Characterization of the cytokine storm reflects hyperinflammatory endothelial dysfunction in COVID-19.

BACKGROUND: Physicians treating patients with coronavirus disease 2019 (COVID-19) increasingly believe that the hyperinflammatory acute stage of COVID-19 results in a cytokine storm. The circulating biomarkers seen across the spectrum of COVID-19 have not been characterized compared with healthy controls, but such analyses are likely to yield insights into the pursuit of interventions that adequately reduce the burden of these cytokine storms. OBJECTIVE: To identify and characterize the host inflammatory response to severe acute respiratory syndrome coronavirus 2 infection, we assessed levels of proteins related to immune responses and cardiovascular disease in patients stratified as mild, moderate, and severe versus matched healthy controls. METHODS: Blood samples from adult patients hospitalized with COVID-19 were analyzed using high-throughput and ultrasensitive proteomic platforms and compared with age- and sex-matched healthy controls to provide insights into differential regulation of 185 markers. RESULTS: Results indicate a dominant hyperinflammatory milieu in the circulation and vascular endothelial damage markers within patients with COVID-19, and strong biomarker association with patient response as measured by Ordinal Scale. As patients progress, we observe statistically significant dysregulation of IFN-γ, IL-1RA, IL-6, IL-10, IL-19, monocyte chemoattractant protein (MCP)-1, MCP-2, MCP-3, CXCL9, CXCL10, CXCL5, ENRAGE, and poly (ADP-ribose) polymerase 1. Furthermore, in a limited series of patients who were sampled frequently, confirming reliability and reproducibility of our assays, we demonstrate that intervention with baricitinib attenuates these circulating biomarkers associated with the cytokine storm. CONCLUSIONS: These wide-ranging circulating biomarkers show an association with increased disease severity and may help stratify patients and selection of therapeutic options. They also provide insights into mechanisms of severe acute respiratory syndrome coronavirus 2 pathogenesis and the host response.

Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis.

BACKGROUND: Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid arthritis. METHODS: We conducted a 52-week, phase 3, double-blind, placebo- and active-controlled trial in which 1307 patients with active rheumatoid arthritis who were receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an anti-tumor necrosis factor α monoclonal antibody) every other week. End-point measures evaluated after adjustment for multiplicity included 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), the Disease Activity Score for 28 joints (DAS28), the Health Assessment Questionnaire-Disability Index, and the Simplified Disease Activity Index at week 12, as well as radiographic progression of joint damage as measured by the van der Heijde modification of the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating greater structural joint damage) at week 24. RESULTS: More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the mTSS at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P=0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol. CONCLUSIONS: In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358 .).

Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Patients with systemic lupus erythematosus have substantial unmet medical need. Baricitinib is an oral selective Janus kinase (JAK)1 and JAK2 inhibitor that we hypothesised might have therapeutic benefit in patients with systemic lupus erythematosus. METHODS: In this double-blind, multicentre, randomised, placebo-controlled, 24-week phase 2 study, patients were recruited from 78 centres in 11 countries. Eligible patients were aged 18 years or older, had a diagnosis of systemic lupus erythematosus, and had active disease involving skin or joints. We randomly assigned patients (1:1:1) to receive once-daily baricitinib 2 mg, baricitinib 4 mg, or placebo for 24 weeks. The primary endpoint was the proportion of patients achieving resolution of arthritis or rash at week 24, as defined by Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K). Efficacy and safety analyses included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02708095. FINDINGS: Between March 24, 2016, and April 27, 2017, 314 patients were randomly assigned to receive placebo (n=105), baricitinib 2 mg (n=105), or baricitinib 4 mg (n=104). At week 24, resolution of SLEDAI-2K arthritis or rash was achieved by 70 (67%) of 104 patients receiving baricitinib 4 mg (odds ratio [OR] vs placebo 1·8, 95% CI 1·0-3·3; p=0·0414) and 61 (58%) of 105 patients receiving baricitinib 2 mg (OR 1·3, 0·7-2·3; p=0·39). Adverse events were reported in 68 (65%) patients in the placebo group, 75 (71%) patients in the baricitinib 2 mg group, and 76 (73%) patients in the baricitinib 4 mg group. Serious adverse events were reported in ten (10%) patients receiving baricitinib 4 mg, 11 (10%) receiving baricitinib 2 mg, and five (5%) receiving placebo; no deaths were reported. Serious infections were reported in six (6%) patients with baricitinib 4 mg, two (2%) with baricitinib 2 mg, and one (1%) with placebo. INTERPRETATION: The baricitinib 4 mg dose, but not the 2 mg dose, significantly improved the signs and symptoms of active systemic lupus erythematosus in patients who were not adequately controlled despite standard of care therapy, with a safety profile consistent with previous studies of baricitinib. This study provides the foundation for future phase 3 trials of JAK1/2 inhibition with baricitinib as a new potential oral therapy for systemic lupus erythematosus. FUNDING: Eli Lilly and Company.

Baricitinib in Patients with Refractory Rheumatoid Arthritis.

BACKGROUND: In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose. RESULTS: Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels. CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01721044.).

Clinical outcomes in patients switched from adalimumab to baricitinib due to non-response and/or study design: phase III data in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate clinical outcomes in patients who changed treatment from adalimumab to baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, during a phase III programme. METHODS: In phase III RA-BEAM, patients were randomised 3:3:2 to placebo, baricitinib 4 mg once daily, or adalimumab 40 mg biweekly. At week 16 or subsequent visits, non-responders were rescued to open-label baricitinib 4 mg. At week 52, patients could enter a long-term extension (LTE) and continue on baricitinib or switch from adalimumab to baricitinib 4 mg with no adalimumab washout period. Percentage of patients achieving low disease activity and remission were assessed, along with physical function, patient's assessment of pain, and safety. RESULTS: Thirty-five (7%) baricitinib-treated and 40 (12%) adalimumab-treated patients were rescued to baricitinib in RA-BEAM; 78% (381/487) of baricitinib-treated and 72% (238/330) of adalimumab-treated patients who were not rescued in RA-BEAM, entered the LTE and continued/were switched to baricitinib. In both baricitinib-rescued and adalimumab-rescued patients, there were significant improvements in all measures up to 12 weeks after rescue compared with the time of rescue. Patients who switched from adalimumab to baricitinib showed improvements in disease control through 12 weeks in the LTE. Exposure-adjusted incidence rates for treatment-emergent adverse events (TEAEs) and infections, including serious events, were similar for patients who switched from adalimumab to baricitinib and those who continued on baricitinib. CONCLUSIONS: Switching from adalimumab to baricitinib (without adalimumab washout) was associated with improvements in disease control, physical function and pain during the initial 12 weeks postswitch, without an increase in TEAEs, serious adverse events or infections. TRIAL REGISTRATION NUMBERS: NCT01710358, NCT01885078.

Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies.

OBJECTIVES: Lipid profiles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modified by treatment with Janus kinase inhibitors and other disease-modifying antirheumatic drugs. METHODS: Lipid data were analysed from phase II and III studies of 4 mg (n=997) and 2 mg (n=479) oral baricitinib administered once daily in patients with moderate-to-severe active RA. Lipoprotein particle size and number and GlycA were evaluated with nuclear magnetic resonance in one phase III study. The effect of statin therapy on lipid levels was evaluated in patients on statins at baseline and in patients who initiated statins during the study. RESULTS: Treatment with baricitinib was associated with increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, but no significant change in LDL-C:HDL-C ratio. Lipid levels plateaued after 12 weeks of treatment. Baricitinib treatment increased large LDL and decreased small, dense LDL particle numbers and GlycA. Lipid changes from baseline were not significantly different between baseline statin users and non-users. In patients who initiated statin therapy during the study, LDL-C, triglycerides (baricitinib 4 mg only) and apolipoprotein B decreased to pre-baricitinib levels; HDL-C and apolipoprotein A-I levels remained elevated. CONCLUSIONS: Baricitinib was associated with increased LDL-C, HDL-C and triglyceride levels, but did not alter the LDL-C:HDL-C ratio. Evaluation of cardiovascular event rates during long-term treatment is warranted to further characterise these findings and their possible clinical implications. TRIAL REGISTRATION NUMBER: NCT00902486, NCT01469013, NCT01185353, NCT01721044, NCT01721057, NCT01711359, NCT01710358, NCT01885078.

Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study.

BACKGROUND: Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor. METHODS: In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3. RESULTS: More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein. CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage. TRIAL REGISTRATION NUMBER: NCT01721057; Results.

Psychometric properties of the single-item measure, severity of worst tiredness, in patients with moderately to severely active rheumatoid arthritis.

BACKGROUND: To assess the reliability, validity, and responsiveness to treatment change of the single-item measure, Severity of Worst Tiredness, in patients with rheumatoid arthritis (RA). METHODS: Data from two Phase 3, randomized, placebo-controlled (RA-BUILD; and active-controlled [RA-BEAM]), clinical studies of the efficacy of baricitinib in adults with moderately to severely active RA were used. The psychometric properties of the single-item measure, Severity of Worst Tiredness, were assessed, including test-retest reliability, convergent and discriminant validity, known-groups validity, and responsiveness, using other patient- and clinician-reported outcomes frequently assessed in RA patients. RESULTS: Test-retest reliability of the Severity of Worst Tiredness was supported through large intraclass correlation coefficients (0.89 ≤ ICC ≤ 0.91). Moderate-to-large correlations were observed between this patient-reported outcome (PRO) and other related patient- and clinician-reported assessments of RA symptoms and patient functioning, supporting construct validity of the measure (│r│ ≥ 0.41). The instrument also displayed known-groups validity through statistically significant differences between mean values of the Severity of Worst Tiredness defined using other indicators of RA severity. Finally, responsiveness was supported by large and statistically significant differences in change scores from Day 1 to Week 12 for patients comparing responders and nonresponders using the American College of Rheumatology 20 (ACR20) criteria. CONCLUSION: The Severity of Worst Tiredness PRO demonstrated adequate reliability, validity, and responsiveness in clinical trials of adults with moderately to severely active RA and is fit for purpose in this patient population.

Baricitinib decreases anti-dsDNA in patients with systemic lupus erythematosus: results from a phase II double-blind, randomized, placebo-controlled trial.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) have substantial unmet medical need. Baricitinib is a Janus kinase (JAK)1 and 2 inhibitor that was shown to have therapeutic benefit in patients with SLE in a phase II clinical trial. The purpose of this study was to evaluate the median change from baseline in conventional serologic biomarkers in subgroups and the overall population of baricitinib-treated patients with SLE, and the SLE Responder Index-4 (SRI-4) response by normalization of anti-dsDNA. METHODS: Data were assessed from the phase II trial I4V-MC-JAHH (NCT02708095). The median change from baseline in anti-dsDNA, IgG, and other conventional serologic markers was evaluated over time in patients who had elevated levels of markers at baseline, and in all patients for IgG. Median change from baseline for baricitinib treatments were compared with placebo. Among patients who were anti-dsDNA positive at baseline, SRI-4 responder rate was compared for those who stayed positive or achieved normal levels by week 24. RESULTS: Significant decreases of anti-dsDNA antibodies were observed in response to baricitinib 2 mg and 4 mg compared to placebo beginning at weeks 2 (baricitinib 2 mg = - 14.3 IU/mL, placebo = 0.1 IU/mL) and 4 (baricitinib 4 mg = - 17.9 IU/mL, placebo = 0.02 IU/mL), respectively, continuing through week 24 (baricitinib 2 mg = - 29.6 IU/mL, baricitinib 4 mg = - 15.1 IU/mL, placebo=3.0 IU/mL). Significant reductions from baseline of IgG levels were found for baricitinib 4 mg-treated patients compared to placebo at weeks 12 (baricitinib 4 mg = - 0.65 g/L, placebo = 0.09 g/L) and 24 (baricitinib 4 mg = - 0.60 g/L, placebo = - 0.04 g/L). For patients who were anti-dsDNA positive at baseline, no relationship between achieving SRI-4 responder and normalization of anti-dsDNA was observed by week 24. CONCLUSIONS: Baricitinib treatment resulted in a rapid and sustained significant decrease in anti-dsDNA antibodies compared to placebo among those with positive anti-dsDNA antibodies at baseline, as well as a significant decrease in IgG levels in the 4 mg group at weeks 12 and 24. These data suggest that baricitinib may influence B cell activity in SLE. Further studies are needed to evaluate if reductions in anti-dsDNA levels with baricitinib treatment reflect the impact of baricitinib on B cell activity. TRIAL REGISTRATION: NCT02708095 .

Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial.

BACKGROUND: The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in studies of hospitalised adults with COVID-19. COV-BARRIER (NCT04421027) was a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in critically ill hospitalised adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation. METHODS: This exploratory trial followed the study design of COV-BARRIER in a critically ill cohort not included in the main phase 3 trial. The study was conducted across 18 hospitals in Argentina, Brazil, Mexico, and the USA. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection on baseline invasive mechanical ventilation or extracorporeal membrane oxygenation were randomly assigned (1:1) to baricitinib (4 mg) or placebo once daily for up to 14 days in combination with standard of care. Participants, study staff, and investigators were masked to study group assignment. Prespecified endpoints included all-cause mortality through days 28 and 60, number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. The efficacy analysis was done in the intention-to-treat population and the safety analysis was done in the safety population. This trial is registered with ClinicalTrials.gov, NCT04421027. FINDINGS: Between Dec 23, 2020, and April 10, 2021, 101 participants were enrolled into the exploratory trial and assigned to baricitinib (n=51) or placebo (n=50) plus standard of care. Standard of care included baseline systemic corticosteroid use in 87 (86%) participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared with placebo (20 [39%] of 51 participants died in the baricitinib group vs 29 [58%] of 50 in the placebo group; hazard ratio [HR] 0·54 [95% CI 0·31-0·96]; p=0·030; 46% relative reduction; absolute risk reduction 19%). A significant reduction in 60-day mortality was also observed in the baricitinib group compared with the placebo group (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%). In every six baricitinib-treated participants, one additional death was prevented compared with placebo at days 28 and 60. The number of ventilator-free days did not differ significantly between treatment groups (mean 8·1 days [SD 10·2] in the baricitinib group vs 5·5 days [8·4] in the placebo group; p=0·21). The mean duration of hospitalisation in baricitinib-treated participants was not significantly shorter than in placebo-treated participants (23·7 days [SD 7·1] vs 26·1 days [3·9]; p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment groups. INTERPRETATION: In critically ill hospitalised patients with COVID-19 who were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, treatment with baricitinib compared with placebo (in combination with standard of care, including corticosteroids) reduced mortality, which is consistent with the mortality reduction observed in less severely ill patients in the hospitalised primary COV-BARRIER study population. However, this was an exploratory trial with a relatively small sample size; therefore, further phase 3 trials are needed to confirm these findings. FUNDING: Eli Lilly and Company.

Clinical effectiveness and safety of baricitinib for the treatment of juvenile idiopathic arthritis-associated uveitis or chronic anterior antinuclear antibody-positive uveitis: study protocol for an open-label, adalimumab active-controlled phase 3 clinical trial (JUVE-BRIGHT).

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and the most common systemic disorder associated with uveitis in childhood. Uveitis is more common in JIA patients who are antinuclear antibody (ANA)-positive, have an early-onset disease, and have oligoarticular arthritis. JIA-associated uveitis (JIA-uveitis) is typically anterior, chronic, bilateral, nongranulomatous, and asymptomatic. Visual outcomes in JIA-uveitis have improved with current screening and treatment options; however, many patients fail to respond or do not achieve long-lasting remission. Baricitinib, an oral selective Janus kinase (JAK)1 and 2 inhibitor, may impact key cytokines implicated in the pathogenesis of JIA-uveitis or ANA-positive uveitis, representing a potential novel treatment option for disease management. METHODS: The multicenter, phase 3 trial will be conducted using an open-label Bayesian design. The study will enroll at least 20 and up to 40 patients aged 2 to <18 years with active JIA-uveitis or chronic ANA-positive uveitis without systemic features. At least 20 patients who have had an inadequate response or intolerance to methotrexate (MTX-IR), but not biologic disease-modifying antirheumatic drugs (bDMARDs), will be randomized (1:1) to open-label baricitinib or adalimumab. Approximately 20 additional patients who are MTX-IR or bDMARD inadequate responders will receive baricitinib treatment. Patients will be treated with once daily oral baricitinib at a fixed dose by age group (4 mg for patients aged ≥6 to <18 years and 2 mg for patients <6 years) or adalimumab (20 mg for patients weighing <30 kg and 40 mg for patients ≥30 kg) as a subcutaneous injection every 2 weeks. Treatment with stable background conventional synthetic DMARDs, low-dose corticosteroids, and/or nonsteroidal anti-inflammatory drugs is allowed. The primary endpoint is the proportion of patients with response at week 24. Patients may continue treatment for up to 5 years. DISCUSSION: This is the first pediatric clinical trial to assess the clinical effectiveness and safety of a JAK inhibitor in JIA-uveitis or chronic ANA-positive uveitis. A novel Bayesian design is used to assess the efficacy of baricitinib, including an adalimumab reference arm, in this small patient population with unmet medical need. TRIAL REGISTRATION: EudraCT 2019-000119-10 . Registered on January 4, 2019; NCT04088409 . Registered on September 12, 2019.

Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. METHODS: In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027. FINDINGS: Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of -2·7 percentage points (95% CI -7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41-0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47-0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. INTERPRETATION: Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19. FUNDING: Eli Lilly and Company. TRANSLATIONS: For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Evidence for enhanced characterization of cortical bone using novel pQCT shape software.

Bone shape, mass, structural geometry, and material properties determine bone strength. This study describes novel software that uses peripheral quantitative computed tomography (pQCT) images to quantify cortical bone shape and investigates whether the combination of shape-sensitive and manufacturer's software enhances the characterization of tibiae from contrasting populations. Existing tibial pQCT scans (4% and 50% sites) from Gambian (n=38) and British (n=38) women were used. Bone mass, cross-sectional area (CSA), and geometry were determined using manufacturer's software; cross-sectional shape was quantified using shape-sensitive software. At 4% site, Gambian women had lower total bone mineral content (BMC: -15.4%), CSA (-13.4%), and trabecular bone mineral density (BMD: -19%), but higher cortical subcortical BMD (6.1%). At 50% site, Gambian women had lower cortical BMC (-7.6%), cortical CSA (-12.6%), and mean cortical thickness (-15.0%), but higher cortical BMD (4.9%) and endosteal circumference (8.0%). Shape-sensitive software supported the finding that Gambian women had larger tibial endosteal circumference (9.8%), thinner mean cortical thickness (-26.5%) but smaller periosteal circumference (-5.6%). Shape-sensitive software revealed that Gambian women had tibiae with shorter maximum width (-7.6%) and thinner cortices (-22% to -41.2%) and more closely resembled a circle or ellipse. Significant differences remained after adjusting for age, height, and weight. In conclusion, shape-sensitive software enhanced the characterization of tibiae in 2 contrasting groups of women.

Baricitinib-associated changes in global gene expression during a 24-week phase II clinical systemic lupus erythematosus trial implicates a mechanism of action through multiple immune-related pathways.

OBJECTIVE: To characterise the molecular pathways impacted by the pharmacologic effects of the Janus kinase (JAK) 1 and JAK2 inhibitor baricitinib in SLE. METHODS: In a phase II, 24-week, randomised, placebo-controlled, double-blind study (JAHH), RNA was isolated from whole blood in 274 patients and analysed using Affymetrix HTA2.0 array. Serum cytokines were measured using ultrasensitive quantitative assays. RESULTS: Gene expression profiling demonstrated an elevation of STAT1, STAT2 and multiple interferon (IFN) responsive genes at baseline in patients with SLE. Statistical and gene network analyses demonstrated that baricitinib treatment reduced the mRNA expression of functionally interconnected genes involved in SLE including STAT1-target, STAT2-target and STAT4-target genes and multiple IFN responsive genes. At baseline, serum cytokines IFN-α, IFN-γ, interleukin (IL)-12p40 and IL-6 were measurable and elevated above healthy controls. Treatment with baricitinib significantly decreased serum IL-12p40 and IL-6 cytokine levels at week 12, which persisted through week 24. CONCLUSION: Baricitinib treatment induced significant reduction in the RNA expression of a network of genes associated with the JAK/STAT pathway, cytokine signalling and SLE pathogenesis. Baricitinib consistently reduced serum levels of two key cytokines implicated in SLE pathogenesis, IL-12p40 and IL-6.

Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients.

Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful for COVID-19 infection via proposed anti-cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. Collectively, these data support further evaluation of the anti-cytokine and anti-viral activity of baricitinib and support its assessment in randomized trials in hospitalized COVID-19 patients.

Use of daily electronic patient-reported outcome (PRO) diaries in randomized controlled trials for rheumatoid arthritis: rationale and implementation.

BACKGROUND: Rheumatoid arthritis (RA) is associated with significantly diminished health-related quality of life. Patient-reported outcomes (PROs) are considered important in RA; however, some symptoms such as morning joint stiffness (MJS) and fatigue that are considered important by patients are not captured by the American College of Rheumatology "core set" measures for RA trials. The US Food and Drug Administration has endorsed electronic capture of clinical trial data including PROs, and electronic PRO (ePRO) systems may lead to more accurate and complete data capture, improved compliance, and patient acceptance compared with paper-based methods. Our objective was to assess the implementation of ePRO measures of Duration and Severity of MJS, Severity of Worst Tiredness, and Severity of Worst Joint Pain in baricitinib RA-BEAM and RA-BUILD phase 3 randomized clinical trials (RCTs). METHODS: A daily electronic diary (handheld device; Invivodata®, Inc.) was utilized to capture PRO data in the RCTs. Three "reporting window" options were incorporated to accommodate differences in patients' routine daily schedules, and alarms were programmed for each reporting window. Duration of MJS was recorded in "hours and minutes," and Severity of MJS, Worst Tiredness, and Worst Joint Pain were captured on a 0 to 10 rating scale, with a higher score indicating more severe symptoms. The patients and site staff were trained to use the daily electronic diary. RESULTS: Patients with moderately to severely active RA used the daily electronic diary in the RA-BEAM study (N = 1305) and RA-BUILD study (N = 684). The average compliance, calculated as total days completed by patients compared with total days expected to complete the diary, through Week 12 was high (RA-BEAM 94% patients; RA-BUILD 93% patients), potentially attributable to appropriate training, clarity of instructions, simple user interface, and electronic device design. Identified process challenges included non-timely issuance of the device, low battery, inadequate training of patients before data collection, inappropriate diary set-up, and first response entry 1 day after the baseline visit. CONCLUSIONS: High compliance rates support the use of the daily electronic PRO diary in large RCTs. Despite the anticipated issues, the daily electronic diary is expected to reduce recall bias and improve the quality of PRO data collection. TRIAL REGISTRATION: RA-BEAM ( NCT01710358 ) and RA-BUILD ( NCT01721057 ).

Correction to: Use of daily electronic patient-reported outcome (PRO) diaries in randomized controlled trials for rheumatoid arthritis: rationale and implementation.

After publication of the original article [1], the authors have notified us of an error in language used in the text.

Toward Accelerated Authorization and Access to New Medicines for Juvenile Idiopathic Arthritis.

A meeting was organized to bring together multiple stakeholders involved in the testing and authorization of new medications for juvenile idiopathic arthritis (JIA) to discuss current issues surrounding clinical trials and access to new medications for children and adolescents with JIA. The Childhood Arthritis and Rheumatology Research Alliance invited representatives of regulatory agencies (Food and Drug Administration and European Medicines Agency), and major pharmaceutical companies with JIA-approved products or products in development, patient and parent representatives, representatives of an advocacy organization (Arthritis Foundation), and pediatric rheumatology clinicians/investigators to a 1-day meeting in April 2018. The participants engaged in discussion regarding issues in clinical trials. As the pharmacologic options to treat inflammatory arthritis rapidly expand, registration trial designs to test medications in JIA patients must adapt. Many methodologies successfully used in the recent past are no longer feasible. The pool of patients meeting entry criteria who are willing to participate is shrinking while the number of medications to be tested is growing. Suggested solutions included proposing innovative clinical trial methods to regulatory agencies, as well as open discussions among stakeholders. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critical. Approaches should include open dialog between regulatory agencies, pharmaceutical companies, and other stakeholders to develop and implement novel study designs, including patient and clinician perspectives to define meaningful trial outcomes, and changing existing study plans.

Characterization and Changes of Lymphocyte Subsets in Baricitinib-Treated Patients With Rheumatoid Arthritis: An Integrated Analysis.

OBJECTIVE: Baricitinib is an orally administered inhibitor of JAK1 and JAK2 that has been shown to be effective in treating rheumatoid arthritis (RA). This study was undertaken to analyze changes in lymphocyte cell subsets during baricitinib treatment and to correlate these changes with clinical outcomes. METHODS: An integrated analysis was conducted by pooling data from 3 completed phase III trials comparing placebo with baricitinib treatment (RA-BEAM, RA-BUILD, and RA-BEACON) and 1 ongoing long-term extension study (RA-BEYOND) in patients with active RA (n = 2,186). RESULTS: Baricitinib treatment was associated with an early transient increase in total lymphocyte count at week 4, which returned to baseline by week 12. Transient changes within normal reference ranges in T cells and subsets were observed with baricitinib treatment, up to week 104. B cells and relevant subpopulations increased after 4 weeks of baricitinib treatment, with no further increases noted through 104 weeks of treatment. Natural killer (NK) cells temporarily increased after 4 weeks of baricitinib treatment, before decreasing below baseline levels and then stabilizing over time. With baricitinib treatment, few correlations were observed between changes in lymphocyte subsets and clinical end points, and most correlations were also observed within the placebo group. A modest potential association between low NK cell numbers and treatment-emergent infections was observed in the baricitinib 4 mg/day treatment group, but not for serious infections or herpes zoster. CONCLUSION: Overall, these findings demonstrate that changes in lymphocyte subsets were largely within normal reference ranges across the baricitinib phase III RA clinical program and were not associated with increased risk of serious infections.