Among the 24 observational studies which include 16 retrospective cohort, 5 prospective cohort, and 3 case control studies, baricitinib has been compared to other drugs such as tocilizumab [28], used in various doses [23, 34], and therapeutic effects of loading dose changes or combination with other drugs have been assessed [24, 25, 26, 27, 28, 29, 34] including IL-6 inhibitors, steroids and LMWHs like enoxaparin. The majority of the findings favor baricitinib due to its benefits in improving COVID-19 in terms of clinical, biochemical, and other disease characteristics. However, baricitinib treatment did not result in a substantial reduction in mortality in some of the studies [24, 27, 28]. Few studies also revealed an increased incidence of adverse reactions such as mouth sores [23], infections [29], and thrombocytopenia [23, 28] with baricitinib treatment. But no study showed an inferiority of baricitinib in efficacy. Major drawbacks stem from the observational nature which introduces numerous methodological limitations and flaws along with biases, and the short duration of treatment and/or follow up periods along with limited sample sizes. Key concerns in these studies include selection bias and confounding errors resulting from lack of randomization which were addressed to some extent in few studies; most could not.. Among the observational studies, 11 received a “fair” score and 13 received a “good” score when evaluated using the study quality evaluation tool [22], validated for evaluating observational research quality.

The findings of three large randomized controlled trials (RCTs) have been published. ACTT-2 results led to the EUA for baricitinib (with remdesivir) in hospitalized COVID-19 patients. The trial found that baricitinib + remdesivir (and standard of care) significantly reduced median time of recovery and mortality rate compared to control group (5.1 vs 7.8%) [47]. A similar reduction in mortality by 38.2% was also reported by Marconi et al.. in the experimental arm of oral baricitinib 4 mg plus standard treatment compared to controls who received placebo in addition to standard treatment (34). There was also improvement in participants’ requirement for oxygen therapy especially in those who received high flow oxygen or for non-invasive ventilation. Encouragingly, fewer episodes of severe adverse events were seen in participants belonging to the baricitinib group compared to the standard of care. The ACTT-4 trial compared the combination of remdesivir with baricitinib or dexamethasone in hospitalized patients with COVID-19 requiring supplemental oxygen or non-invasive ventilation and showed that both combinations resulted in similar efficacy outcomes like mechanical ventilation-free survival by day 29, mortality and clinical status improvement. However, the baricitinib combination was found to be safer as dexamethasone was associated with significantly higher proportion of treatment-related adverse events, as well as severe or life-threatening adverse events [51]. The risk of bias was assessed using the risk of bias (ROB 2.0) tool [21]. All three RCTs were graded as having overall ‘low risk of bias’. Besides these RCTs, results of three other interventional trials also support similar findings for the clinical utility of baricitinib among different COVID-19 patient populations.

As results from more ongoing RCTs get published, the evidence is likely to grow stronger.

3.1 Ongoing clinical trials

In addition to the published data, it is important to review the key ongoing registered clinical trials on use of baricitinib in treatment of COVID-19 to gain an understanding of the type of evidence expected in the future. There are currently multiple (>10) ongoing clinical trials evaluating the safety and efficacy of oral baricitinib alone or in combination for treatment of COVID-19 patients. Table 2 provides key features of some of these registered trials, usually multicentric RCTs, listed on global clinical trial registries whose results have not been declared or published. One trial each is in phase III and IV, one is in phase II/III, four are in phase II, and one is in phase Ib/II.

S. N.	Trial identifierand phase	Trial setting -Patient population	Last updated status	Official title	Sponsor/lead institution, Country
1	NCT-04390464 [52]; Phase- IV	Hospitalized	Recruiting status unknown	mulTi-Arm Therapeutic study in pre-ICu patients admitted with Covid-19—Repurposed Drugs (TACTIC-R):	Cambridge University Hospitals NHS Foundation Trust; United Kingdom
2	NCT-04832880 [53, 54]; Phase- III	Hospitalized	Not yet recruiting	Factorial, Multicentric, Randomized Clinical Trial of Remdesivir and Immunotherapy in Combination with Dexamethasone for Moderate COVID-19 (the AMMURAVID Trial)	ASST Fatebenefratelli Sacco; Italy
3	NCT-04320277 [55]; Phase- II/III	Hospitalized	Recruiting status unknown	Baricitinib Combined with Antiviral Therapy in Symptomatic Patients Infected by COVID-19: an Open-label, Pilot Study (BARI-COVID)	Hospital of Prato; Italy
4	NCT-04399798 [56]; Phase- II	Hospitalized	Recruiting status unknown	Baricitinib for coRona Virus pnEumonia (COVID-19): a THerapeutic Trial (BREATH): A proof-of Concept Study of the Use of Janus Kinase 1 and 2 Inhibitor, Baricitinib, in the Treatment of COVID-19-related Pneumonia:	IRCCS Policlinico S. Matteo; Italy
5	NCT-04393051 [57]; Phase- II	Hospitalized	Recruiting status unknown	BARICIVID-19 STUDY: Multicenter, Randomized, Phase IIa Clinical Trial Evaluating Efficacy and Tolerability of Baricitinib as add-on Treatment of In-patients With COVID-19 Compared to Standard Therapy	Azienda Ospedaliero, Universitaria Pisana; Italy
6	NCT-04346147 [58]; Phase- II	Hospitalized	Active, not recruiting	Clinical Trial to Evaluate Efficacy of 3 Types of Treatment in Patients with Pneumonia by COVID-19 (Covid19COVINIB): Prospective, Phase II, Randomized, Open-label, Parallel Group Study to Evaluate the Efficacy of Baricitinib, Imatinib or Supportive Treatment in Patients with SARS Cov2 Pneumonia	Hospital Universitario de Fuenlabrada; Spain
7	NCT-04321993 [59]; Phase- II	Hospitalized	Recruiting	Treatment of Moderate to Severe Coronavirus Disease (COVID-19) in Hospitalized Patients	Lisa Barrett, Nova Scotia Health Authority; Canada
8	20-0356 [60]; Phase- Ib/II	Hospitalized	Recruiting	A Phase I/II Clinical Trial to evaluate the efficacy of baricitinib to prevent respiratory insufficiency progression in onco-hematological patients affected with COVID19: A structured summary of a study protocol for a randomized controlled trial	Institutional Crowd Funding; Spain

Table 2.

Registered on-going clinical trials to evaluate the efficacy and safety of baricitinib in COVID-19 patients.

Among the late phase trials, the TACTIC-R is a phase IV multi-arm platform trial proposed to be conducted at multiple centers across U.K. [52, 61]. It is a parallel 3-arm (1:1:1) randomized trial evaluating baricitinib 4 mg OD and ravulizumab as a potential treatment for COVID-19 among hospitalized patients in comparison to standard treatment alone over a 14-day treatment period with follow-ups at day 28 and day 90 post-discharge. The safety and efficacy of different treatment arms will be assessed on a 7-point pulmonary scale, death, invasive mechanical ventilation, non-invasive ventilation or high flow oxygen, low flow oxygen, no oxygen, and status at discharge.

The phase III AMMURAVID RCT is proposed to be conducted across 21 study locations in Italy [53, 54] and is expected to enroll approximately 4000 participants with hospitalized COVID-19. The trial aims at evaluating the efficacy of remdesivir, baricitinib (4 mg), and remdesivir plus baricitinib vs the control arm (IV dexamethasone 6 mg × 10 days). The primary objective is minimization of progression of severe respiratory failure in COVID-19, as well as effect on immune response markers.

The BARI-COVID is an open-label, non-randomized trial [55] to investigate the efficacy of baric prospective cohort, and 3 case control studies itinib in combination with antiviral treatments in hospitalized patients with mild to moderate COVID-19. It is expected to enroll 200 participants in Italy. The experimental arm participants will be given 4 mg baricitinib orally in combination with lopinavir/ritonavir once daily. Participants in the control arm will be given antiviral treatment or hydroxychloroquine for 2 weeks. Comparison of proportion of participants requiring ICU hospitalization and assessment of CRP, IL-6, and TNF levels are the primary endpoints.

BREATH [56], a pilot treatment trial in Italy, is an open label study to evaluate the safety and efficacy of oral baricitinib 4 mg for 7 days in hospitalized patients with COVID-19 pneumonia. There are no comparator or control arms. Measurement of oxygenation impairment (PaO₂/FiO₂) and mortality on day 8 are endpoints. On 15th day, assessment of the participants will be done for median SpO₂, number, types and severity of adverse events, biological assessments (level of various interleukins, TNF alpha, interferon gamma, viral load etc.) and rate of mortality.

Baricivid-19 [57], a phase II multicenter RCT in Italy, enrolled 126 patients (current status unclear) to compare baricitinib at a dose of 4 mg orally for 14 days (plus standard of care) against standard of care in hospitalized patients with COVID-19 pneumonia. The primary outcome is reduction in invasive ventilation at week 1 and 2, and there are multiple secondary endpoints like mortality (at 14, 28 days), time to invasive mechanical ventilation, length of hospital/ICU stays, toxicity.

Covid19COVINIB [58], an open label phase II RCT is proposed to enroll 165 patients to compare baricitinib and imatinib to supportive care therapy in patients with early COVID-19 pneumonia. The participants are designated to receive 400 mg OD of oral imatinib and 4 mg OD of oral baricitinib. Clinical improvement by at least two points on a 7-point ordinal scale is the primary end point, while safety (number of major side effects and early treatment cessation) and tolerability after 30 days are the secondary end points.

Another phase II trial is proposed in Canada, a non-randomized study on 800 adult patients hospitalized with moderate–severe COVID-19. Participants are to receive 2 mg oral baricitinib once day for 10 days, and the control arm would receive normal treatment. The primary objective of is to assess how long it takes for individuals to show clinical improvements in respiratory rate, fever, normal pulmonary function, and oxygen saturation.

The primary goal of the BARCOVID19 [60] trial in Spain is to ascertain the tolerability of baricitinib in oncohematological patients who have COVID-19 in phase I. It is anticipated that 136 participants will enroll in the trial. The aim of phase II of this trial is to establish if baricitinib (2–4 mg) reduces the inflammatory response caused by COVID-19, and prevents the development of severe ARDS in oncohematological patients as compared to other therapies given at the discretion of the investigator. Remdesivir or dexamethasone administration will be allowed if specific indications exist.

These ongoing clinical trials include different phases, randomized/non-randomized, single/multicentric studies in geographically diverse locations, with different doses of baricitinib. Indications include the different disease severities, and assessments are at varying timepoints or intervals for a plethora of COVID-19 related outcomes. However, the recruiting status of most of these trials is uncertain. Nevertheless, if evidence comes from these studies, it can be expected to be robust. The TACTIC-R platform trial in the UK is especially interesting, being a phase IV study, as baricitinib is still under review for approval of use in COVID-19 by the EMA [9], and its approval for COVID-19 in UK could not be found. The NICE recently approved the medication for moderate to severe atopic dermatitis in March 2021 [62]. Current knowledge about the Omicron variant of the SARS-CoV-2 virus is relatively limited in terms of its transmissibility, severity of disease as well as effectiveness of currently available vaccines and treatments including the newer treatments [63]. It has raised further question marks over the adequacy of treatment options available for management of COVID-19, for all grades of disease, and the apprehension towards new waves of the pandemic persists.

3.2 Current status of recommendation and limitations

In terms of the current status of recommendations for baricitinib in COVID-19 treatment, the US NIH COVID-19 treatment guidelines (February 2022) include baricitinib as an add-on treatment option to corticosteroids and/or remdesivir for hospitalized adult patients requiring oxygen or non-invasive ventilation, with the strength of recommendation being weak in patients requiring supplemental oxygen, and moderate in patients needing high flow oxygen or non-invasive ventilation [64]. It is also recommended that baricitinib not be used in combination with tocilizumab as both are potent immunosuppressants, leading to increased risk of infection. The WHO therapeutics and COVID-19 living guidelines have given strong recommendation (since January 2022) for the use of baricitinib as an alternative to IL-6 inhibitors in combination with corticosteroids in patients with severe or critical COVID-19, which includes hospitalized patients with SpO₂ < 90%, signs of pneumonia, signs of severe respiratory distress, ARDS, sepsis /septic shock or requiring mechanical ventilation. However, baricitinib does not find a place as of now in the treatment recommendations/guidelines for COVID-19 from the UK-NICE or in countries like India, even though the drug has actually received an emergency approval in India [65, 66].

The qualitative synthesis of evidence that has been described in this chapter is quite comprehensive. But despite using the comprehensive WHO database of COVID research, a collection of most of the recognized electronic databases globally, for the literature search, there may still have been omissions especially from areas like gray or non-published literature. Majority of the studies finally selected were observational- mostly retrospective cohort, whereas only six published interventional studies could be found at the time of writing. In the hierarchy of evidence, observational studies are considered a relatively lower level of evidence. Non-uniformity of studies in terms of participants, outcomes, confounders etc. affects the external validity in the final analyses. As most of these studies are hospital based, a Berksonian bias is also likely to be present. The results of multiple clinical trials are not yet available as these are still ongoing or their current status is unknown.

4. Conclusion

Multiple observational and interventional studies published till date show that baricitinib used alone or in combination with other drugs, as an add-on to standard of care, reduces the mortality and producessignificant clinical improvements in patients hospitalized with severe to moderate COVID-19, particularly those requiring high flow oxygen or ventilation. Approval of the drug by the FDA for treatment of COVID-19 among hospitalized adults, as well as the strong recommendation by the WHO for its use as an add-on alternative option to be used in combination with corticosteroids, accurately justifies its current status as an established therapeutic approach for COVID-19.

Conflict of interest

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