Attainment of treat-to-target endpoints in SLE patients with high disease activity in the atacicept phase 2b ADDRESS II study

OBJECTIVE Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. METHODS Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician’s Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response. RESULTS Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. CONCLUSION At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. TRAIL REGISTRATION ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568

Safety and clinical activity of atacicept in the long-term extension of the Phase IIb ADDRESS II study in systemic lupus erythematosus

Objectives: Atacicept reduced SLE disease activity in the Phase IIb ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II. Methods: In the 24-week, randomised, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary end point. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares. Results: 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4–93.2%). 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo. Conclusion: Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy

Efficacy and Safety of Atacicept in Patients With Systemic Lupus Erythematosus: Results of a Twenty‐Four–Week, Multicenter, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Arm, Phase IIb Study

OBJECTIVE: To evaluate the efficacy and safety of atacicept, an antagonist of BLyS/APRIL-mediated B cell activation, in patients with systemic lupus erythematosus (SLE). METHODS: ADDRESS II was a phase IIb, multicentre study (NCT01972568). Patients with active, autoantibody-positive SLE receiving standard therapy were randomized (1:1:1) to atacicept (75 or 150 mg) or placebo for 24 weeks. The primary endpoint was the SLE responder index (SRI)-4 at Week 24. RESULTS: The ITT population included 306 patients. There was a trend towards improved SRI-4 response rate with atacicept 75 mg (57.8% [adjusted OR 1.78], P = 0.045) and 150 mg (53.8% [adjusted OR 1.56], P = 0.121) versus placebo (44.0%) at Week 24 (primary analysis; screening visit as baseline). In a pre-specified sensitivity analysis using study Day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg (55.9% [adjusted OR 1.88], P = 0.029) and 150 mg (55.8% [adjusted OR 1.96], P = 0.020) achieved SRI-4 response at Week 24 versus placebo (41%). In pre-defined subpopulations with baseline high disease activity (HDA), serologically active disease (SA), or both, statistically significant improvements in SRI-4 and SRI-6 response rates were seen with atacicept versus placebo. Severe flare risk was reduced with atacicept in both the ITT and HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept versus placebo. CONCLUSION: Atacicept showed evidence of efficacy in SLE, particularly in HDA and SA patients. Reductions in disease activity and severe flare were observed with atacicept treatment, along with an acceptable safety profile

8 Efficacy and safety of atacicept in patients with systemic lupus erythematosus: results of a 24-week randomisedrandomized, placebo-controlled, phase iib study

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Moisture transport by Atlantic tropical cyclones onto the North American continent

Tropical Cyclones (TCs) are an important source of freshwater for the North American continent. Many studies have tried to estimate this contribution by identifying TC-induced precipitation events, but few have explicitly diagnosed the moisture fluxes across continental boundaries. We design a set of attribution schemes to isolate the column-integrated moisture fluxes that are directly associated with TCs and to quantify the flux onto the North American Continent due to TCs. Averaged over the 2004–2012 hurricane seasons and integrated over the western, southern and eastern coasts of North America, the seven schemes attribute 7 to 18 % (mean 14 %) of total net onshore flux to Atlantic TCs. A reduced contribution of 10 % (range 9 to 11 %) was found for the 1980–2003 period, though only two schemes could be applied to this earlier period. Over the whole 1980–2012 period, a further 8 % (range 6 to 9 % from two schemes) was attributed to East Pacific TCs, resulting in a total TC contribution of 19 % (range 17 to 22 %) to the ocean-to-land moisture transport onto the North American continent between May and November. Analysis of the attribution uncertainties suggests that incorporating details of individual TC size and shape adds limited value to a fixed radius approach and TC positional errors in the ERA-Interim reanalysis do not affect the results significantly, but biases in peak wind speeds and TC sizes may lead to underestimates of moisture transport. The interannual variability does not appear to be strongly related to the El Nino-Southern Oscillation phenomenon

Clinical trial parameters that influence outcomes in lupus trials that use the systemic lupus erythematosus responder index

Objective: The SLE Responder Index (SRI) is a composite endpoint used in SLE trials. This investigation examined the clinical trial elements that drive response measured by the SRI. Methods: Analyses are based on data from two phase 3 trials (n = 2262) that evaluated the impact of an anti-B-cell activating factor antibody on disease activity using SRI-5 as the primary endpoint (ClinicalTrials.gov NCT01196091 and NCT01205438). Results: The SRI-5 response rate at week 52 for all patients was 32.8%. Non-response due to a lack of SLEDAI improvement, concomitant medication non-compliance or dropout was 31, 16.5 and 19.1%, respectively. Non-response due to deterioration in BILAG or Physician's Global Assessment after SLEDAI improvement, concomitant medication compliance and trial completion was 0.5%. Disease activity in three SLEDAI organ systems was highly prevalent at baseline: mucocutaneous, 90.6%; musculoskeletal, 82.9%; and immunologic, 71.6%. Disease activity in each of the other organ systems was <11% of patients. Four clinical manifestations were highly prevalent at baseline: arthritis, 82.6%; rash, 69.2%; alopecia, 58.2%; and mucosal ulcer, 32.5%. The combined prevalence of renal, vascular and CNS disease at baseline was 17.6%; these patients had high SRI-5 response rates. Adjustments to corticosteroids were allowed during the first 24 weeks. Increases in corticosteroids above 2.5 mg/day were observed in 16.2% of placebo patients over the first 24 weeks after randomization. Conclusion: The primary drivers of SRI-5 response were SLEDAI improvement, concomitant medication adherence and trial completion. Arthritis, rash, alopecia and mucosal ulcer were the most prevalent clinical manifestations at baseline. Corticosteroid increases and rare, highly weighted disease manifestations in SLEDAI can confound the SRI signal

Predictors of Hospitalization for Injection Drug Users Seeking Care for Soft Tissue Infections

BACKGROUND: Soft tissue infections (STIs) from injection drug use are a common cause of Emergency Department visits, hospitalizations, and operating room procedures, yet little is known about factors that may predict the need for these costly medical services. OBJECTIVE: To describe a cohort of injection drug users seeking Emergency Department care for STIs and to identify risk factors associated with hospitalization. We hypothesized that participants who delayed seeking care would be hospitalized more often than those who did not. DESIGN: Cohort study using in-person structured interviews and medical record review. Logistic regression assessed the association between hospital admission and delay in seeking care as well as other demographic, clinical, and psychosocial factors. PARTICIPANTS: Injection drug users who sought Emergency Department care for STIs from May 2001 to March 2002. RESULTS: Of the 136 participants, 55 (40%) were admitted to the hospital. Delay in seeking care was not associated with hospital admission. Participants admitted for their infection were significantly more likely to be living in a shelter (P = .01) and to report being hospitalized 2 or more times in the past year (P < .01). CONCLUSIONS: We identified a subpopulation of injection drug users, mostly living in shelters, who were hospitalized frequently in the past year and who were more likely to be hospitalized for their current infections compared to others. As members of this subpopulation can be easily identified and located, they may benefit from interventions to reduce the health care utilization resulting from these infections