ABSTRACT
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.).
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Azetidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Aged , Antirheumatic Agents/adverse effects , Azetidines/adverse effects , Female , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Logistic Models , Male , Middle Aged , Protein Kinase Inhibitors/adverse effects , Purines , Pyrazoles , Severity of Illness Index , Sulfonamides/adverse effectsABSTRACT
Numerous cytokines have been implicated in the pathogenesis of inflammatory diseases, and their dysregulation is a main feature of rheumatoid arthritis (RA). Cytokines stimulate signal transduction through several intracellular pathways, including Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathways, leading to changes in cell activation, proliferation and survival. Consequently, agents that selectively target elements of the JAK/STAT pathways have received significant attention in recent years as potential new treatments for the disease. Baricitinib, an oral selective inhibitor of JAK1 and JAK2, offers an effective treatment for RA in a wide range of patients. The in vitro selectivity of different JAK inhibitors is an important consideration given that key cytokines, growth factors and hormone receptors involved in the pathogenesis of RA signal through specific JAKs. However, it is complex and far from understood how the in vitro effects of JAK inhibitors extrapolate into in vivo and clinical effects in individual patients. This narrative review focuses on the clinical efficacy and safety of baricitinib, but also provides an overview of its mechanism of action in relation to JAK1/JAK2 signalling and discusses the possible clinical implications in patients with RA.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid , Janus Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/enzymology , Azetidines/therapeutic use , Humans , Janus Kinase 1 , Janus Kinase 2 , Purines , Pyrazoles , Sulfonamides/therapeutic useABSTRACT
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.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Azetidines/administration & dosage , Cholesterol, HDL/drug effects , Cholesterol, LDL/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Lipid Metabolism/drug effects , Sulfonamides/administration & dosage , Administration, Oral , Adult , Aged , Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/diagnosis , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Purines , Pyrazoles , Randomized Controlled Trials as Topic , Reference Values , Severity of Illness Index , Treatment OutcomeABSTRACT
Objective: RA patients who have failed biologic DMARDs (bDMARDs) represent an unmet medical need. We evaluated the effects of baseline characteristics, including prior bDMARD exposure, on baricitinib efficacy and safety. Methods: RA-BEACON patients (previously reported) had moderate to severe RA with insufficient response to one or more TNF inhibitor and were randomized 1:1:1 to once-daily placebo or 2 or 4 mg baricitinib. Prior bDMARD use was allowed. The primary endpoint was a 20% improvement in ACR criteria (ACR20) at week 12 for 4 mg vs placebo. An exploratory, primarily post hoc, subgroup analysis evaluated efficacy at weeks 12 and 24 by ACR20 and Clinical Disease Activity Index (CDAI) ⩽10. An interaction P-value ⩽0.10 was considered significant, with significance at both weeks 12 and 24 given more weight. Results: The odds ratios predominantly favored baricitinib over placebo and were generally similar to those in the overall study (3.4, 2.4 for ACR20 weeks 12 and 24, respectively). Significant quantitative interactions were observed for baricitinib 4 mg vs placebo at weeks 12 and 24: ACR20 by region (larger effect Europe) and CDAI ⩽10 by disease duration (larger effect ⩾10 years). No significant interactions were consistently observed for ACR20 by age; weight; disease duration; seropositivity; corticosteroid use; number of prior bDMARDs, TNF inhibitors or non-TNF inhibitors; or a specific prior TNF inhibitor. Treatment-emergent adverse event rates, including infections, appeared somewhat higher across groups with greater prior bDMARD use. Conclusion: Baricitinib demonstrated a consistent, beneficial treatment effect in bDMARD-refractory patients across subgroups based on baseline characteristics and prior bDMARD use. Trial registration: ClinicalTrials.gov (https://clinicaltrials.gov/), NCT01721044.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Azetidines/administration & dosage , Biological Products/therapeutic use , Drug Tolerance , Sulfonamides/administration & dosage , Administration, Oral , Dose-Response Relationship, Drug , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Purines , Pyrazoles , Severity of Illness Index , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVES: To assess baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis, who had insufficient response or intolerance to ≥1 tumour necrosis factor inhibitors (TNFis) or other biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: In this double-blind phase III study, patients were randomised to once-daily placebo or baricitinib 2 or 4â mg for 24â weeks. PROs included the Short Form-36, EuroQol 5-D, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, duration of morning joint stiffness (MJS) and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis. Treatment comparisons were performed with logistic regression for categorical measures or analysis of covariance for continuous variables. RESULTS: 527 patients were randomised (placebo, 176; baricitinib 2â mg, 174; baricitinib 4â mg, 177). Both baricitinib-treated groups showed statistically significant improvements versus placebo in most PROs. Improvements were generally more rapid and of greater magnitude for patients receiving baricitinib 4â mg than 2â mg and were maintained to week 24. At week 24, more baricitinib-treated patients versus placebo-treated patients reported normal physical functioning (HAQ-DI <0.5; p≤0.001), reductions in fatigue (FACIT-F ≥3.56; p≤0.05), improvements in PtGA (p≤0.001) and pain (p≤0.001) and reductions in duration of MJS (p<0.01). CONCLUSIONS: Baricitinib improved most PROs through 24â weeks compared with placebo in this study of treatment-refractory patients with previously inadequate responses to bDMARDs, including at least one TNFi. PRO results aligned with clinical efficacy data for baricitinib. TRIAL REGISTRATION NUMBER: NCT01721044; Results.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Azetidines/therapeutic use , Patient Reported Outcome Measures , Protein Kinase Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Adult , Arthritis, Rheumatoid/complications , Double-Blind Method , Efficiency , Humans , Pain Measurement , Presenteeism , Purines , Pyrazoles , Quality of Life , Severity of Illness Index , Surveys and Questionnaires , Young AdultABSTRACT
OBJECTIVES: To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate. METHODS: In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8â mg baricitinib for 12â weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12â weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12-24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12. RESULTS: Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p<0.001). At week 12, significant differences versus placebo were also observed in patients achieving ACR50, ACR70 and remission as measured by Disease Activity Score for 28-joint counts, Clinical Disease Activity Index and Simplified Disease Activity Index. Patients receiving 2, 4, or 8â mg baricitinib maintained or improved in all measures through 24â weeks. Similar proportions of patients experienced at least one adverse event in the placebo and baricitinib groups. Serious infections developed in three patients receiving baricitinib. No cases of tuberculosis, herpes zoster, opportunistic infections or deaths were reported. Dose-dependent decreases in haemoglobin were observed with baricitinib. CONCLUSIONS: Baricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24. TRIAL REGISTRATION NUMBER: NCT01185353.
Subject(s)
Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Azetidines/administration & dosage , Enzyme Inhibitors/administration & dosage , Sulfonamides/administration & dosage , Antirheumatic Agents/adverse effects , Azetidines/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Enzyme Inhibitors/adverse effects , Female , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Male , Methotrexate/therapeutic use , Middle Aged , Purines , Pyrazoles , Sulfonamides/adverse effectsABSTRACT
OBJECTIVE: Pain reduction with baricitinib was assessed in patients with rheumatoid arthritis (RA) who either used opioids or did not use opioids during three randomized, double-blind phase 3 trials. METHODS: Analysis populations were as follows: i) baricitinib 4 mg once daily versus placebo groups integrated from RA-BEAM (NCT01710358) for patients with inadequate response (IR) to methotrexate, RA-BUILD (NCT01721057) with IR to conventional disease-modifying antirheumatic drugs, and RA-BEACON (NCT01721044) with IR to at least one tumor necrosis factor inhibitors; ii) baricitinib 2 mg versus placebo from RA-BUILD and RA-BEACON; and iii) adalimumab 40 mg every other week versus placebo from RA-BEAM. Pain was measured by the Patient Assessment of Pain Visual Analog Scale. Analysis of covariance modeling assessed differences in pain reduction between treatments at each time point through Week 24, with an interaction term to test heterogeneous treatment effects across opioid users and nonusers. RESULTS: Baricitinib 4 mg had greater pain reduction versus placebo in opioid users and nonusers (P < 0.05) at all time points starting from Week 1; the pain reduction was similar between opioid users and nonusers. Baricitinib 2 mg had greater pain reduction versus placebo in opioid users and nonusers starting at Week 4. A significant difference in pain reduction was not observed for adalimumab versus placebo in the opioid users but was observed in nonusers at all time points. CONCLUSION: Pain reduction was observed and was similar between opioid users and nonusers with baricitinib 2 mg and 4 mg but not adalimumab in this post hoc analysis.
ABSTRACT
Elevated circulating endothelial cell (CEC) and circulating endothelial progenitor cell (CEPC) counts may indicate vascular damage and disease status, but data on these cell populations in patients with severe sepsis are limited. This study compared CEC and CEPC counts in patients with and without severe sepsis following intensive care unit (ICU) admission. Venous blood samples were collected within 24 h, 48-72 h, and 120-144 h. Baseline demographics, 28-day mortality, ICU and hospital days, and Sequential Organ Failure Assessment (SOFA) scores were recorded. Patients with (n=18) and without (n=28) severe sepsis were balanced for mean age (63.7 and 61.3 years, respectively) and gender. There were no differences in 28-day mortality, ICU days, or hospital days. Baseline SOFA scores were higher in the sepsis group. At 48-72 h, patients with severe sepsis had significantly higher median CEC counts (51.5 vs. 28.0 cells/4 ml of blood, P=0.02). CEC values for all ICU patients were significantly (P<0.05) higher than in healthy volunteers. CEPC counts in both cohorts ranged from 0 to >21 colonies/4 ml blood (mean=1.13±2.25; median=0) without significant differences at any time point. This study demonstrates the ability to quantify CECs and CEPCs using consensus methodology. Understanding the relationship between CEC/CEPC counts and outcomes may provide insight into the mechanisms of endothelial cell changes in severe sepsis.
Subject(s)
Blood Cells/pathology , Endothelial Cells/pathology , Sepsis/blood , Stem Cells/pathology , Adult , Aged , Aged, 80 and over , Blood Cell Count , Female , Humans , Intensive Care Units , Length of Stay/statistics & numerical data , Male , Middle Aged , Prognosis , Sepsis/diagnosis , Sepsis/pathology , Severity of Illness Index , Shock/blood , Shock/diagnosis , Shock/pathology , Time FactorsABSTRACT
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.
Subject(s)
Arthritis, Juvenile , Uveitis , Adalimumab/adverse effects , Adolescent , Antibodies, Antinuclear , Arthritis, Juvenile/diagnosis , Arthritis, Juvenile/drug therapy , Azetidines , Bayes Theorem , Child , Clinical Trials, Phase III as Topic , Humans , Multicenter Studies as Topic , Purines , Pyrazoles , Sulfonamides , Treatment Outcome , Uveitis/diagnosis , Uveitis/drug therapyABSTRACT
The framework of equipoise has been promulgated as an underlying requirement for conducting ethical clinical research. Equipoise is the term used for a state of indifference about which treatment intervention or innovation will provide the most benefit and the least harm to recipients. Drawing on healthcare, research, and ethics literature, this paper analyses the implications of equipoise from the perspective of several proponents and critics. Specifically the historical evolution of the concept based on Fried and Freedman's arguments is traced. A critique of the concept, informed by contrasting perspectives, is offered. An alternative framework of non-exploitation as presented by Miller and Brody is argued to be superior in facilitating both the ultimate goals of research on human subjects and those of the healthcare professions'.
Subject(s)
Clinical Trials as Topic/ethics , Ethics, Research , Nursing Research , Philosophy, Nursing , Uncertainty , Decision Making , Humans , Research Design , Therapeutic Human Experimentation/ethicsABSTRACT
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.
Subject(s)
Antiviral Agents/pharmacology , Artificial Intelligence , Azetidines/pharmacology , Betacoronavirus , Coronavirus Infections/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Protein Kinase Inhibitors/therapeutic use , Sulfonamides/pharmacology , Adult , Aged , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Azetidines/pharmacokinetics , Azetidines/therapeutic use , COVID-19 , Cytokines/antagonists & inhibitors , Drug Evaluation, Preclinical , Drug Repositioning , Female , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Leukocytes/drug effects , Liver , Male , Middle Aged , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Purines , Pyrazoles , SARS-CoV-2 , Spheroids, Cellular/drug effects , Spheroids, Cellular/virology , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic use , COVID-19 Drug TreatmentABSTRACT
The purpose of the study was to assess the proportion of patients who achieve pain relief thresholds, the time needed to reach the thresholds, and the relationship between pain and inflammation among patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate in RA-BEAM (NCT0170358). A randomized, double-blind trial was conducted, comparing baricitinib (N = 487), adalimumab (N = 330), and placebo (N = 488) plus methotrexate. Pain was evaluated by patient's assessment on a 0-100 mm visual analog scale (VAS). The following were assessed through a 24-week placebo-controlled period: the proportion of patients who achieved ≥30%, ≥50%, and ≥70% pain relief, the time to achieve these pain relief thresholds, remaining pain (VAS ≤ 10 mm, ≤20 mm, or ≤40 mm), and the relationship between inflammation markers and pain relief. Baricitinib-treated patients were more likely (p < 0.05) to achieve ≥30%, ≥50%, and ≥70% pain relief than placebo- and adalimumab-treated patients, as early as Week 1 vs. placebo and at Week 4 vs. adalimumab. A greater proportion of baricitinib-treated patients achieved ≤20 mm or ≤40 mm remaining pain vs. placebo- and adalimumab-treated patients. Baricitinib-treated patients tended to demonstrate consistent pain relief independent of levels of inflammation control. In RA patients with an inadequate response to methotrexate, baricitinib provided greater and more rapid pain relief than adalimumab and placebo. Analyses suggest the relationship between inflammation and pain may be different for baricitinib and adalimumab treatments.
ABSTRACT
OBJECTIVE: To assess the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) up to 128 weeks in a phase IIb study (NCT01185353). METHODS: After a 24-week blinded period, eligible patients entered an initial 52-week open-label extension (OLE); patients receiving 8 mg once daily (QD) continued with that dose and all others received 4 mg QD. Doses could be escalated to 8 mg QD at 28 or 32 weeks at investigator discretion when ≥ 6 tender and ≥ 6 swollen joints were present. Patients completing the first OLE were eligible to enter a second 52-week OLE and receive 4 mg QD regardless of previous dose. RESULTS: In the 4-mg (n = 108) and 8-mg (n = 93) groups, treatment-emergent adverse events (AE) occurred in 63% and 67%, serious AE in 16% and 13%, infections in 35% and 40%, and serious infections in 5% and 3% of patients, respectively. Exposure-adjusted incidence rates for AE for all baricitinib groups in the second OLE were similar to or lower than rates observed in the first OLE. No opportunistic infections, tuberculosis cases, or lymphomas were observed through 128 weeks; 1 death occurred during the first OLE. Among all patients in both OLE, the proportions who achieved disease improvement at Week 24 were similar or increased at weeks 76 and 128. CONCLUSION: In a phase IIb study in RA, the safety and tolerability profile of baricitinib, up to 128 weeks, remained consistent with earlier observations, without unexpected late signals. Clinical improvements seen in the 24-week blinded period were maintained during the OLE.
Subject(s)
Antirheumatic Agents/adverse effects , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Azetidines/adverse effects , Azetidines/therapeutic use , Methotrexate/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Administration, Oral , Adolescent , Adult , Aged , Antirheumatic Agents/administration & dosage , Azetidines/administration & dosage , Blood Sedimentation , C-Reactive Protein/analysis , Dose-Response Relationship, Drug , Double-Blind Method , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Male , Middle Aged , Purines , Pyrazoles , Severity of Illness Index , Sulfonamides/administration & dosage , Treatment Outcome , Young AdultABSTRACT
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.
Subject(s)
Antirheumatic Agents/pharmacology , Arthritis, Rheumatoid/drug therapy , Azetidines/pharmacology , Lymphocyte Subsets/drug effects , Sulfonamides/pharmacology , Adalimumab/pharmacology , Adult , Arthritis, Rheumatoid/blood , Clinical Trials, Phase III as Topic , Double-Blind Method , Drug Therapy, Combination , Female , Humans , Lymphocyte Count , Male , Middle Aged , Purines , Pyrazoles , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
BACKGROUND: Baricitinib was efficacious in a 24-week phase III study in patients with rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti rheumatic drugs (DMARDs) (csDMARDs) (RA-BUILD). OBJECTIVES: To evaluate radiographic progression of structural joint damage in RA-BUILD patients over 48 weeks of baricitinib treatment in the long-term extension study, RA-BEYOND. METHODS: In RA-BUILD, patients were randomised to placebo, baricitinib 2 mg or 4 mg once daily, with rescue possible from week 16. Patients completing RA-BUILD and entering RA-BEYOND continued to receive the baricitinib dose received at the end of RA-BUILD. Patients receiving placebo were switched to baricitinib 4 mg in RA-BEYOND. Joint damage was measured using the van der Heijde modified total Sharp score. To account for missing scores and scores obtained after rescue, switch or discontinuation of study drug, data were analysed using (1) linear extrapolation (LE) and (2) observed/last observation carried forward (LOCF). The observed/LOCF method used all available observed data, including after rescue or switch, with patients analysed according to original treatment assignment. RESULTS: Using LE, radiographic progression at 24 and 48 weeks was statistically significantly lower for both baricitinib 2 or 4 mg compared with placebo. Only baricitinib 4 mg demonstrated statistically significant inhibition of progressive radiographic joint damage compared with patients initially randomised to placebo using observed/LOCF at week 48. CONCLUSIONS: Once daily oral baricitinib inhibited radiographic progression of structural joint damage in patients with an inadequate response or intolerance to csDMARDs over 48 weeks. The most robust benefit was seen for the 4 mg dose.
ABSTRACT
OBJECTIVE: To assess the effects of baricitinib on lipid profiles in patients with moderate-to-severe rheumatoid arthritis. METHODS: Treatment with once-daily doses of baricitinib (1, 2, 4, or 8 mg) or placebo was studied in 301 randomized patients. Changes in lipid profile and lipoprotein particle size and particle number were assessed at weeks 12 and 24, and associations with clinical efficacy were evaluated. Apolipoproteins were assessed at weeks 4 and 12 in the placebo group and the 4-mg and 8-mg baricitinib groups. RESULTS: Treatment with baricitinib resulted in dose-dependent increases in serum lipid levels from baseline to week 12 (low-density lipoprotein [LDL] cholesterol increases of 3.4 mg/dl and 11.8 mg/dl in the 1 mg and 8 mg treatment groups, respectively; high-density lipoprotein [HDL] cholesterol increases of 3.3 mg/dl and 8.1 mg/dl, respectively; triglycerides increases of 6.4 mg/dl and 15.4 mg/dl, respectively). Group-wise mean increases in LDL cholesterol were coincident with mean increases in large LDL particles and mean reductions in small dense LDL particles. Increases from baseline to week 12 in apolipoprotein A-I, apolipoprotein B, and apolipoprotein CIII were observed with 4-mg doses of baricitinib (9.5%, 6.8%, and 23.0%, respectively) and with 8-mg doses (12.2%, 7.1%, and 19.7%, respectively), with no increase in LDL-associated apolipoprotein CIII (-4.5% with 4-mg baricitinib; -9.0% with 8-mg baricitinib). Baricitinib reduced HDL-associated serum amyloid A when administered at 4 mg (-36.0%) and 8 mg (-32.0%); a significant reduction in lipoprotein (a) was observed only with 8-mg doses (-16.6%). Increased HDL cholesterol at week 12 correlated with improved Disease Activity Scores and Simplified Disease Activity Index; changes in total cholesterol, LDL cholesterol, and triglycerides did not reveal a similar relationship. CONCLUSION: Baricitinib-associated increases in serum lipid levels were observed in this study. Increases in levels of HDL cholesterol correlated with improved clinical outcomes.
Subject(s)
Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Azetidines/administration & dosage , Sulfonamides/administration & dosage , Antirheumatic Agents/therapeutic use , Apolipoprotein A-I/metabolism , Apolipoprotein C-III/metabolism , Apolipoproteins B/metabolism , Arthritis, Rheumatoid/metabolism , Azetidines/therapeutic use , Cholesterol, HDL/metabolism , Cholesterol, LDL/metabolism , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Lipoprotein(a)/metabolism , Male , Middle Aged , Purines , Pyrazoles , Serum Amyloid A Protein/metabolism , Severity of Illness Index , Sulfonamides/therapeutic use , Triglycerides/metabolismABSTRACT
PURPOSE: The role of protein C in critical illness is assessed. SUMMARY: Conversion of protein C to activated protein C (APC) requires thrombin and thrombomodulin. When thrombin is not bound to thrombomodulin, it can convert fibrinogen to fibrin, factor V to factor Va, and factor VIII to factor VIIIa but will not convert protein C to APC. When thrombin is bound to thrombomodulin, it can convert protein C to APC but cannot convert fibrinogen, factor V, or factor VIII. Activation of protein C is accelerated by the presence of endothelial protein C receptors. In conjunction with protein S, APC limits coagulation by inactivating factors Va and VIIIa, which decreases thrombin-mediated inflammation. By inhibiting the formation of thrombin and the release of proinflammatory cytokines, APC reduces the inflammatory response to infection. By inducing cell signaling, APC directly modulates the cellular response to infection, resulting in antiinflammatory, cytoprotective, and barrier-protective activities. APC is metabolized by protease inhibitors and other proteins in the plasma. Conversion of protein C to APC is impaired in severe sepsis. During severe sepsis, endogenous levels of the inactive precursor protein C are reduced because of decreased production by the liver and degradation by enzymes. More than 85% of patients with severe sepsis have low levels of protein C. Absolute levels of protein C correlate with morbidity and mortality outcomes of the sepsis population, regardless of age, infecting microorganism, presence of shock, disseminated intravascular coagulation, degree of hypercoagulation, or severity of illness. CONCLUSION: The protein C pathway is a natural homeostatic regulator with multiple mechanisms of action. Blood protein C concentration is inversely correlated with morbidity and mortality in sepsis and other critical illness.