Effect of belimumab on kidney-related outcomes in patients with lupus nephritis: post hoc subgroup analyses of the phase 3 BLISS-LN trial.

BACKGROUND: Data on belimumab efficacy in patients with lupus nephritis (LN) according to diagnosis duration or induction therapy are limited. Post hoc analyses of the phase 3, randomized, double-blind BLISS-LN study (GSK BEL114054; NCT01639339) were performed to assess belimumab efficacy on kidney-related outcomes in newly diagnosed and relapsed LN subgroups and according to the use of glucocorticoid (GC) pulses at induction. METHODS: BLISS-LN randomized 448 patients with active LN to monthly intravenous belimumab 10 mg/kg or placebo plus standard therapy. Post hoc analyses assessed primary efficacy renal response (PERR) and complete renal response (CRR) at week 104, time to kidney-related event or death and time to first LN flare from week 24 in newly diagnosed and relapsed patients and patients with/without GC pulses at induction. RESULTS: A greater proportion of patients achieved a PERR with belimumab versus placebo in the newly diagnosed {69/148 [46.6%] versus 55/148 [37.2%]; odds ratio [OR] 1.36 [95% confidence interval (CI) 0.85-2.20]} and relapsed [27/75 (36.0%) versus 17/75 (22.7%); OR 2.31 (95% CI 1.07-5.01)] subgroups. Similarly for CRR [newly diagnosed: 50/148 (33.8%) versus 36/148 (24.3%); OR 1.49 (95% CI 0.88-2.51) and relapsed: 17/75 (22.7%) versus 8/75 (10.7%); OR 3.11 (95% CI 1.16-8.31)]. The probability of kidney-related event or death, or LN flare was lower with belimumab versus placebo in both subgroups. Belimumab was associated with improved kidney outcomes versus placebo with or without GC pulses at induction. CONCLUSION: Data suggest consistent benefits of belimumab on kidney outcomes for newly diagnosed and relapsed patients, and irrespective of GC pulses at induction.

MOONLIGHT study: the design of a comparative study of the effectiveness of belimumab in patients with a history of lupus nephritis from the post-Marketed effectiveness of belimumab cOhOrt and JapaN Lupus NatIonwide reGistry (LUNA) coHorT.

INTRODUCTION: Lupus nephritis (LN) is more prevalent in patients with SLE of Asian ethnicity than in Caucasian patients. Belimumab became available in Japan in 2017 to treat patients with SLE, including those with LN. In the BLISS-LN trial (NCT01639339), belimumab showed a favourable effect on renal outcomes when combined with standard therapy (ST) starting at the induction treatment phase for active LN, but real-world effectiveness of belimumab in LN has not been extensively studied. Here we describe the protocol for the MOONLIGHT (post-Marketed effectiveness of belimumab cOhOrt and JapaN Lupus NatIonwide ReGistry (LUNA) coHorT) study, which will use data from a Japan postmarketing surveillance study and the Lupus Registry of Nationwide Institutions (LUNA) to evaluate the real-world effectiveness of belimumab plus ST versus ST alone in patients with a history of active LN who are not in the induction phase. METHODS AND ANALYSIS: This multicentre, retrospective, observational study (GSK Study 214710) will enrol adults with SLE and a history of active LN, holding ≥3 years of complete follow-up data from the initiation of belimumab (no continuous treatment required). Data for patients with belimumab plus ST treatment (postmarketing registry data, belimumab cohort) will be compared with those for patients with ST only treatment (LUNA data, comparison cohort). Patients who discontinue/initiate belimumab after the start of the follow-up may be included in the comparison/belimumab cohort, respectively. The primary endpoint will be the occurrence of renal flares, for which belimumab's effectiveness will be estimated using a marginal structural model to consider time-dependent treatment and confounding factors. Secondary endpoints will include change in corticosteroid dose, renal disease activity, extrarenal disease activity, disease severity/activity biomarkers, LN class changes, end-stage kidney disease events and hospitalisations. ETHICS AND DISSEMINATION: This study will be conducted according to the Declaration of Helsinki and the local ethical guidelines. Findings will be submitted to peer-reviewed journals and presented at scientific meetings.

10 Years of belimumab experience: What have we learnt?

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease affecting both adults and children. Belimumab is the only biologic approved for SLE, and the first in a class of drugs known as B-lymphocyte stimulator-specific inhibitors. The introduction of intravenous belimumab in 2011 was a major advance, being the first new therapy approved for SLE in over 50 years. As of April 2021, more than 7200 people with SLE have received belimumab in clinical studies, and it is approved in over 75 countries for the treatment of adults with SLE. A subcutaneous, self-injectable belimumab formulation was licensed in 2017 by both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Belimumab was then approved for use in children in Europe, the USA and Japan in 2019, and China and Brazil in 2020. Recently, belimumab became the first FDA-approved drug for the treatment of adults with active lupus nephritis (LN), the most-common severe manifestation of SLE.Over the past 10 years, belimumab has established its position as a disease modifier in the SLE treatment paradigms. Robust evidence from randomised clinical studies and observational, real-world studies has demonstrated the tolerability and efficacy of belimumab for reducing disease activity and the risk of new, severe SLE flares. This enables patients to taper their glucocorticoid use, which limits damage accumulation. Significantly more patients with active LN met the criteria for renal responses and were at less risk of a renal-related event or death after receiving belimumab plus standard therapy, compared with standard therapy on top of mandatory steroid reduction. Ongoing clinical studies are evaluating belimumab's effectiveness in various indications beyond SLE. Post-marketing and registry studies are gathering additional data on key areas such as pregnancy outcomes after belimumab exposure and belimumab co-administration with other biologics.

The role of baseline BLyS levels and type 1 interferon-inducible gene signature status in determining belimumab response in systemic lupus erythematosus: a post hoc meta-analysis.

BACKGROUND: Elevated B lymphocyte stimulator (BLyS) levels in patients with systemic lupus erythematosus (SLE) correlate positively with disease activity; BLyS expression is directly linked to interferon (IFN) pathway activation. This post hoc meta-analysis of BLISS-52 and BLISS-76 explored the relationship between baseline BLyS mRNA/protein levels and/or type 1 IFN-inducible gene signature (IFN-1) and responses to the BLyS-targeting monoclonal antibody belimumab in SLE. METHODS: In BLISS-52 and BLISS-76, patients with autoantibody-positive SLE and a SELENA-SLEDAI score ≥ 6 and receiving stable standard SLE therapy were randomised to intravenous belimumab 10 mg/kg or placebo, plus standard of care (SoC), for 52 or 76 weeks. For this post hoc meta-analysis, patients with an appropriate mRNA sample were stratified by BLyS mRNA expression (tertiles: high/medium/low; revised quantiles: high/low), IFN-1 mRNA expression (high/low) and BLyS protein level (high/low). Co-primary endpoints were correlation between baseline BLyS and IFN-1 mRNA levels and SLE Responder Index (SRI)4 response at week 52 within BLyS/IFN-1 subgroups. Secondary endpoints included time to first severe SELENA-SLEDAI Flare Index (SFI) flare. RESULTS: Of 554 patients included in this analysis, 281 had received belimumab and 273 had received placebo. Baseline BLyS and IFN-1 mRNA levels were highly correlated (Spearman's rank correlation coefficient 0.7799; 95% confidence interval [CI] 0.7451, 0.8106; p < 0.0001). The proportion of SRI4 responders was higher with belimumab versus placebo in all subgroups, but the difference reached statistical significance in the medium BLyS mRNA tertile (odds ratio [OR] 2.17; 95% CI 1.16, 4.04; p = 0.0153), high BLyS mRNA quantile (OR 1.58; 95% CI 1.02, 2.44; p = 0.0402), high IFN-1 mRNA (OR 1.58; 95% CI: 1.08, 2.31; p = 0.0186) and high BLyS protein (OR 3.57; 95% CI 1.63, 7.83; p = 0.0015) subgroups only. The risk of severe SFI flare was significantly lower with belimumab than placebo in the high BLyS mRNA quantile (hazard ratio [HR] 0.59; 95% CI 0.36, 0.97; p = 0.0371) and high BLyS protein (HR 0.39; 95% CI 0.19, 0.79; p = 0.0090) subgroups. CONCLUSIONS: This post hoc meta-analysis demonstrated a tendency towards improved response to add-on intravenous belimumab 10 mg/kg versus SoC alone in patients with high baseline BLyS protein and IFN-1 mRNA levels and medium/high BLyS mRNA levels.

Albiglutide efficacy and safety in the Latino/Hispanic subpopulation for the integrated phase III program.

OBJECTIVE: to evaluate the efficacy and safety of albiglutide compared with placebo and active comparators from an integrated trial subpopulation of Latino/Hispanic patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled on their current regimen of diet and exercise, with or without oral antidiabetic drugs (OADs) and/or insulin. METHODS: Latino/Hispanic patient subpopulations (N = 1204) across 7 phase III albiglutide studies (N = 4400) were evaluated post-hoc for efficacy and safety. Comparators were placebo, sulfonylureas, insulin, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors. Glycatedhemoglobin (HbA1c) change from baseline to the time of the primary endpoint assessment (from 26 to 104 weeks) was evaluated in patients on diet and exercise and/or OADs, with or without insulin. Patients were allowed to continue in the study if hyperglycemic rescue was required, according to a prespecified algorithm and at the discretion of the investigator. RESULTS: At baseline in the Latino/Hispanic subpopulation, the mean HbA1c was 8.3%, mean age was 53 years, mean body mass index was 32 kg/m2, and mean duration of T2DM was 8.0 years. The primary endpoint of mean HbA1c difference (albiglutide - placebo) was -0.94% for the Latino/Hispanic subpopulation and -0.86% (p < 0.001) for the overall phase III population. Changes in fasting plasma glucose mirrored those of HbA1c. Weight loss with albiglutide was numerically greater than with OADs and insulin in both populations, but it was smaller than with liraglutide. Within the Latino/Hispanic subpopulation, more injection-site reactions were reported with albiglutide vs all comparators, while gastrointestinal and hypoglycemic adverse events were comparable between the two groups, and the latter was uncommon when used without insulin and/or a sulfonylurea. CONCLUSIONS: In the Latino/Hispanic population, albiglutide resulted in effective lowering of glucose and modest weight loss, and it was generally well tolerated.

Efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2): 52 week primary endpoint results from a randomised, placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise.

AIMS/HYPOTHESIS: Additional safe and effective therapies for type 2 diabetes are needed, especially ones that do not cause weight gain and have a low risk of hypoglycaemia. The present study evaluated albiglutide as monotherapy. METHODS: In this placebo-controlled study, 309 patients (aged ≥ 18 years) with type 2 diabetes inadequately controlled by diet and exercise and who were not using a glucose-lowering agent (HbA1c 7.0-10.0% [53.00-85.79 mmol/mol], body mass index 20-45 kg/m(2), and fasting C-peptide ≥ 0.26 nmol/l) were randomised (1:1:1 on a fixed randomisation schedule using an interactive voice response system) to receive once-weekly albiglutide 30 mg (n = 102) or 50 mg (n = 102) or matching placebo (n = 105). The study treatments were blinded to both patients and study personnel. All study data were collected at individual patient clinic visits. The primary efficacy endpoint was change in HbA1c from baseline to week 52. The primary analysis was applied to the intent-to-treat population. Additional efficacy and safety endpoints were assessed. RESULTS: At week 52, both albiglutide 30 mg and 50 mg were superior to placebo in reducing HbA1c. The least-squares means treatment difference from placebo was -0.84% (95% CI -1.11%, -0.58%; p < 0.0001) with albiglutide 30 mg and -1.04% (-1.31%, -0.77%; p < 0.0001) with albiglutide 50 mg. Injection-site reactions were reported more frequently with albiglutide (30 mg: 17.8%; 50 mg: 22.2%) than with placebo (9.9%). Other commonly reported adverse events included nausea, diarrhoea, vomiting and hypoglycaemia; the incidences of these were generally similar across treatment groups. CONCLUSIONS/INTERPRETATION: Albiglutide is safe and effective as monotherapy and significantly lowered HbA1c levels over 52 weeks, did not cause weight gain, and had good gastrointestinal tolerability and a low rate of hypoglycaemia compared with placebo. Trial registration ClinicalTrials.gov NCT00849017 Funding This study was sponsored by GlaxoSmithKline.

Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: a randomized phase III study.

OBJECTIVE: To evaluate weekly subcutaneous albiglutide versus daily sitagliptin in renally impaired patients with type 2 diabetes and inadequately controlled glycemia on a regimen of diet and exercise and/or oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS: In this phase III, randomized, double-blind, multicenter, 52-week study, the primary study end point was HbA1c change from baseline at week 26 in patients with renal impairment, as assessed with estimated glomerular filtration rate and categorized as mild, moderate, or severe (≥60 to ≤89, ≥30 to ≤59, and ≥15 to ≤29 mL/min/1.73 m(2), respectively). Secondary end points included fasting plasma glucose (FPG), weight, achievement of treatment targets, hyperglycemic rescue, and safety. RESULTS: Baseline demographics were similar across treatment and renal impairment groups with overall mean age of 63.3 years, BMI of 30.4 kg/m(2), HbA1c of 8.2% (66 mmol/mol), and diabetes disease duration of 11.2 years. HbA1c change from baseline at week 26 was significantly greater for albiglutide than sitagliptin (-0.83% vs. -0.52%, P = 0.0003). Decreases in HbA1c, FPG, and weight were seen through week 52. Time to hyperglycemic rescue through week 52 was significantly longer for albiglutide than sitagliptin (P = 0.0017). Results of safety assessments were similar between groups, and most adverse events (AEs) were mild or moderate. The incidences of gastrointestinal AEs for albiglutide and sitagliptin were as follows: overall, 31.7%, 25.2%; diarrhea, 10.0%, 6.5%; nausea, 4.8%, 3.3%; and vomiting, 1.6%, 1.2%, respectively. CONCLUSIONS: Once-weekly albiglutide therapy in renally impaired patients with type 2 diabetes provided statistically superior glycemic improvement with almost similar tolerability compared with daily sitagliptin therapy.

Weight loss, glycemic control, and cardiovascular disease risk factors in response to differential diet composition in a weight loss program in type 2 diabetes: a randomized controlled trial.

OBJECTIVE: To test whether a weight loss program promotes greater weight loss, glycemic control, and improved cardiovascular disease risk factors compared with control conditions and whether there is a differential response to higher versus lower carbohydrate intake. RESEARCH DESIGN AND METHODS: This randomized controlled trial at two university medical centers enrolled 227 overweight or obese adults with type 2 diabetes and assigned them to parallel in-person diet and exercise counseling, with prepackaged foods in a planned menu during the initial phase, or to usual care (UC; two weight loss counseling sessions and monthly contacts). RESULTS: Relative weight loss was 7.4% (95% CI 5.7-9.2%), 9.0% (7.1-10.9%), and 2.5% (1.3-3.8%) for the lower fat, lower carbohydrate, and UC groups (P < 0.001 intervention effect). Glycemic control markers and triglyceride levels were lower in the intervention groups compared with UC group at 1 year (fasting glucose 141 [95% CI 133-149] vs. 159 [144-174] mg/dL, P = 0.023; hemoglobin A1c 6.9% [6.6-7.1%] vs. 7.5% [7.1-7.9%] or 52 [49-54] vs. 58 [54-63] mmol/mol, P = 0.001; triglycerides 148 [134-163] vs. 204 [173-234] mg/dL, P < 0.001). The lower versus higher carbohydrate groups maintained lower hemoglobin A1c (6.6% [95% CI 6.3-6.8%] vs. 7.2% [6.8-7.5%] or 49 [45-51] vs. 55 [51-58] mmol/mol) at 1 year (P = 0.008). CONCLUSIONS: The weight loss program resulted in greater weight loss and improved glycemic control in type 2 diabetes.

Food deserts in Leon County, FL: disparate distribution of Supplemental Nutrition Assistance Program-accepting stores by neighborhood characteristics.

OBJECTIVE: Examine whether neighborhood characteristics of racial composition, income, and rurality were related to distribution of Supplemental Nutrition Assistance Program (SNAP)-accepting stores in Leon County, Florida. DESIGN: Cross-sectional; neighborhood and food store data collected in 2008. SETTING AND PARTICIPANTS: Forty-eight census tracts as proxy of neighborhoods in Leon County, Florida. All stores and SNAP-accepting stores were identified from a commercial business directory and a United States Department of Agriculture SNAP-accepting store list, respectively (n = 288). MAIN OUTCOME MEASURES: Proportion of SNAP-accepting stores across neighborhoods. ANALYSIS: Descriptive statistics to describe distribution of SNAP-accepting stores by neighborhood characteristics. Proportions of SNAP-accepting stores were compared by neighborhood characteristics with Wilcoxon-Mann-Whitney and Kruskal-Wallis tests. RESULTS: Of 288 available stores, 45.1% accepted SNAP benefits. Of the 48 neighborhoods, 16.7% had no SNAP-accepting stores. Proportions of SNAP-accepting grocery stores were significantly different by neighborhood racial composition and income. Primarily black neighborhoods did not have any supermarkets. Results were mixed with regard to distribution of food stores and SNAP-accepting stores by neighborhood racial composition, income, and rurality. CONCLUSIONS AND IMPLICATIONS: This study suggests disparities in distribution of SNAP-accepting stores across neighborhood characteristics of racial composition, income, and rurality.

Store type and demographic influence on the availability and price of healthful foods, Leon County, Florida, 2008.

INTRODUCTION: The availability of healthful foods varies by neighborhood. We examined the availability and price of more healthful foods by store type, neighborhood income level, and racial composition in a community with high rates of diet-related illness and death. METHODS: We used the modified Nutrition Environment Measures Survey in Stores to conduct this cross-sectional study in 2008. We surveyed 73 stores (29% supermarkets, 11% grocery stores, and 60% convenience stores) in Leon County, Florida. We analyzed the price and availability of foods defined by the 2005 Dietary Guidelines for Americans as "food groups to encourage." We used descriptive statistics, t tests, analysis of variance, and χ(2) tests in the analysis. RESULTS: Measures of availability for all more healthful foods differed by store type (P < .001). Overall, supermarkets provided the lowest price for most fresh fruits and vegetables, low-fat milk, and whole-wheat bread. Availability of 10 of the 20 fruits and vegetables surveyed, shelf space devoted to low-fat milk, and varieties of whole-wheat bread differed by neighborhood income level (P < .05), but no trends were seen for the availability or price of more healthful foods by neighborhood racial composition. CONCLUSION: Store type affects the availability and price of more healthful foods. In particular, people without access to supermarkets may have limited ability to purchase healthful foods. Nutrition environment studies such as this one can be used to encourage improvements in neighborhoods that lack adequate access to affordable, healthful food, such as advocating for large retail stores, farmer's markets, and community gardens in disadvantaged neighborhoods.

Incidents analysis in radiation therapy: application of the human factors analysis and classification system.

The purpose of this investigation was to analyse incidents discovered in our radiation therapy department by means of human factor analysis and classification system (HFAC S). We adapted the original framework of the HFAC S and apply it to the analysis of incidents discovered in our radiotherapy department during a five-year period. Results showed that recurrent causal factors of incidents were attention failures and distracted/overconfidence behaviour as well as loss of situational awareness and mental fatigue. In our radiation therapy department the HFAC S allowed to highlight recurrent errors causal factors. Consequently we defined corrections factors for operators behaviour and implemented an operational protocol which improve operators attitude.

Codeswitching in Bilingual Children with Specific Language Impairment.

Children with specific language impairment (SLI) exhibit limited grammatical skills compared to their peers with typical language. These difficulties may be revealed when alternating their two languages (i.e., codeswitching) within sentences. Fifty-eight Spanish-English speaking children with and without SLI produced narratives using wordless picture books and conversational samples. The results indicated no significant differences in the proportion of utterances with codeswitching (CS) across age groups or contexts of elicitation. There were significant effects for language dominance, language of testing, and a significant dominance by language of testing interaction. The English-dominant children demonstrated more CS when tested in their nondominant language (Spanish) compared to the Spanish-dominant children tested in their weaker English. The children with SLI did not display more CS or more instances of atypical CS patterns compared to their typical peers. The findings indicate that children with SLI are capable of using grammatical CS, in spite of their language difficulties. In addition, the analyses suggest that CS is sensitive to sociolinguistic variables such as when the home language is not socially supported in the larger sociocultural context. In these cases, children may refrain from switching to the home language, even if that is their dominant language.

Validating the food behavior questions from the elementary school SPAN questionnaire.

BACKGROUND: The School Physical Activity and Nutrition (SPAN) questionnaire was developed as a surveillance instrument to measure physical activity, nutrition attitudes, and dietary and physical activity behaviors in children and adolescents. The SPAN questionnaire has 2 versions. OBJECTIVE: This study was conducted to evaluate the validity of food consumption items from the elementary school version of the SPAN questionnaire. DESIGN: Validity was assessed by comparing food items selected on the questionnaire with food items reported from a single 24-hour recall covering the same reference period. SETTING: 5 elementary schools in Indiana. PARTICIPANTS: Fourth-grade student volunteers (N = 121) from 5 elementary schools. MAIN OUTCOME MEASURE: Agreement between responses to SPAN questionnaire items and reference values obtained through 24-hour dietary recall. ANALYSIS: The agreement between the questionnaire and the 24-hour recall was measured using Spearman correlation, percentage agreement, and kappa statistic. RESULTS: Correlation between SPAN item responses and recall data ranged from .25 (bread and related products) to .67 (gravy). The percentage agreement ranged from 26% (bread and related products) to 90% (gravy). The kappa statistic varied from .06 (chocolate candy) to .60 (beans). CONCLUSIONS AND IMPLICATIONS: Results from this study indicate that the SPAN questionnaire can be administered in the classroom quickly and easily to measure many previous day dietary behaviors of fourth graders. However, questions addressing consumption of "vegetables," "candy," and "snacks" need further investigation.