Mirikizumab, a humanized anti-interleukin-23p19 monoclonal antibody, is approved for the treatment of moderate-to-severe ulcerative colitis (UC) and Crohn’s disease (CD). Two phase 1, open-label, two-arm, randomized studies compared pharmacokinetics and safety of mirikizumab (200 mg, Study AMBW; 300 mg, Study AMBX) to establish bioequivalence. Mirikizumab was administered subcutaneously using an autoinjector or a prefilled syringe (PFS) as a single dose in healthy participants. Participants (male and female) were randomized 1:1 to mirikizumab by a PFS (reference) and an autoinjector (test). Participants were sub-randomized (1:1:1) to one of three injection sites (abdomen, arm, thigh) and stratified into one of three weight groups. Primary endpoints were maximum observed drug concentration (Cmax), and area under concentration versus time curves (time zero to infinity [AUC0–∞]; time to last time point with measurable concentration [AUC0–tlast]). Secondary objectives were safety and immunogenicity. In Study AMBW, 90

Baricitinib is approved for the treatment of adults with moderate-to-severe atopic dermatitis (AD) who are candidates for systemic therapy and has received regulatory authorization in Europe for moderate-to-severe AD in patients 2 to <18 years. This study aims to optimize dosing for baricitinib in pediatric patients with atopic dermatitis using pharmacokinetic/pharmacodynamic modeling leveraging adult data. The phase III, randomized, double-blind, placebo-controlled study, BREEZE-AD-PEDS (NCT03952559, registration date: 2019-05-16), enrolled patients (aged 2 to <18 years) with moderate-to-severe AD. During a pharmacokinetic (PK) lead-in period, baricitinib concentration data from age-based dose cohorts (4 mg once daily [QD]: 10 to <18 years; 2 mg QD: 2 to <10 years) were compared with actual and simulated concentration values from adult patients receiving baricitinib 4 mg QD. A population PK model incorporating allometric scaling was developed to determine weight-based dosing in pediatric patients that matches adult exposures. The exposure–response (E-R) relationships were analyzed for the primary endpoint: a validated Investigator Global Assessment® (vIGA-AD) score of 0 or 1 (clear to almost clear skin) with ≥2-point improvement from baseline at week 16. Baricitinib pharmacokinetics were characterized from 393 pediatric patients using a 2-compartment model with allometric scaling on clearance and volume of distribution. The age-based and subsequent weight-based dosing (2 mg for patients 10 to <30 kg and 4 mg for patients ≥30 kg) was comparable to the 4-mg adult exposure. A clear E-R relationship was observed for the primary endpoint when sorted for age or weight groups. The population PK model developed using baricitinib concentrations from adult patients, with allometric scaling for weight on clearance and volume, adequately predicted exposures in the pediatric population. The PK modeling, with E-R analysis, informed an appropriate weight-based dosing regimen.

Mirikizumab, a p19-directed antibody against interleukin-23 (IL-23), is administered by subcutaneous (SC) injection. Injection site pain (ISP) associated with citrate buffers may negatively affect patient adherence to SC-administered treatments. We assessed the bioequivalence and safety of the citrate-free (CF) and original formulations of mirikizumab. The formulations were assessed in three phase 1, two-arm, randomized, single-dose, parallel design studies in healthy participants: study A (NCT04548219), study B (NCT05515601), and study C (NCT05644353). Participants were randomized 1:1 to either formulation, then further randomized to injection site locations of abdomen, arm, or thigh. The relative bioavailability (RBA) study A had a primary objective of assessing the RBA of a single 200 mg dose. Bioequivalence (BE) studies B and C had the primary objective of assessing the BE of a 200 and 300 mg dose, respectively. In all studies, the primary endpoints were Cmax, AUC(0–∞), and AUC(0–tlast). The secondary objective was to assess safety and tolerability by treatment-emergent adverse events and serious adverse events. In study A, ISP was quantified prospectively using the 100-mm validated visual analogue scale (VAS) assessment form. The primary objective was met in all studies. The RBA study found no significant difference in exposure between the formulations. BE was demonstrated between CF and original mirikizumab in both BE studies, with the 90

Mirikizumab, an anti-interleukin-23 p19 monoclonal antibody, is approved for treating adults with moderately to severely active ulcerative colitis and Crohn’s disease. For ulcerative colitis maintenance therapy, mirikizumab is administered via two 1-ml subcutaneous (SC) injections. Volume and number of SC administrations can impact injection site reactions and local pain, as well as treatment compliance. We assessed the pharmacokinetic (PK) and safety comparability of an investigational one 2-ml SC injection compared with the commercially available two 1-ml SC injections. In this phase 1 study, USA-based healthy adults were stratified by weight and randomized (1:1) to receive citrate-free 200 mg SC mirikizumab as either two 1-ml injections (each 100 mg) or one 2-ml (200 mg) injection, delivered by an autoinjector. Participants in each arm were subrandomized by injection site location (arm, abdomen, or thigh). Blood sampling and safety assessments were conducted up to 10 weeks post dose. The primary endpoint was PK, and the secondary endpoint was safety. A total of 244 participants received one injection and 240 received two injections (mean age 42.5 years; 51.0

The objective of this phase 1 single-dose study was to evaluate the safety, tolerability, and pharmacokinetics of mirikizumab in Chinese healthy adults. Sixty participants were randomized within 5 planned dose cohorts: intravenous (IV) 300 mg, IV 600 mg, IV 1200 mg, subcutaneous (SC) 200 mg, and SC 400 mg to receive mirikizumab (10 participants in each cohort) or placebo (2 participants in each cohort). No death or serious adverse events occurred. Twenty-eight (56.0%) participants who received mirikizumab reported 49 treatment-emergent adverse events (TEAEs) and 8 (80.0%) participants who received placebo reported 18 TEAEs. The majority of TEAEs were mild in severity. Following IV 300-1200 mg mirikizumab, the arithmetic mean of both area under the concentration versus time curve from time 0 to infinity (AUC0-∞) and maximum observed drug concentration (Cmax) increased by approximately 3.5-fold, and the arithmetic mean half-life (t1/2) ranged from 9.64 to 12.0 days. Following SC 200 and 400 mg mirikizumab, the arithmetic mean of both AUC0-∞ and Cmax increased by approximately 1.6-fold, the median time to Cmax (tmax) was 2.98 days for both, and the arithmetic mean t1/2 was 10.6 and 10.5 days, respectively. Absolute bioavailability based on pooled SC and IV dose data was 38.2%. In this study, the safety and pharmacokinetic profile of mirikizumab were consistent with what has been reported in other studies.

Baricitinib is approved for the treatment of rheumatoid arthritis (RA) in more than 70 countries, and juvenile idiopathic arthritis (JIA) in the European Union. Population pharmacokinetic (PK) models were developed in a phase 3 trial to characterize PK in pediatric patients with JIA and identify weight-based dosing regimens. The phase 3, randomized, double-blind, placebo-controlled withdrawal, efficacy and safety trial, JUVE-BASIS, enrolled patients (aged 2 to <18 years) with polyarticular course JIA. During a safety/PK period, baricitinib concentration data from age-based dose cohorts were compared to concentrations from adult patients receiving 4-mg QD. PK data were used to develop a population PK model with allometric scaling to determine a weight-based posology in pediatric patients with JIA that matched the adult 4-mg exposure. Baricitinib plasma concentrations from 217 pediatric patients were used to characterize PK. Based on the adult model, pediatric PK was best described using a 2-compartment model with allometric scaling on clearance and volume of distribution and renal function (estimated with glomerular filtration rate [GFR], a known covariate affecting PK of baricitinib) on clearance. The PK modeling suggested the optimal dosing regimen based on weight for pediatric patients as: 2-mg QD for patients 10 to <30 kg and 4-mg QD for patients ≥30 kg. The use of a population PK model of baricitinib treatment in adult patients with RA, with the addition of allometric scaling for weight on clearance and volume terms, was useful to predict exposures and identify weight-based dosing in pediatric patients with JIA.

BACKGROUND:Efficacy and safety of mirikizumab, a p19-targeted anti-interleukin-23 monoclonal antibody, for moderately to severely active ulcerative colitis was demonstrated previously. We evaluated clinical response, baseline characteristics, and clinical status in patients not responding by 12 weeks (W) of induction who then received extended induction treatment. METHOD:Patients unresponsive to 300 mg of intravenous (IV) mirikizumab every 4 weeks by W12 received 3 additional 300 mg IV doses every 4 weeks. Week-4 responders received 200 mg mirikizumab every 4 weeks subcutaneously until W52. Patients responding by W12 but subsequently losing response received rescue therapy with 300 mg IV for 3 doses every 4 weeks. Logistic regression modelling was performed for patients not achieving W12 clinical response to assess baseline characteristics and W12 efficacy parameters and potential prognostic factors of clinical response at W24. RESULTS:Of patients not achieving clinical response during induction, 53.7% achieved response following extended induction. After 52W, 72.2%, 43.1%, and 36.1% of patients achieved clinical response, endoscopic, and clinical remission, respectively. Of induction responders who subsequently lost response, 63.2% and 36.8% achieved symptomatic response and remission, respectively, after receiving rescue therapy No prior biologic or tofacitinib treatment, no immunomodulators at baseline, age older than 40 years, and W12 modified Mayo Score improvement were positively associated with a response to extended induction. The safety profile was similar to initial induction, with 38.3% treatment emergent adverse events, mostly mild. CONCLUSION:With "extended induction," total of 80.3% mirikizumab-treated patients achieved clinical response by W24. Potential prognostic factors determining response include disease severity, disease phenotype, C-reactive protein, and previous biologic therapy.

AbstractMirikizumab is a p19‐directed anti‐interleukin‐23 antibody approved for the treatment of adults with moderate‐to‐severe ulcerative colitis (UC). Here, we report the first data of mirikizumab pharmacokinetics (PK) and exposure–response (E/R) relationships in pediatric participants (aged 2 to <18 years weighing >10 kg) with moderate‐to‐severe UC from the phase II, open‐label study SHINE‐1 (NCT04004611). PK parameters were analyzed using a model developed previously in adults with fixed‐exponent allometry for body weight. Serum samples collected from 26 participants during the 12‐week induction and 40‐week maintenance periods of SHINE‐1 were analyzed. Estimated body weight‐adjusted systemic clearance, volume of distribution, and subcutaneous bioavailability were 0.021 L/h, 0.069 L/kg, and 49.8%, respectively. Covariate analysis identified no clinically significant covariates other than body weight. In the exposure range studied, E/R analysis using post hoc grouping by average concentration quartile and comparison of observed change from baseline in modified Mayo Score (MMS) at Week 12 with the adult model prediction revealed no obvious E/R relationship in clinical response, clinical remission, or endoscopic response, consistent with observations in adults. The E/R relationship for observed change from baseline in MMS at Week 12 is also similar to the adult model prediction. The PK modeling and E/R analyses suggested optimal doses of intravenous mirikizumab 300 mg for weight >40 kg, 5 mg/kg for weight ≤40 kg every 4 weeks (Q4W) during induction, and subcutaneous mirikizumab 200 mg (>40 kg), 100 mg (>20 to ≤40 kg), or 50 mg (≤20 kg) Q4W during maintenance therapy for pediatric patients with moderate‐to‐severe UC.

Introduction: Mirikizumab (Miri) is being developed for the treatment of immune-mediated diseases involving the IL-23 pathway, such as ulcerative colitis and Crohn’s disease. The analyses aim to evaluate the safety, tolerability, and pharmacokinetics (PK) of Miri after a single dose in Chinese healthy adults. Methods: This study (NCT04137380) is a randomized, subject and investigator blinded, placebo-controlled, phase 1 single-dose study. The study consisted of 5 planned dose cohorts: 3 intravenous (IV) dose cohorts (300, 600, and 1200 mg) and 2 subcutaneous (SC) dose cohorts (200 and 400 mg). Subjects were randomized within each cohort to receive Miri (10 subjects) or placebo (2 subjects). The primary objective is to assess the safety and tolerability of single Miri doses in Chinese healthy subjects. Frequencies of treatment-emergent adverse events (TEAEs) were summarized by treatment and visual analog scale (VAS) pain scores were summarized and plotted by time point. The secondary objective is to evaluate the PK of single Miri doses in Chinese healthy subjects. The PK parameters were calculated by standard noncompartmental methods of analysis and summarized by treatment. Results: Sixty subjects were enrolled in the study and 59 completed the study. One subject was discontinued due to physician decision as she was pregnant. Overall, 28 (56.0%) subjects who received Miri reported 49 TEAEs and 8 (80.0%) subjects who received placebo reported 18 TEAEs during the study. The majority of TEAEs were mild in severity. No death or serious adverse events occurred during the study. No injection site reaction TEAEs were reported in SC treatment groups. The distribution of VAS pain scores was similar across the SC treatment including placebo. Following IV doses of 300 to 1200 mg Miri, the geometric mean of both AUC(0-∞) and Cmax increased by approximately 3.5-fold, suggesting linear PK over IV dose range, and the geometric mean t1/2 ranged from 9.53 to 11.9 days. Following SC doses of 200 and 400 mg Miri, the median tmax was 2.98 days and the geometric mean t1/2 was 10.6 and 10.4 days, respectively. The geometric mean of both AUC(0-∞) and Cmax increased by approximately 1.6-fold, suggesting linear PK over SC dose range. Absolute bioavailability based on pooled IV and SC data was 38.2% (Table 1). Conclusion: Intravenous doses of Miri up to 1200 mg and SC doses up to 400 mg were well tolerated by Chinese healthy subjects, and the PK profile in Chinese subjects was comparable with that observed in the Caucasian population. Table 1. - Summary of Pharmacokinetic Parameters of Mirikizumab Following Intravenous or Subcutaneous Administration to Chinese Healthy Subjects Intravenous Parameter 300 mg (N=10) 600 mg (N=10) 1200 mg (N=10) n Geometric mean (Geometric CV%) n Geometric mean (Geometric CV%) n Geometric mean (Geometric CV%) AUC(0-tlast) (ug.day/mL) 5 964 (15%) 10 2010 (12%) 9 3300 (24%) AUC(0-∞) (ug.day/mL) 10 936 (12%) 10 2030 (12%) 10 3320 (23%) %AUC(tlast-∞) (%) 10 2.02 (553%) 10 0.547 (133%) 10 0.422 (299%) Cmax (ug/mL) 10 145 (6%) 10 266 (16%) 10 511 (10%) tmax (day)# 10 0.03 (0.03-0.25) 10 0.05 (0.05-0.06) 10 0.10 (0.09-0.10) t½ (day)* 10 9.53 (7.73-11.7) 10 11.9 (9.26-15.0) 10 10.4 (8.18-15.9) CL (L/day) 10 0.321 (12%) 10 0.296 (12%) 10 0.361 (23%) Vz (L) 10 4.41 (14%) 10 5.07 (17%) 10 5.41 (13%) Vss (L) 10 3.98 (12%) 10 4.38 (14%) 10 4.43 (13%) Subcutaneous Parameter 200 mg (N=10) 400 mg (N=10) n Geometric mean (Geometric CV%) n Geometric mean (Geometric CV%) AUC(0-tlast) (ug.day/mL) 7 248 (34%) 10 417 (46%) AUC(0-∞) (ug.day/mL) 10 263 (29%) 10 421 (46%) %AUC(tlast-∞) (%) 10 1.93 (139%) 10 0.779 (52%) Cmax (ug/mL) 10 14.9 (28%) 10 23.1 (44%) tmax (day)# 10 2.98 (2.97-6.95) 10 2.98 (2.97-7.04) t½ (day)* 10 10.6 (9.16-12.0) 10 10.4 (8.44-11.9) CL/F (L/day) 10 0.759 (29%) 10 0.951 (46%) Vz/F (L) 10 11.6 (25%) 10 14.2 (39%) Vss/F (L) 10 301 (27%) 10 377 (42%) F (%)† 10 42.8 10 34.2 Abbreviations: %AUC(tlast-∞) = percentage of AUC(0-∞) extrapolated; AUC(0-∞) = area under the concentration vs time curve from time zero to infinity; AUC(0-tlast) = area under the concentration vs time curve from time zero to time t, where t is the last time point with a measurable concentration; CL = total body clearance of drug calculated after intravenous administration; CL/F = total body clearance of drug calculated after extravascular administration; Cmax = maximum observed drug concentration; CV = coefficient of variation; F = absolute bioavailability; N = number of subjects; n = number of observations; t1/2 = half-life associated with the terminal rate constant in noncompartmental analysis; tmax = time of maximum observed drug concentration; Vss = volume of distribution at steady state after intravenous administration; Vss/F = apparent volume of distribution at steady state after extravascular administration; Vz = volume of distribution during the terminal phase after intravenous administration; Vz/F = apparent volume of distribution during the terminal phase after extravascular administration.#Median (minimum-maximum).*Geometric mean (minimum-maximum).†The geometric mean F (pooled), the absolute bioavailability of pooled 200 mg and 400 mg subcutaneous administration treatments (n=20), is 38.2%.

Advances in the technologies to enable patient-centric sampling (PCS) have the potential to improve blood sample collection by enabling clinical trial participants to collect samples via self-collection or with the help of a caregiver in their home. Typically, blood samples to assess pharmacokinetics and pharmacodynamics of a drug during clinical development are collected at a clinical site via venous blood draw. In this position paper by the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), the potential value PCS can bring to patients, to the clinical datasets generated, and to clinical trial sponsors is discussed, along with considerations for program decision making, bioanalytical feasibility, operations, and regulatory implications. With an understanding of the value of PCS and considerations when implementing during clinical drug development, we can bring the promise of PCS closer to reality and enable decentralized clinical trials.

Background: Baricitinib (BARI), an oral selective inhibitor of Janus kinase 1 and Janus kinase 2, modulates proinflammatory cytokine signaling.

ABSTRACTBackgroundThe efficacy and safety of baricitinib, an oral selective Janus kinase 1/2 inhibitor, in addition to standard of care (SOC) in hospitalised adults with COVID-19 is unknown.MethodsIn this phase 3, global, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America (ClinicalTrials.govNCT04421027). Hospitalised adults with COVID-19 receiving SOC were randomly assigned (1:1) to once-daily baricitinib 4-mg or placebo for up to 14 days. SOC included systemic corticosteroids in 79·3% of participants (dexamethasone ∼90%). The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28. All-cause mortality by days 28 and 60 were key secondary and exploratory endpoints, respectively. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively.FindingsBetween June 11, 2020 and January 15, 2021, 1525 participants were randomly assigned to baricitinib 4-mg (n=764) or matched placebo (n=761). Overall, 27·8% of participants receiving baricitinib vs 30·5% receiving placebo progressed (primary endpoint, odds ratio 0·85, 95% CI 0·67-1·08; p=0·18). The 28-day all-cause mortality was 8·1% (n=62) for baricitinib and 13·1% (n=100) for placebo, corresponding to a 38·2% reduction in mortality (hazard ratio [HR] 0·57, 95% CI 0·41-0·78; nominal p=0·0018). The 60-day all-cause mortality was 10·3% (n=79) for baricitinib and 15·2% (n=116) for placebo (HR 0·62, 95% CI 0·47-0·83; p=0·0050). Frequency of serious adverse events (14·7% [n=110] vs 18·0% [n=135]), serious infections (8·5% [n=64] vs 9·8% [n=74]), and venous thromboembolic events (2·7% [n=20] vs 2·5% [n=19]) was similar between baricitinib and placebo, respectively.InterpretationWhile reduction of disease progression did not achieve statistical significance, treatment with baricitinib in addition to SOC (including dexamethasone) significantly reduced mortality, with a similar safety profile to SOC, in hospitalised COVID-19 participants.FundingEli Lilly and Company.Research in contextEvidence before this studyWe searched PubMed using the terms “COVID-19”, “SARS-CoV-2”, “treatment”, “baricitinib” and “JAK inhibitor” for articles in English published up to April 31, 2020, regardless of article type. We considered previous and current clinical trials of investigational medications in COVID-19, as well as previous clinical trials of the Janus kinase (JAK)1 and JAK2 inhibitor, baricitinib, before undertaking this study. At the time the COV-BARRIER study was designed, there were no approved therapies for the treatment of COVID-19. Management of COVID-19 was supportive, and limited phase 3 randomised placebo-controlled studies had been completed. Limited phase 2 and 3 data on the antimalarial hydroxychloroquine and protease inhibitor lopinavir/ritonavir were available, and trials investigating the use of the antiviral remdesivir were ongoing. Baricitinib’s mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID-19 given its known anti-cytokine properties and potential for targeting host proteins for its antiviral mechanism. Additionally, early case series evaluating the efficacy and safety of baricitinib in the hospitalised patient population supported further evaluation of baricitinib as a potential treatment option for hospitalised patients with COVID-19. While COV-BARRIER was enrolling, ACTT-2, a phase 3 study evaluating baricitinib plus remdesivir was completed showing that baricitinib added to remdesivir improved time to recovery and other outcomes.Added value of this studyThis was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC) and included antivirals, anticoagulants, and corticosteroids. After the earliest publication of the RECOVERY study in June 2020, the treatment of hospitalised patients with COVID-19 changed with the adoption of dexamethasone as SOC. As a result of its design, COV-BARRIER became the first trial to evaluate the benefit/risk of baricitinib when added to the most current SOC (dexamethasone) in these patients. This was a randomised, double-blind, placebo-controlled trial conducted globally in regions with high COVID-19 hospitalisation rates. The reduction in the composite primary endpoint of progression to non-invasive ventilation, high flow oxygen, invasive mechanical ventilation, or death for baricitinib plus SOC (including dexamethasone) compared to placebo plus SOC did not reach statistical significance. However, in a pre-specified key secondary endpoint, treatment with baricitinib reduced 28-day all-cause mortality by 38·2% compared to placebo (HR 0·57, 95% CI 0·41-0·78; nominal p=0·0018); one additional death was prevented per 20 baricitinib-treated participants. The reduction of all-cause mortality with baricitinib was maintained by day 60 in an exploratory analysis. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively.Implications of all the available evidenceIn this phase 3 trial, baricitinib given in addition to SOC (which predominantly included dexamethasone) did not reduce a composite endpoint of disease progression, but showed a strong effect on reducing mortality by 28 days, an effect which was maintained by 60 days. In the ACTT-2 study, baricitinib further reduced time to recovery above the background use of remdesivir. Taken together, these findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on all available evidence, baricitinib is a potentially effective oral treatment option to decrease mortality in hospitalised patients with COVID-19.

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 (79middot3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91middot3%) were on dexamethasone; 287 (18middot9%) participants were receiving remdesivir. Overall, 27middot8% of participants receiving baricitinib and 30middot5% receiving placebo progressed to meet the primary endpoint (odds ratio 0middot85 [95% CI 0middot67 to 1middot08], p=0middot18), with an absolute risk difference of -2middot7 percentage points (95% CI -7middot3 to 1middot9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0middot57 [95% CI 0middot41-0middot78]; nominal p=0middot0018), a 38middot2% 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 0middot62 [95% CI 0middot47-0middot83]; p=0middot0050). 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. Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Tailoring electromagnetic waves in full space is a significant issue enabling diverse functionalities for wireless communications. Classical approaches using tunable materials can achieve intensity modulation but lack phase modulation. In this paper, we present a general strategy for simultaneous wavefront manipulation and energy allocation by introducing a filter layer into the metasurface design. By adjusting the filter layer with different impedances, an energy allocation with a desired wavefront could be switched smoothly from transmission to reflection mode. Numerical simulations and experimental measurements are performed to verify the effectiveness of the proposed strategy. As a practical example, a high-gain bifunctional transmit/reflect array is experimentally demonstrated with excellent performance.