Impact of dupilumab across seasons in patients with type 2, uncontrolled, moderate-to-severe asthma.

BACKGROUND: Seasonal variability could influence asthma exacerbations. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4/IL-13, key and central drivers of type 2 inflammation. In the 52-week QUEST study (NCT02414854), add-on dupilumab every 2 weeks vs placebo significantly reduced exacerbations and improved prebronchodilator forced expiratory volume in 1 second in patients with uncontrolled, moderate-to-severe asthma. TRAVERSE (NCT02134028), the open-label QUEST extension study, enrolled patients with moderate-to-severe asthma to investigate long-term safety and efficacy of dupilumab, including patients who previously received placebo that initiated dupilumab therapy. OBJECTIVE: To investigate long-term dupilumab efficacy in reducing exacerbations across yearly seasons in patients with type 2 inflammatory asthma with and without clinical evidence of allergic asthma. METHODS: Unadjusted annualized exacerbation rate and proportions of patients experiencing severe asthma exacerbations are reported by month and season and for both hemispheres. RESULTS: The proportion of patients with type 2 asthma experiencing 1 or more severe asthma exacerbations during QUEST was 20.8% vs 10.0% in spring, 18.2% vs 7.3% in summer, 22.2% vs 12.6% in autumn, and 26.4% vs 12.0% in winter, for placebo- vs dupilumab-treated patients, respectively; P was less than .001 for placebo vs dupilumab in all seasons. Reductions in the proportion of patients experiencing severe exacerbations across seasons in subgroups with and without evidence of allergic asthma were similar to the overall type 2 population. Reductions in severe exacerbations observed during QUEST were sustained during TRAVERSE, up to 96 weeks across both hemispheres. CONCLUSION: Dupilumab reduced asthma exacerbations, with no difference in the reduction between seasons, in patients with type 2 inflammation, with and without evidence of allergic asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02414854, NCT02134028.

Efficacy of dupilumab in patients with uncontrolled, moderate-to-severe asthma with fungal sensitization.

BACKGROUND: Fungal sensitization (FS) exacerbates asthma in patients who have elevated type 2 inflammatory response. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13, key and central drivers of type 2 inflammation in multiple diseases. OBJECTIVE: This post hoc analysis, funded by the manufacturers of dupilumab, was conducted to assess dupilumab efficacy in patients from the phase 3 LIBERTY ASTHMA QUEST trial (NCT02414854) and TRAVERSE open-label extension (NCT02134028) study who had uncontrolled, moderate-to-severe asthma with type 2 inflammatory phenotype (defined as blood eosinophil count ≥150 cells/µL or FeNO ≥25 ppb) and with FS (defined as IgE specific to Alternaria alternata, Aspergillus fumigatus or Cladosporium herbarum >0.35 IU/mL). METHODS: We evaluated annualized rate of severe exacerbations (AER), change from baseline in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1 ), asthma control (per 5-item Asthma Control Questionnaire [ACQ-5]) and biomarker levels (blood eosinophil count, fractional exhaled nitric oxide [FeNO], total IgE, fungal-specific IgEs, thymus and activation-regulated chemokine [TARC] and eotaxin-3). RESULTS: Dupilumab vs. placebo reduced AER, improved pre-BD FEV1 and asthma control (ACQ-5), and reduced serum IgE levels, blood eosinophil count, TARC, eotaxin-3 and FeNO in patients both with and without FS after 52 weeks of treatment in QUEST. Reductions in asthma exacerbation rates and improvements in all other variables were sustained over the TRAVERSE open-label extension study. CONCLUSION: Dupilumab demonstrated efficacy during prolonged treatment in patients with uncontrolled, moderate-to-severe asthma with FS.

Dupilumab sustains efficacy in patients with moderate-to-severe type 2 asthma regardless of inhaled corticosteroids dose.

BACKGROUND: Dupilumab, a human monoclonal antibody, blocks the shared receptor component for interleukins-4/13, key and central drivers of type 2 inflammation. The TRAVERSE (NCT02134028) open-label extension study demonstrated the long-term safety and efficacy of dupilumab in patients ≥12 years who completed a previous dupilumab asthma study. The safety profile was consistent with that observed in the parent studies. Here, we assess whether dupilumab sustains long-term efficacy in patients regardless of inhaled corticosteroid (ICS) dose at parent study baseline (PSBL). METHODS: Patients from phase 2b (NCT01854047) or phase 3 (QUEST; NCT02414854) studies receiving high- or medium-dose ICS at PSBL and enrolled in TRAVERSE were included. We analyzed unadjusted annualized severe exacerbation rates, change from PSBL in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1 ), 5-item asthma control questionnaire, and type 2 biomarkers in patients with type 2 asthma at baseline (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥25 ppb), and subgroups defined by baseline blood eosinophils or FeNO. RESULTS: Of patients with type 2 asthma (n = 1666), 891 (53.5%) were receiving high-dose ICS at PSBL. In this subgroup, unadjusted exacerbation rates for dupilumab versus placebo were 0.517 versus 1.883 (phase 2b) and 0.571 versus 1.300 (QUEST) over the parent study (52 weeks) and remained low throughout TRAVERSE (0.313-0.494). Improvements in pre-BD FEV1 were sustained throughout TRAVERSE. Similar clinical efficacy was observed among patients receiving medium-dose ICS at PSBL and biomarker subgroups. CONCLUSIONS: Dupilumab showed sustained efficacy for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 asthma on high- or medium-dose ICS.

Dupilumab improves long-term outcomes in patients with uncontrolled, moderate-to-severe GINA-based type 2 asthma, irrespective of allergic status.

BACKGROUND: Previous research has shown greater efficacy of dupilumab in patients with uncontrolled asthma and type 2 inflammation. We analyzed dupilumab's efficacy in patients from the TRAVERSE study with or without evidence of allergic asthma and type 2 inflammation per current GINA guidelines (≥150 eosinophils/µL or FeNO ≥20 ppb). METHODS: All patients aged ≥12 years who rolled over from the placebo-controlled QUEST study (NCT02414854) to TRAVERSE (NCT02134028) received add-on dupilumab 300 mg every 2 weeks for up to 96 weeks. We assessed annualized severe asthma exacerbation rates (AERs) and changes from parent-study baseline (PSBL) in pre-bronchodilator FEV1 and 5-item asthma control questionnaire (ACQ-5) score in patients with moderate-to-severe type 2 asthma with and without evidence of allergic asthma at PSBL. RESULTS: In TRAVERSE, dupilumab consistently reduced AER across all subgroups. By Week 96, dupilumab increased pre-bronchodilator FEV1 from PSBL by 0.35-0.41 L in patients receiving placebo during QUEST (placebo/dupilumab) and 0.34-0.44 L in those receiving dupilumab during QUEST (dupilumab/dupilumab) with an allergic phenotype at baseline. In patients without evidence of allergic asthma, pre-bronchodilator FEV1 improved by 0.38-0.41 L and 0.33-0.37 L, respectively. By Week 48, ACQ-5 scores decreased from PSBL by 1.63-1.69 (placebo/dupilumab) and 1.74-1.81 (dupilumab/dupilumab) points across subgroups with allergic asthma, and 1.75-1.83 (placebo/dupilumab) and 1.78-1.86 (dupilumab/dupilumab) in those without. CONCLUSIONS: Long-term treatment with dupilumab reduced exacerbation rates and improved lung function and asthma control in patients with asthma with type 2 inflammation as per current GINA guidance and irrespective of evidence of allergic asthma.

Long-term efficacy of dupilumab in asthma with or without chronic rhinosinusitis and nasal polyps.

BACKGROUND: Coexisting chronic rhinosinusitis and nasal polyps (CRS-NPs) substantially increases the disease burden of asthma. Dupilumab, a fully human monoclonal antibody, has established efficacy and an acceptable safety profile in asthma and CRS with NP. OBJECTIVE: To evaluate long-term dupilumab efficacy in TRAVERSE (NCT02134028) patients with uncontrolled, moderate-to-severe (QUEST) or oral corticosteroid (OCS)-dependent (VENTURE) asthma with or without coexisting CRS-NP. METHODS: In TRAVERSE, 317 of 1530 (21%) QUEST and 61 of 187 (48%) VENTURE patients had self-reported CRS-NP; they received subcutaneous 300 mg dupilumab every 2 weeks up to 96 weeks. Patients were categorized by parent study treatment group (placebo/dupilumab, dupilumab/dupilumab). End points included annualized asthma exacerbation rates and mean change from parent study baseline in prebronchodilator forced expiratory volume in 1 second, Asthma Control Questionnaire 5 score, Asthma Quality of Life Questionnaire score, and OCS dose. RESULTS: Patients with coexisting CRS-NP had higher OCS dose and a history of more exacerbations. Concluding TRAVERSE, exacerbation rates decreased from 2.39 to 0.32 and 2.32 to 0.35 in dupilumab/dupilumab and 2.36 to 0.41 and 2.36 to 0.45 in placebo/dupilumab by week 96 from QUEST and VENTURE baselines, respectively. Non-CRS-NP results were similar. Improvements in forced expiratory volume in 1 second, Asthma Control Questionnaire 5 score, and Asthma Quality of Life Questionnaire score during parent studies were maintained in TRAVERSE; placebo/dupilumab patients achieved similar improvements to dupilumab/dupilumab by week 48. By week 96, 71% and 39% of OCS-dependent patients with CRS-NP and 83% and 47% without CRS-NP treated with dupilumab/dupilumab and placebo/dupilumab, respectively, stopped OCS. CONCLUSION: Long-term dupilumab efficacy was maintained in patients with asthma with or without self-reported coexisting CRS-NP, including OCS-sparing effects observed in OCS-dependent severe asthma. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02528214, NCT02414854, and NCT02134028.

Efficacy of dupilumab in patients with moderate-to-severe asthma and persistent airflow obstruction.

BACKGROUND: The 52-week, phase 3 LIBERTY ASTHMA QUEST study (NCT02414854) in patients aged above or equal to 12 years with uncontrolled, moderate-to-severe asthma demonstrated the efficacy and safety of dupilumab 200 mg and 300 mg every 2 weeks vs matched placebo. OBJECTIVE: To assess whether dupilumab improves clinical outcomes in QUEST patients with persistent airflow obstruction (PAO) defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity ratio less than 0.7 at baseline. METHODS: End points were annualized rate of severe exacerbations, pre and post-bronchodilator forced expiratory volume in 1 second over time, proportion achieving reversal of PAO, and quality of life. Efficacy was evaluated in patients with or without PAO at baseline in subpopulations with eosinophils ≥ 150 cells/µL or fractional exhaled nitric oxide (FeNO) ≥ 25 ppb or eosinophils ≥ 300 cells/µL and FeNO ≥ 25 ppb. RESULTS: Of 1902 patients enrolled in QUEST, 1039 (55%) had PAO at baseline. Dupilumab vs placebo rapidly and significantly improved lung function in patients with PAO and elevated type 2 inflammatory biomarkers at baseline. Dupilumab improved probability of reversing airflow obstruction (hazard ratio vs placebo 1.616 [95% confidence interval, 1.272-2.052] and 1.813 [1.291-2.546]; both P < .001) and significantly reduced severe exacerbations by 69% (relative risk, 0.411; 95% confidence interval [0.327-0.516]; P < .0001) and by 75% (0.252 [0.178-0.356]; P < .0001) in patients with PAO with eosinophils ≥ 150 cells/µL or FeNO ≥ 25 ppb and eosinophils ≥ 300 cells/µL and FeNO ≥ 25 ppb, respectively. Similar results were observed in patient subgroups without PAO. CONCLUSION: In patients with uncontrolled moderate-to-severe asthma, treatment with dupilumab facilitates reversal of PAO status and improves clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02414854.

Dupilumab long-term efficacy in patients with non-OCS-dependent asthma with and without evidence of allergic asthma.

OBJECTIVE: The open-label extension TRAVERSE study (NCT02134028) assessed dupilumab long-term safety and efficacy in patients who completed Phase 2/3 dupilumab asthma studies. This post hoc analysis evaluated long-term efficacy in type 2 patients with and without evidence of allergic asthma who enrolled in TRAVERSE from Phase 3 QUEST (NCT02414854) and Phase 2b (NCT01854047) studies. Non-type 2 patients with evidence of allergic asthma were also assessed. METHODS: Unadjusted annualized exacerbation rates during parent study and TRAVERSE treatment period, and changes from parent study baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV1) and in 5-item Asthma Control Questionnaire (ACQ-5) scores were assessed in patients from QUEST and Phase 2b; change from parent study baseline in total IgE level was assessed in patients enrolled from Phase 2b. RESULTS: 2062 patients from Phase 2b and QUEST enrolled in TRAVERSE. Of these, 969 were type 2 with evidence of allergic asthma; 710 were type 2 without evidence of allergic asthma; and 194 were non-type 2 with evidence of allergic asthma at parent study baseline. In these populations, reductions in exacerbation rates observed during parent studies were sustained during TRAVERSE. Type 2 patients who switched from placebo arm to dupilumab in TRAVERSE experienced similar reductions in severe exacerbation rates, and improvements in lung function and asthma control to those patients who already received dupilumab during the parent study. CONCLUSION: Dupilumab efficacy was sustained for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 inflammatory asthma, with or without evidence of allergic asthma.ClinicalTrials.gov identifier: NCT02134028.

Temporal profile of serum neurofilament light in multiple sclerosis: Implications for patient monitoring.

OBJECTIVE: To understand how longitudinal serum neurofilament light chain (sNfL) patterns can inform its use as a prognostic biomarker in multiple sclerosis (MS) and evaluate whether sNfL reflects MS disease activity and disease-modifying therapy usage. METHODS: This was a post hoc analysis of longitudinal data and samples from the ADVANCE trial (NCT00906399) of patients with relapsing-remitting MS (RRMS). sNfL was measured every 3 months for 2 years, then every 6 months for 4 years. Regression models explored how sNfL data predicted 4-year values of brain volume, expanded disability status scale score, and T2 lesions. sNfL levels were assessed in those receiving placebo, peginterferon beta-1a, and those with disease activity. RESULTS: Baseline sNfL was a predictor of 4-year brain atrophy and development of new T2 lesions. Clinical (p = 0.02) and magnetic resonance imaging (MRI) (p < 0.01) outcomes improved in those receiving peginterferon beta-1a whose sNfL decreased to <16 pg/mL after 12 months versus those whose sNfL remained ⩾16 pg/mL. Mean sNfL levels decreased in peginterferon beta-1a-treated patients and increased in placebo-treated patients (-9.5% vs. 6.8%; p < 0.01). sNfL was higher and more variable in patients with evidence of active MS. CONCLUSION: These data support sNfL as a prognostic and disease-monitoring biomarker for RRMS.

Responder definition of the Multiple Sclerosis Impact Scale physical impact subscale for patients with physical worsening.

BACKGROUND: The 29-item Multiple Sclerosis Impact Scale (MSIS-29) was developed to examine the impact of multiple sclerosis (MS) on physical and psychological functioning from a patient's perspective. OBJECTIVE: To determine the responder definition (RD) of the MSIS-29 physical impact subscale (PHYS) in a group of patients with relapsing-remitting MS (RRMS) participating in a clinical trial. METHODS: Data from the SELECT trial comparing daclizumab high-yield process with placebo in patients with RRMS were used. Physical function was evaluated in SELECT using three patient-reported outcomes measures and the Expanded Disability Status Scale (EDSS). Anchor- and distribution-based methods were used to identify an RD for the MSIS-29. RESULTS: Results across the anchor-based approach suggested MSIS-29 PHYS RD values of 6.91 (mean), 7.14 (median) and 7.50 (mode). Distribution-based RD estimates ranged from 6.24 to 10.40. An RD of 7.50 was selected as the most appropriate threshold for physical worsening based on corresponding changes in the EDSS (primary anchor of interest). CONCLUSION: These findings indicate that a ≥7.50 point worsening on the MSIS-29 PHYS is a reasonable and practical threshold for identifying patients with RRMS who have experienced a clinically significant change in the physical impact of MS.

Incident severe thrombocytopenia in veterans treated with pegylated interferon plus ribavirin for chronic hepatitis C infection.

PURPOSE: We sought to determine the incidence and risks for severe thrombocytopenia (platelets < 50,000/µL) in United States Veteran patients treated with pegylated interferon (PEG-IFN) plus ribavirin for hepatitis C virus-positive (HCV) chronic liver disease (CLD). METHODS: Using a retrospective, observational cohort study design to analyze databases from the New England Veterans Healthcare System, we identified 979 patients diagnosed with HCV-positive CLD treated solely with PEG-IFN plus ribavirin. The cohort was stratified by pre-treatment platelet counts of 50,000-100,000/µL (N = 90), >100,000-150,000/µL (N = 162), and >150,000µL (N = 727). The cumulative incidence of severe thrombocytopenia and major bleeding events were determined for each baseline platelet group for 48 weeks following treatment initiation. Multivariable Cox regression was used to identify risk factors for incident severe thrombocytopenia. RESULTS: Overall, severe thrombocytopenia occurred in 6.1% (N = 60), but in 41.1% of patients with pre-treatment platelet counts 50, 000-100,000/µL compared with 11.7% (p < 0.001) and 0.55% (p < 0.001) in the two higher pre-treatment platelet groups. Most episodes occurred within the first 12 weeks of treatment. Median nadir count for these 60 patients was 35,000/µL (inter-quartile range 28,000, 44,000). Baseline platelet counts of 50,000-100,000/µL [adjusted hazard ratio (HR) = 3.81; 95%CI = 2.07-7.00] and hemoglobin <10 g/dL (adjusted HR = 3.39; 95%CI = 1.45-7.960) associated with severe thrombocytopenia. Major bleeding events during the 48-week observation period were rare (N = 5, 0.51%). CONCLUSIONS: The incidence of severe thrombocytopenia in a large, observational cohort of veteran patients with HCV CLD treated with PEG-IFN plus ribavirin was 6.1%. Low pre-treatment platelet counts and hemoglobin levels associated with early, incident severe thrombocytopenia.

Impact of Exacerbation History on Dupilumab Efficacy in Children with Uncontrolled Moderate-to-Severe Asthma: LIBERTY ASTHMA VOYAGE Study.

Purpose: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4/-13, key and central drivers of type 2 inflammation in multiple diseases. This post hoc analysis of the Phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959) evaluated the efficacy of dupilumab in children aged 6 to 11 years with moderate-to-severe asthma with a type 2 inflammatory phenotype (blood eosinophil count ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥20 ppb) and a history of 1, 2, or ≥3 prior exacerbations. The impact of baseline type 2 biomarker levels on the efficacy of dupilumab in this population was also investigated. Patients and Methods: Patients were stratified by the number of exacerbations in the prior year (1, 2, or ≥3) and level of FeNO or blood eosinophil count at baseline. Endpoints included rate of severe exacerbations, percentage of non-exacerbators, and change from baseline in both lung function parameters (pre- and post-bronchodilator [BD] percent predicted forced expiratory volume in 1 s (ppFEV1) and ppFEV1/forced vital capacity [FVC] ratio) and Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) score. Results: A total of 350 patients were included in this analysis. Across patients with 1, 2, or ≥3 prior exacerbations and different levels of type 2 biomarkers, dupilumab reduced the risk of severe asthma exacerbations vs placebo by 53.0-96.0% and improved both pre-BD ppFEV1 and pre-BD FEV1/FVC ratio at Week 52. Dupilumab led to significant reductions in ACQ-7-IA scores in all groups of patients by Week 52. Conclusion: In children with uncontrolled, moderate-to-severe asthma with a type 2 phenotype, dupilumab consistently reduced the risk of asthma exacerbations, improved lung function, and reduced ACQ-7-IA scores, regardless of exacerbation history.

Dupilumab sustains lung function improvements in patients with moderate-to-severe asthma.

BACKGROUND: TRAVERSE (NCT02134028), a phase 3 open-label extension study, assessed dupilumab safety and efficacy in patients with asthma aged ≥12 years who completed a previous dupilumab asthma study. This analysis evaluated changes in multiple lung function parameters in patients with moderate-to-severe asthma with elevated type 2 biomarkers (baseline eosinophils ≥150 cells·µL-1 or fractional exhaled nitric oxide ≥25 ppb) who completed QUEST (parent study) and 2 years of dupilumab treatment in TRAVERSE. METHODS: Endpoints analyzed included: pre-bronchodilator forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), forced expiratory flow (FEF25-75 %), and pre- and post-bronchodilator FEV1/FVC at parent study baseline (PSBL) at Weeks 0, 2, 48, and 96 in TRAVERSE, as well as pre- and post-bronchodilator FEV1 slopes in QUEST and TRAVERSE. Statistical analyses were descriptive. RESULTS: Dupilumab improved pre-bronchodilator FEV1, FVC, and FEF25-75 % in QUEST; these improvements were sustained in TRAVERSE. In QUEST patients who received placebo, dupilumab initiation in TRAVERSE resulted in rapid lung function improvements. Mean (standard deviation) changes from PSBL at TRAVERSE Weeks 48 and 96 in pre-bronchodilator FEV1 were 0.52 (0.59) and 0.45 (0.49) L in the dupilumab/dupilumab group and 0.47 (0.42) and 0.44 L (0.45) in the placebo/dupilumab group, respectively. Similar trends were observed for FVC and FEF25-75 %. Dupilumab also improved FEV1 slopes in QUEST and TRAVERSE. CONCLUSION: Dupilumab demonstrated sustained improvements across multiple spirometric lung function measurements for up to 3 years; patients who received placebo in QUEST experienced rapid lung function improvement upon initiation of dupilumab in TRAVERSE.

Dupilumab Reduces Exacerbations Independent of Changes in Biomarkers in Moderate-to-Severe Asthma.

BACKGROUND: Changes from baseline in fractional exhaled nitric oxide (FeNO) and blood eosinophil count (Eos) may be related to efficacy outcomes in dupilumab-treated patients with moderate-to-severe asthma. OBJECTIVE: This post hoc analysis investigated biomarker changes in placebo- and dupilumab-treated patients with uncontrolled moderate-to-severe asthma enrolled in QUEST (NCT02414854). METHODS: Spline analyses of annualized severe exacerbation rate (AER) and change from baseline in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) at week 52 were performed as a function of the fold change in FeNO at week 52 and the maximum fold change in Eos over weeks 0-12 (also change from baseline in pre-BD FEV1 at week 12). RESULTS: The combined placebo and dupilumab groups comprised 638 and 1264 patients, respectively. FeNO levels declined rapidly by week 2 and then gradually to week 52 in patients treated with dupilumab versus placebo; Eos, after initially increasing with dupilumab, declined slightly from baseline in both treatment groups. AER during QUEST showed no significant association with the change in biomarkers in either treatment group. The change from baseline in pre-BD FEV1 at week 52 was inversely associated with the fold change in FeNO in both groups, with a significant difference between the dupilumab and placebo curves (P = .014), and was positively associated with the fold change in Eos in both groups (P = .022). CONCLUSIONS: Relative changes in FeNO and Eos were not associated with AER, regardless of treatment arm. However, changes in both biomarkers showed a predictive value for lung function improvement; for FeNO, this was specific to the dupilumab treatment arm.

Dupilumab Improves Lung Function Parameters in Pediatric Type 2 Asthma: VOYAGE Study.

BACKGROUND: Uncontrolled asthma in growing children can impair lung growth that may lead to adverse complications in later life. Dupilumab, a human monoclonal antibody, blocks the shared receptor for IL-4 and IL-13, key drivers of type 2 inflammation. OBJECTIVE: To extensively evaluate the effect of dupilumab on lung function in children (6-11 years) with moderate-to-severe asthma enrolled in phase 3 LIBERTY ASTHMA VOYAGE (NCT02948959). METHODS: Children with asthma were randomized 2:1 to add-on dupilumab 100/200 mg by bodyweight or placebo every 2 weeks, for 52 weeks. We analyzed spirometry parameters in children with type 2 asthma (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥20 parts per billion [ppb] at baseline) and within subgroups defined by baseline blood eosinophils or FeNO values. RESULTS: A total of 116 (49%) dupilumab-treated children and 59 (52%) on placebo had impaired lung function (prebronchodilator percent-predicted forced expiratory volume in 1 second [ppFEV1] <80%) at baseline. Dupilumab improved pre- and postbronchodilator ppFEV1 as early as week 2, sustained for up to 52 weeks (least-squares mean difference vs placebo at week 52: 7.79 percentage points; 95% confidence interval [CI]: 4.36-11.22; P < .001 and 4.37 points; 95% CI: 0.95-7.78; P = .01, respectively). Sustained improvements were also observed in other lung function parameters, including pre- and postbronchodilator forced vital capacity (FVC), prebronchodilator forced expiratory flow, and FEV1/FVC ratio across all populations. CONCLUSIONS: Dupilumab led to significant, sustained lung function improvements across a range of lung function measures in children (6-11 years) with uncontrolled, moderate-to-severe type 2 asthma.

Temporal Relationship Between Serum Neurofilament Light Chain and Radiologic Disease Activity in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Serum neurofilament light chain (sNfL) levels correlate with multiple sclerosis (MS) disease activity, but the dynamics of this correlation are unknown. We evaluated the relationship between sNfL levels and radiologic MS disease activity through monthly assessments during the 24-week natalizumab treatment interruption period in RESTORE (NCT01071083). METHODS: In the RESTORE trial, participants with relapsing forms of MS who had received natalizumab for ≥12 months were randomized to either continue or stop natalizumab and followed with MRI and blood draws every 4 weeks to week 28 and again at week 52 The sNfL was measured, and its dynamics were correlated with the development of gadolinium-enhancing (Gd+) lesions. Log-linear trend in sNfL levels were modeled longitudinally using generalized estimating equations with robust variance estimator from baseline to week 28. RESULTS: Of 175 patients enrolled in RESTORE, 166 had serum samples for analysis. Participants with Gd+ lesions were younger (37.7 vs 43.1, p = 0.001) and had lower Expanded Disability Status Scale scores at baseline (2.7 vs 3.4, p = 0.017) than participants without Gd+ lesions. sNfL levels increased in participants with Gd+ lesions (n = 65) compared with those without (n = 101, mean change from baseline to maximum sNfL value, 12.1 vs 3.2 pg/mL, respectively; p = 0.003). As the number of Gd+ lesions increased, peak median sNfL change also increased by 1.4, 3.0, 4.3, and 19.6 pg/mL in the Gd+ lesion groups of 1 (n = 12), 2-3 (n = 18), 4-9 (n = 21), and ≥10 (n = 14) lesions, respectively. However, 46 of 65 (71%) participants with Gd+ lesions did not increase above the 95th percentile threshold of the group without Gd+ lesions. The initial increase of sNfL typically trailed the first observation of Gd+ lesions, and the peak increase in sNfL was a median [interquartile range] of 8 [0, 12] weeks after the first appearance of the Gd+ lesion. DISCUSSION: Although sNfL correlated with the presence of Gd+ lesions, most participants with Gd+ lesions did not have elevations in sNfL levels. These observations have implications for the use and interpretation of sNfL as a biomarker for monitoring MS disease activity in controlled trials and clinical practice.

Thrombocytopenia and bleeding in veterans with non-hepatitis C-related chronic liver disease.

BACKGROUND: Thrombocytopenia in chronic liver disease (CLD) typically reflects disease severity and may indicate an increased risk for bleeding. AIMS: To describe the longitudinal course of thrombocytopenia and risks for bleeding in veteran patients with non-hepatitis C-related CLD. METHODS: We identified 2,349 patients with non-hepatitis C-related CLD from databases of the New England Veterans Healthcare System between 1999 and 2008. The cohort was stratified by baseline platelet counts of <50,000, 50-100,000, > 100,000-150,000, and >150,000/µl. Primary outcomes were the incidence and hazard rates for bleeding episodes requiring hospitalization and incident severe thrombocytopenia (<50,000/µl). RESULTS: Over a median follow-up of 3.3 years (IQR 1.2, 6.3), incident major bleeds, predominantly gastrointestinal, occurred in 254 patients (10.8 % of the cohort) and in 19.9 % of those with baseline platelets <50,000/µl. Incident severe thrombocytopenia occurred in 315 patients (13.4 % of cohort) and in 40.7 % of those with baseline platelet counts between 50,000 and 100,000/µl. Baseline platelet counts between 50,000 and 100,000/µl independently predicted bleeding [adjusted HR 2.89 (1.76, 4.73) p < 0.001] as did esophageal varices, hemoglobin ≤ 9.9 g %, and INR 1.4-2.0. Incident severe thrombocytopenia and minimum platelet counts <25,000/µl each associated with bleeding episodes, but the average of minimum platelet counts recorded for those who bled was 76,000/µl. CONCLUSIONS: Among veteran patients with non-hepatitis C-related CLD, baseline platelet counts of 50,000 to 100,000/µl increased subsequent risks for both incident severe thrombocytopenia and major bleeding events. Whereas associations between severe thrombocytopenia and bleeding most likely reflect CLD severity, liver-related coagulopathies, and co-morbid bleeding risks, interventions to enhance platelet production may be beneficial for such patients.

Higher maternal prenatal cortisol and younger age predict greater infant reactivity to novelty at 4 months: an observation-based study.

Distress-linked activation of the maternal hypothalamic-pituitary-adrenal (HPA)-axis is considered a pathway by which affect regulation impacts the fetal milieu and neurodevelopment. There is little direct evidence for this conceptual model. In 103 women [mean age 27.45 (±5.65) years] at 36-38 weeks gestation, salivary cortisol was measured before/after stress tasks; distress questionnaires were completed. At 18.49 (±1.83) weeks, infants underwent the Harvard Infant Behavioral Reactivity Protocol assessing cry/motor responses to novelty; women reported on infant behavior and postnatal distress. Prenatal cortisol and distress were not significantly correlated (all ps > .10). Proportional odds logistic regressions showed that neither prenatal nor postnatal distress was associated with infant responses to the Harvard Protocol yet pre-stress cortisol and maternal age were: The odds of being classified as High Reactive were 1.60 times higher [95% CI: 1.04, 2.46] for each unit of added cortisol and .90 times lower [95% CI: .82, .99] for every additional year in maternal age. No associations were found between cortisol or prenatal distress and mother-rated infant behavior; postnatal distress was positively associated with mother-rated infant negative behavior (p = .03). Observer and mother-rated infant behavior were not associated (all ps > .05). Based on independent observations of infants in contrast to maternal perceptions, these results lend support to the hypothesis that pregnant women's HPA-axis activity influences infant behavior. The impact of maternal distress was not supported, except in so far as postnatal distress may increase the likelihood of making negative judgments about infant behavior.

Processing speed test: Results from a Japanese normative sample of healthy participants compared with a US normative sample.

BACKGROUND: The Processing Speed Test (PST), a validated iPad®-based cognitive screening test for MS, has been applied to the cognitive assessment of Japanese MS patients using US normative data. METHODS: To develop PST normative data from Japanese healthy volunteers and compare the PST score distribution between Japanese and US healthy volunteers, 254 healthy Japanese-speaking volunteers were enrolled and stratified by age (20-65 years). Potential participants with a Mini-Mental State Examination score < 27 were excluded. PST raw scores (total correct) were from the Japan cohort and compared with age-restricted US normative data and propensity score-matched data created by matching sex, age, and educational level from a published study of 428 healthy participants. PST score distributions and standardized z-scores were compared using t-test and Kolmogorov-Smirnov test statistics. RESULTS: The mean age of the Japan cohort was 44.1 years. The PST scores of Japanese volunteers were significantly different from those of the age-restricted (mean ± SD 61.8 ± 10.1 vs 53.7 ± 10.8; p < 0.001) and the propensity score-matched US cohort (62.1 ± 10.1 vs 53.3 ± 10.6; p < 0.001). CONCLUSION: Regression analyses centered on US normative data could underestimate disease severity in Japanese MS patients, suggesting that separate normative data should be considered for each population sample.

Impact of exacerbation history on long-term efficacy of dupilumab in patients with asthma.

Background: The phase 3 QUEST (NCT02414854) and TRAVERSE (NCT02134028) studies demonstrated the efficacy of dupilumab 200/300 mg versus placebo every 2 weeks for 52 weeks (QUEST) and dupilumab 300 mg up to an additional 96 weeks (TRAVERSE) in patients ≥12 years of age with uncontrolled, moderate-to-severe asthma. Overall, safety was consistent with the known dupilumab safety profile. This post hoc analysis assessed long-term dupilumab efficacy for up to 3 years by exacerbation history. Patients and methods: Unadjusted annualised severe exacerbation rates (AER) and change from parent study baseline (PSBL) in pre-bronchodilator forced expiratory volume in 1 s (FEV1) and 5-item Asthma Control Questionnaire (ACQ-5) score were assessed in patients with PSBL eosinophils ≥150 cells·µL-1 or fractional exhaled nitric oxide ≥20 ppb and 1 (n=624), 2 (n=344), or ≥3 (n=311) exacerbations in the year before enrolment in QUEST. Results: In all three groups, dupilumab treatment progressively reduced AER range to 0.17-0.30 during TRAVERSE (Weeks 48-96), increased pre-bronchodilator FEV1 range by 0.28-0.49 L by Week 96 and improved asthma control (reduced ACQ-5 score range by 1.51-2.03 by Week 48). For patients who first received dupilumab upon TRAVERSE enrolment, AER decreased, and lung function and asthma control improved rapidly, as was observed upon initiation of dupilumab in QUEST. Dupilumab was efficacious regardless of exacerbation history. Conclusion: For patients with uncontrolled, moderate-to-severe asthma with elevation of at least one type 2 biomarker, dupilumab treatment provides sustained, long-term reduction of exacerbation rates and improvements in lung function and asthma control irrespective of exacerbation history.