LS Mean Research Articles

A comparison of the rapid-acting insulin analogue glulisine with lispro and aspart for the pump treatment of patients with type 1 diabetes.

(1) To describe the population of patients with type 1 diabetes (T1DM) using the rapid-acting insulin analogue glulisine versus lispro and aspart during continuous subcutaneous insulin infusion (CSII); (2) to describe insulin relative effectiveness based on hemoglobin A1c (HbA1c), fasting blood glucose (FBG) and dose; (3) to determine rates of hyperglycemia, hypoglycemia, and diabetic ketoacidosis (DKA). The analysis used March 2021 data from the Diabetes-Patienten-Verlaufsdokumentation registry, which contains data of 618,903 patients with diabetes. Patients were propensity-matched by age, sex, and diabetes duration. Overall, 42,736 patients of any age were eligible for analysis based on insulin pump usage with either glulisine (N = 707) or lispro/aspart (N = 42,029) between 2004 and 2020. Patients receiving glulisine were older (median 20.0 vs. 16.2years), equally often male (47.2% vs. 47.8%) and had a longer diabetes duration (median 9.4 vs. 7.4years). After propensity score matching, 707 pairs remained (total N = 1414). Patient characteristics between groups were similar. Achieved HbA1c values were also comparable: 8.04%, 64mmol/mol versus 7.96%, 63mmol/mol for glulisine and lispro/aspart [LS mean difference 0.08 (95%CI -0.08, 0.25)]. FBG was 9.37mmol/L (168.9mg/dL) and 9.58mmol/L (172.6mg/dL) in the glulisine and lispro/aspart groups [LS mean diff. -0.21; (95%CI -1.13, 0.72)]. Total daily insulin doses and prandial to total insulin ratios were also similar. Glulisine group patients had higher rates of lipodystrophy (0.85% vs. 0.71%) (LS mean diff. 0.18 [95% CI -1.01, 1.38]) and non-severe DKA (3.11% vs. 0.57%; p = 0.002). Fewer patients in the glulisine group had severe hypoglycemic events (7.66 vs. 9.09; p = 0.333) and severe ketoacidosis events (0.57% vs. 1.56%; p = 0.082) but more had hypoglycemic coma events (p = 0.773), although the differences were not statistically significant. Insulin glulisine had comparable glucose control to lispro/aspart. The use of glulisine was less frequent in the present analysis compared to the previous trials.

The effect of IV ketamine in patients with major depressive disorder and elevated features of borderline personality disorder

BackgroundComorbid borderline personality disorder and major depressive disorder is common and often not adequately responsive to standard antidepressant therapies. Ketamine is a potentially life-saving option. Methods153 adult patients with MDD were assessed with the Personality Assessment Inventory (PAI) Borderline Subscale. Data was normally distributed with a mean + SD of 38.95 + 11.54. Patients >1 SD above the mean were assigned to the MDD + BF group. All others were assigned to the MDD–BF group. Patients were administered IV ketamine 0.5 mg/kg of ketamine over 40 min. Mood was assessed using the Beck Depression Inventory-II at baseline, 3 and 24 h post-ketamine. Scores between the MDD + BF and MDD–BF group at each time point were compared using t-test or analysis of covariance (ANCOVA) model. The primary outcome was response at 24 h. ResultsThe LS mean change in BDI at 24 h was −23.8 (15.3) for MDD + BF and −21.0 (13.5) for MDD–BF (F [1151] = 0.043, p = 0.51). The LS mean change in BDI at 3 h was −21.3 (13.2) for MDD + BF and −19.6 (13.2) for MDD–BF (F[1151] = 0.045, p = 0.83). The LS mean change in BDI at 14 days was −23.2 (15.3) for MDD + BF and −15.3 (15.2) for MDD–BF (F[1130] = 4.24, p = 0.04). LimitationsPeople in the MDD + BF group were not necessarily diagnosable with borderline personality disorder. ConclusionsThese data indicate that IV ketamine is effective in MDD patients with and without elevated borderline features. This can provide clinicians some reassurance about using ketamine in this population.

Racial and ethnic differences in patient ratings of colorectal and non-small-cell lung cancer care: A SEER-CAHPS study.

Although significant racial and ethnic disparities exist in colorectal and lung cancer treatment and survival, racial differences in patient-reported experience of care are not well understood. The purpose of this study was to examine differences in patient-reported ratings of colorectal and non-small-cell lung cancer care by race/ethnicity. Medicare beneficiaries with AJCC stage I-IV colorectal and non-small-cell lung cancer (2003-2013) who completed a Medicare Consumer Assessment of Healthcare Providers (CAHPS) survey within 5years of cancer diagnosis were identified in the linked SEER-CAHPS dataset. Scores were compared by race/ethnicity, defined as White, Black, or any other race/ethnicity. Of the 2,621 identified patients, 161 (6.1%) were Black, 2,279 (87.0%) White, and 181 (6.9%) any other race/ethnicity. Compared to White patients, Black patients were younger, had lower educational level, and had higher census tract poverty indicator (p < 0.001). Black patients rated their ability to get care quickly significantly lower than White patients (63.5 (SE 3.38) vs. 71.4 (SE 2.12), p < 0.01), as did patients of any other race/ethnicity (LS mean 66.2 (SE 2.89), p = 0.02). Patients of any other race/ethnicity reported their ability to get needed care significantly lower than White patients (LS mean 81.9 (SE 2.46) vs. 86.7 (SE 1.75), p = 0.02); however, there was no difference in ability to get needed care between Black and White patients. Patient ratings for getting care quickly were lower in non-White patients, indicating racial disparities in perceived timeliness of care.

†Safety and Efficacy of Bempedoic Acid in Patients with Hypertension

<h3>Lead Author's Financial Disclosures</h3> KCF has received honorarium for consultancy from Amgen, Boehringer Ingelheim, Medtronic, Novartis, and Quantum Genomics. <h3>Study Funding</h3> Esperion Therapeutics, Inc. <h3>Background/Synopsis</h3> Patients with hypercholesterolemia often have hypertension (HTN), further increasing cardiovascular disease risk. Statins may affect blood pressure (BP) due to vascular effects. Bempedoic acid (BA) is an ATP citrate lyase inhibitor that lowers LDL-C. <h3>Objective/Purpose</h3> To investigate the safety and lipid-lowering effect of BA in patients with hypercholesterolemia and comorbid HTN. <h3>Methods</h3> Data were pooled from 4 phase 3 studies; patients were randomized 2:1 to BA or placebo (PBO) for 12-52 weeks. In 2 studies, patients also received moderate- to high-intensity statin, and in 2 studies, patients with statin intolerance received low-dose or no statin. Patients were grouped based on history of HTN, which was treated pharmacologically. Percent change from baseline to week 12 of LDL-C and other lipid parameters, and vital signs and adverse events were assessed. Moreover, in a 6 week 1:1 randomized phase 2 study (NCT02178098), the safety and efficacy of BA were assessed in patients with uncontrolled HTN (BP ≥140/90 and ≤180/110 mmHg) not receiving statins or other lipid-lowering therapies. <h3>Results</h3> Of the 3,623 (2,425 BA, 1,198 PBO) patients included, 78% had a history of HTN. At week 12, the PBO-corrected least squares mean (95% CI) percent change in LDL-C was −19.2% (−20.9, −17.5; P<.0001) in patients with HTN and −20.9% (−24.2, −17.5; P<.0001) in patients without HTN (interaction P=.3697). Results were similar for ApoB levels (−13.0% [−14.5, −11.5; P<.0001] for patients with HTN and −15.3% [−18.0, −12.6; P<.0001] for patients without HTN [interaction P=.1586]). Overall, through 12-52 weeks, the BA safety profile was similar in patients with or without HTN with no clinically meaningful changes in BP. In the phase 2 study (n=143; mean baseline [SD] BP 155/96 [12/6] mmHg), the PBO-corrected LS mean (95% CI) percent change in LDL C was −24.2% (−30.3, −18.1; P<.0001) at week 6. Through 6 weeks of BA treatment, 24-hour ambulatory BP monitoring showed no change from baseline in BP; BA was generally well-tolerated with a consistent safety profile across treatment groups. <h3>Conclusions</h3> Regardless of HTN status, BA was generally well-tolerated and significantly lowered LDL-C with no clinically meaningful BP changes.

Comparing a daily versus weekly titration algorithm in people with type 2 diabetes switching from basal insulin to iGlarLixi in the LixiLan ONE CAN randomized trial.

AimTo compare the efficacy and safety of a simple daily titration algorithm compared with a weekly dose adjustment of iGlarLixi in people with type 2 diabetes.Materials and MethodsLixiLan ONE CAN (NCT03767543), a randomized, 26‐week, open‐label, multicentre phase 3 trial conducted in Canada, involved 265 people with type 2 diabetes and an HbA1c of ≥7.5% to ≤ 10.5% or less (≥58 to ≤91 mmol/mol) on basal insulin for 6 months or longer. Participants were randomized 1:1 with instructions to self‐titrate iGlarLixi daily (1 unit/day) or once weekly (2 or 4 units/week) to a common target fasting plasma glucose of 4.4 to 5.6 mmol/L (79 to 101 mg/dl). The primary objective was to show non‐inferiority of the daily versus weekly titration algorithm.ResultsAt 26 weeks, daily titration of iGlarLixi was not inferior to a weekly titration for both the prespecified primary endpoint of change in HbA1c from baseline (least square [LS] mean change: −1.24% vs. −0.92%, respectively; LS mean difference: 0.32%; 95% CI [0.07, 0.57]; P < .0001) and for the secondary endpoint of change in weight from baseline (LS mean change: −0.22 vs. +0.81 kg, respectively; LS mean difference: 1.03 kg; 95% CI [0.01, 2.06]; P < .0001). Indeed, for both the primary and secondary outcome, the daily titration of iGlarLixi was superior. There were no statistically significant differences in hypoglycaemia incidence between the two titration strategies during the 26‐week study.ConclusionA daily titration algorithm for switching basal insulin to iGlarLixi was shown to be non‐inferior and superior for glycaemic control and weight compared with weekly titration.

Efficacy and safety of self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester (MND-2119) versus highly purified eicosapentaenoic acid ethyl ester in patients with hypertriglyceridemia: Results from a 12-week randomized, double-blind, active-controlled, phase 3 study

BackgroundIn Japan, eicosapentaenoic acid ethyl ester (EPA-E) is administered twice-daily or three-times-daily for dyslipidemia. We have developed MND-2119, a novel self-emulsifying formulation of highly purified EPA-E, which can be administered once-daily. ObjectiveThe objective of this study was to assess non-inferiority in the efficacy of MND-2119 in patients with hypertriglyceridemia compared with highly purified EPA-E. MethodsIn this multicenter, 12-week, double-blind study, patients with high triglyceride (TG levels between ≥ 150 and < 500 mg/dL) undergoing lifestyle modification were randomized to MND-2119 2 g/day (n=145), MND-2119 4 g/day (n=145), EPA-E 1.8 g/day (n=145) or EPA-E 2.7 g/day (n=145). The primary endpoint was percentage change in TG levels from baseline to end of treatment. ResultsMND-2119 2, 4 g/day and EPA-E 1.8, 2.7 g/day reduced TG levels from baseline by −10.09%, −15.51%, −9.30%, and −8.80%, respectively. The TG reduction rate of MND-2119 2 g/day was non-inferior to that of EPA-E 1.8 g/day (LS mean difference: -0.42, 95%CI: -5.76 to 4.91). Moreover, the TG reduction rate of MND-2119 4 g/day was superior to that of MND-2119 2 g/day (LS mean difference: -5.74, 95%CI: -10.59 to -0.89). There were no remarkable safety differences between MND-2119 2 g/day and EPA-E 1.8 g/day and between MND-2119 4 g/day and EPA-E 2.7 g/day. ConclusionNon-inferiority of MND-2119 2 g/day to EPA-E 1.8 g/day for efficacy, and superiority of MND-2119 4 g/day over MND-2119 2 g/day for efficacy were verified. MND-2119 was safe and well tolerated.

The Biota orientalis, oil extract Epiitalis®, is efficacious at reducing the symptoms of knee osteoarthritis: a pilot, multi-site, dose-ranging, randomized, blinded, placebo-controlled trial

ObjectiveTo explore the safety, and efficacy of a proprietary hydrolyzed oil extract from seeds of Biota orientalis (hBO/Epiitalis®, Interpath Pty Ltd) in patients with knee pain due to osteoarthritis (OA).MethodsPatients aged 40–65 with X-ray diagnosed knee OA and knee pain ≥ 60 on a 100-point VAS (visual analog scale) were enrolled and randomized into four groups to receive daily hBO for 56 days as high (hBO-HD, 640 mg), mid (hBO-MD, 320 mg) or low (hBO-LD, 160 mg) doses, or a matched placebo oil. The primary outcome was change in VAS knee pain from baseline to 56 days in the mITT (modified intention to treat) population. Exploratory outcomes were the mWOMAC (modified Western Ontario and McMaster Universities Arthritis Index), and the SF-36 QoL (quality of life) questionnaire. The OMERACT-OARSI (Outcome Measures in Arthritis Clinical Trials–Osteoarthritis Research Society International) responder index was also calculated.Results223 patients were included in the mITT population. Reductions in VAS scores between baseline and day 56 [Least square mean (LS mean) and 95% confidence interval (CI) of LS mean] were 36.4 (31.7–41.0), 37.9 (33.2–42.7), 35.7 (31.2–40.1) and 9.8 (14.5–15.2) for the hBO-HD, hBO-MD, hBO-LD, and placebo groups respectively. The VAS changes in all hBO groups were significantly different (p < 0.0001) vs. changes in the placebo group. hBO treatment led to similar quantitative beneficial changes in mWOMAC, SF-36 and OMERACT-OARSI responder index. There were no SAEs and no adverse events ascribed to the intervention.ConclusionIn a 56-day trial, hBO was safe, and was efficacious at reducing symptoms in patients with knee OA. Registration: NCT04117490; Oct 7, 2019.

Benzodiazepine use during cariprazine treatment in acute schizophrenia

IntroductionAlthough antipsychotics are first-line treatments for schizophrenia, benzodiazepines (BZDs) are often used as concomitant medications in acutely exacerbated patients due to their anxiolytic and sedative effects. Cariprazine (CAR), a D3-preferring dopamine D2/D3 partial agonist antipsychotic, has been examined in many clinical studies for the treatment of acute schizophrenia, with and without benzodiazepines.ObjectivesTo delineate the effects of benzodiazepine-use during cariprazine treatment in acute schizophrenia.MethodsPooled data of cariprazine-treated (1.5-6mg/day) and placebo-treated patients from four short-term, randomised, double-blind trials (NCT00404573, NCT01104766, NCT01104779, NCT00694707) were analysed. Baseline characteristics (age, duration of illness) and efficacy outcome parameters (Total and Hostility Factor Score of the Positive and Negative Syndrome Scale [PANSS]) were compared in patients receiving benzodiazepines (for more ≥3 consecutive days) and not receiving benzodiazepines (&lt;3 consecutive days).ResultsAltogether, 36.7% and 40.7% of the CAR-treated and PBO-treated patients required BZDs. BZD-taking was associated with a higher age in both the CAR-treated (p=0.0002) and PBO-treated (p&lt;0.0001) patients, and with longer illness-duration in both treatment groups (p&lt;0.0001). PANSS Total Score at baseline was similar for BZD users and non-users (CAR: LS Mean=96.36 and 96.27; PBO: LS Mean=95.55 and 96.66). Change from baseline in the PANSS Total Score was greater for patients who did not use BZD vs those who did (CAR: LS Mean= -23.8 vs LS Mean 17.2, p&lt;0.0001; PBO: LS Mean= -14.0 vs LS Mean 12.9, p=0.5776).ConclusionsThese findings may suggest that requiring benzodiazepines is a potential indicator of longer illness duration and poorer response in acute schizophrenia.DisclosureI am an employee of Gedeon Richter Plc.

802-P: Safety, Pharmacokinetics, and Pharmacodynamics of Once-Weekly Basal Insulin Fc (BIF) in Japanese Patients with Type 2 Diabetes: A Phase 1 Open-Label, Randomized, Active-Controlled Trial

The aim was to investigate the safety, pharmacokinetics (PK) , and pharmacodynamics (PD) of once-weekly Basal Insulin Fc (BIF) , a novel long-acting IgG Fc-fusion protein being developed for the treatment of diabetes. This multiple-site, open-label, randomized, active-controlled, multiple-dose Phase 1 study investigated individualized weekly subcutaneous injections of BIF compared to once-daily insulin degludec over 6 weeks in Japanese patients with T2D on stable doses of basal insulin, with or without antihyperglycemic medication. In a 5-week lead-in period to treatment, all patients titrated insulin degludec to a fasting glucose (FG) target of 100 to 139 mg/dL. Outcomes included safety (primary) and PK and PD (secondary) . ClinicalTrials.gov NCT04276428. Patients were randomized to receive BIF (n=18) or insulin degludec (n=10) . TEAE incidence was low for both BIF (n=4; 22.2%) and insulin degludec (n=2; 20.0%) . All TEAEs were mild, nonserious, and unrelated to BIF. A total of 6 (33.3%) and 2 (20.0%) patients reported hypoglycemic events during BIF and insulin degludec treatment, respectively, none of which were severe. Median tmax was 3 or 4 days. Geometric mean t1/2 of BIF was 15 days. The peak to trough ratio (Cmax to 168 hours postdose concentration after final dose at Week 6) was 1.13. Mean FG was statistically significantly increased from baseline from Weeks 3 to 7 following first dose of insulin degludec but was not increased with BIF (LS means [SE] change: Week 3 BIF, -6.6 [4.7]; degludec, 22.1 [5.9]; Week 7 BIF, -3.5 [7.1]; degludec, 25.3 [9.3] mg/dL) . The 7-point SMPG profile was unchanged with BIF over treatment. In Japanese patients with T2D, once-weekly BIF was well tolerated and associated with prolonged PK and improved glycemic control. PK/PD profiles in Japanese patients are consistent with prior studies and support participation in Phase 3 studies. Disclosure R. Nasu: None. T. Oura: Employee; Eli Lilly Japan K.K. Stock/Shareholder; Eli Lilly and Company. K. Ohwaki: None. M. Imori: Employee; Eli Lilly Japan K.K. K. Furihata: Other Relationship; Eli Lilly and Company, Pfizer Japan Inc. Funding Eli Lilly Japan K.K.

814-P: Treatment Satisfaction in People with T2D Switched from Basal Insulin (BI) to Insulin Glargine 300 U/mL (Gla-300) : Patient-Reported Outcomes from ARTEMIS-DM Study

Treatment satisfaction is the key for treatment adherence, to improve long-term outcomes and avoid diabetes complications. However, there is limited data on treatment satisfaction in people with T2D who switch to Gla-300 from other BI in regions outside US and Europe. The current analysis of the 26-week ARTEMIS-DM study presents patient perspective on treatment satisfaction using the Insulin Treatment Satisfaction Questionnaire (ITSQ) , in people with T2D, from Asia, Middle East Africa (MEA) and Latin America (LaTAm) , uncontrolled on BI and who switched to Gla-300. A total of 362/372 (97.3%) participants completed the study. Mean ± SD ITSQ total score increased from baseline 76.30 ± 15.63 to 83.51 ± 13.29 and 84.42 ± 13.15 at Weeks 12 and 26, respectively. Improvements were noted for all ITSQ domain scores, especially glycemic control (baseline: 65.83; mean change from baseline to Week 12: 15.12 and Week 26: 16.06) (Table) . Despite similar mean baseline scores (73.to 79.31) , LS mean change in ITSQ total score was numerically greater in LaTAm (10.86) and MEA (10.40) compared with Asia (1.56) at Week 26. In ARTEMIS-DM study, in people with T2D uncontrolled on BI, switching to Gla-300 demonstrated improvement in treatment satisfaction and specifically in glycemic control in a diverse population from multiple geographic regions. Disclosure K.Alrubeaan: Research Support; Sanofi. E.G.Wilmot: Advisory Panel; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Sanofi, Research Support; Insulet Corporation, Novo Nordisk, Speaker's Bureau; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk, Sanofi. A.Roborel de climens: Employee; IQVIA Inc., Sanofi. M.N.Mabunay: Employee; Sanofi. V.Pilorget: None. B.Berthou: None. G.Frechtel: None. B.Sethi: None. Funding Sanofi

105-LB: Glucose Variability with Second-Generation Basal Insulin Analogs Glargine 300 U/mL and Degludec 100 U/mL, Evaluated by CGM in People with T1D—The InRange Randomized Controlled Trial

Background: InRange has previously demonstrated that insulin glargine 300 U/mL (Gla-300) is non-inferior to insulin degludec 100 U/mL (IDeg-100) in terms of time in glucose range 70--180 mg/dL (primary endpoint) and total glucose coefficient of variation (CV) as measured by CGM in people with T1D. Methods: InRange (NCT04075513) was a multicenter, randomized, active-controlled, parallel-group, 12-week open-label trial comparing Gla-300 vs. IDeg-100 in adults with T1D using 20-day CGM profiles (≥10 days evaluable) . Here we present data for within- and between-day CV. Results: Overall, 343 participants were randomized (172 Gla-300, 171 IDeg-100) : mean ± SD age was 42.8 ± 13.3 years and T1D duration was 20.5 ± 12.8 years. Both within-day and between-day glucose CV at Week 12 were similar with Gla-300 and IDeg-100 (Table) . Within-day glucose CV at Week 12 was below the threshold for glycemic stability (36%) in both groups and was also similar in both treatment groups irrespective of glycemic stability at baseline (CV ≤36% or &amp;gt;36%) . The LS mean within-day glucose CV of participants with CV &amp;gt;36% at baseline reached 33.67 (Gla-300) and 35.38 (IDeg-100) at Week 12. Conclusion: Using clinically relevant CGM metrics, InRange shows that Gla-300 and IDeg-100 provide similar within- and between-day glucose variability in people with T1D. Disclosure R. M. Bergenstal: Advisory Panel; Hygieia, Medtronic, Roche Diabetes Care, Zealand Pharma A/S, Consultant; Abbott Diabetes, Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Onduo LLC, Sanofi, United HealthCare Services, Inc., Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi. T. Battelino: Advisory Panel; Abbott Diabetes, Indigo Diabetes, Lilly Diabetes, Medtronic, Novo Nordisk, Sanofi, Research Support; Medtronic, Novartis Pharmaceuticals Corporation, Novo Nordisk, Zealand Pharma A/S, Speaker’s Bureau; Abbott Diabetes, Dexcom, Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Sanofi, Stock/Shareholder; DreaMed Diabetes, Ltd. S. Edelman: Consultant; Abbott Diabetes, Lilly Diabetes, Sanofi-Aventis U. S., Xeris Pharmaceuticals, Inc. P. Choudhary: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Medtronic, Research Support; Novo Nordisk, Speaker’s Bureau; Dexcom, Inc., Glooko, Inc., Insulet Corporation, Sanofi. T. Danne: Consultant; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Lilly, Medtronic, Novo Nordisk, Roche Pharmaceuticals, Sanofi, Ypsomed AG, Research Support; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Lilly, Medtronic, Novo Nordisk, Roche Pharmaceuticals, Sanofi, Ypsomed AG, Stock/Shareholder; DreaMed Diabetes, Ltd. E. Renard: Consultant; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Insulet Corporation, LifeScan, Lilly, Novo Nordisk, Roche Diabetes Care, Sanofi, Tandem Diabetes Care, Inc. J. Westerbacka: Employee; Sanofi, Stock/Shareholder; Sanofi. B. Mukherjee: Employee; Sanofi, Stock/Shareholder; Sanofi. P. Picard: n/a. V. Pilorget: None. Funding Sanofi

LB0006 SARILUMAB IN PATIENTS WITH RELAPSING POLYMYALGIA RHEUMATICA: A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED TRIAL (SAPHYR)

BackgroundInterleukin-6 (IL-6) is elevated in patients with active polymyalgia rheumatica (PMR) and is associated with disease activity, relapse and severity. Clinical trials with IL-6 receptor (IL-6R) inhibitors in PMR showed higher remission rates and reduced glucocorticoid (GC) use vs GC alone.1-4ObjectivesThe SAPHYR study (NCT03600818) assessed the efficacy and safety of sarilumab (SAR), a fully human anti IL-6Rα monoclonal antibody, with a 14 week (wk) GC taper in patients with steroid resistant active PMR who flared on ≥7.5 mg/day prednisone or equivalent.MethodsPatients were randomized (1:1) to 52 wks of treatment with SAR 200 mg every 2 wks (Q2W) + 14 wk GC tapered regimen (SAR arm) OR placebo Q2W + 52 wk GC tapered regimen (comparator arm). The primary endpoint was the proportion of patients achieving sustained remission at wk 52, defined as disease remission by wk 12, absence of disease flare, CRP normalization from wks 12 to 52 and adherence to the per protocol GC taper from wks 12 to 52.ResultsThe study was terminated early due to protracted recruitment timelines during the COVID-19 pandemic, resulting in 118 of the intended 280 patients recruited between Oct 2018 and Jul 2020, and 117 were treated (SAR n=59, comparator n=58). The demographics were balanced; patients were primarily female, Caucasian, and a median age of ~70 years (Table 1). Overall, 78 patients completed the treatment (SAR n=42; comparator n=36). Primary reasons for treatment discontinuation were adverse events (AEs; SAR n=7, comparator n=4) and lack of efficacy (SAR n=4, comparator n=9). Sustained remission rate was significantly higher in the SAR arm vs the comparator arm (28.3% vs 10.3%; P=0.0193). Results of a sensitivity analysis excluding CRP from the sustained remission definition was consistent with the primary analysis (31.7% vs 13.8%; P=0.0280). All sustained remission components favored SAR (Figure 1). Patients in the SAR arm were 44% less likely to have a flare after achieving clinical remission vs the comparator arm (16.7% vs 29.3%; HR 0.56; 95% CI 0.35–0.90; P=0.0158). The comparator arm required more additional GCs vs the SAR arm, mainly due to PMR flare (median difference in actual and expected cumulative dose 199.5 mg vs 0.0 mg; P=0.0189). The cumulative GC toxicity index scores numerically favored SAR but the difference was not statistically significant. PMR activity scores improved in the SAR arm vs the comparator arm (LS mean -15.57 vs -10.27, nominal P=0.0002). Patient reported outcomes (eg, physical and mental health component scores, disability index, etc) favored SAR (Figure 1). Incidence of treatment-emergent AEs (TEAEs) was numerically higher in the SAR arm vs the comparator arm (94.9% vs 84.5%) and included neutropenia (15.3%) and arthralgia (15.3%) in the SAR arm, and insomnia (15.5%) in the comparator arm. Conversely, the frequency of serious AEs was higher in the comparator arm vs the SAR arm (20.7% vs 13.6%). No deaths were reported.Table 1.Demographics and baseline characteristicsParameterSAR + 14 wk GC taperPlacebo + 52 wk GC taper(n=60)(n=58)Age, median years (range)69 (51–88)70 (52–88)Sex (female), n (%)45 (75.0)37 (63.8)Race, n (%) Caucasian50 (83.3)48 (82.8) Asian1 (1.7)2 (3.4) Not reported9 (15.0)8 (13.8)PMR duration (diagnosis date to baseline),* median days (range)292 (78–3992)310 (66–2784)Any prior disease modifying anti rheumatic drugs, n (%) Methotrexate5 (8.3)10 (17.2) Leflunomide2 (3.3)1 (1.7) Azathioprine01 (1.7) Hydroxychloroquine1 (1.7)1 (1.7) Adalimumab1 (1.7)0 Tocilizumab01 (1.7)CRP (mg/L), median (range)6.8 (0.5–38.2)5.7 (0.1–62.3)Erythrocyte sedimentation rate (mm/h), median (range)25.0 (2.0–115.0)22.0 (5.0–85.0)*SAR n = 54; comparator n= 50.ConclusionSAR + 14 wk GC taper demonstrated significant efficacy vs the comparator arm in steroid refractory PMR patients, including clinically meaningful improvement in quality of life. Safety was consistent with the known safety profile of SAR.

A prospective study on the difference of clinical outcomes between elderly and adult patients with allergic rhinitis

ObjectiveThe guiding significance of existing guidelines for the diagnosis, treatment and health management of AR in elderly patients is unclear. The aim of this study is to analyze the clinical characteristics and therapeutic effects of elderly and adult AR patients by prospective study. MethodsA total of 131 AR patients were recruited and divided into elderly group and adult group according to age. After receiving the same pharmacological treatment for 4 weeks, the differences of the two groups in clinical scores including TNSS-4, RQLQ and VAS were compared. ResultsAfter 4 weeks treatment, all clinical scores in the adult group were improved compared with the baseline levels, while in the elderly group, only the TNSS-4 score was significantly reduced, and the RQLQ and VAS scores were not significantly improved. The changes of TNSS-4, RQLQ, and VAS scores in the elderly group were significantly inferior to those in the adult group (LS mean differences were 1.60, 8.80, and 11.10, respectively; P < 0.001). ConclusionWe confirmed that elderly and adult AR patients had different clinical characteristics and outcomes, and the degree of improvement in the adult group was significantly better than that in the elderly group. Therefore, it is urgent for us to establish a clinical guideline suitable for the elderly AR population to give more scientific and reasonable recommendations for diagnosis and treatment.

Randomized Phase 2 Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease.

The goal of this work was to determine whether locally acting ACE-083 is safe and well tolerated and increases muscle volume, motor function, and quality of life (QoL) in adults with Charcot-Marie-Tooth disease (CMT) type 1. This phase 2 study enrolled adults with CMT1 or CMTX (N = 63). Part 1 was open label and evaluated the safety and tolerability of different dose levels of ACE-083 for use in part 2. Part 2 was a randomized, placebo-controlled, 6-month study of 240 mg/muscle ACE-083 injected bilaterally into the tibialis anterior muscle, followed by a 6-month, open-label extension in which all patients received ACE-083. Pharmacodynamic endpoints included total muscle volume (TMV; primary endpoint), contractile muscle volume (CMV), and fat fraction. Additional secondary endpoints included 6-minute walk test, 10-m walk/run, muscle strength, and QoL. Safety was assessed with treatment-emergent adverse events (TEAEs) and clinical laboratory tests. In part 1 (n = 18), ACE-083 was generally safe and well tolerated at all dose levels, with no serious adverse events, TEAEs of grade 3 or greater, or death reported. In part 2 (n = 45 enrolled, n = 44 treated), there was significantly greater change in TMV with ACE-083 compared with placebo (least-squares mean difference 13.5%; p = 0.0096). There was significant difference between ACE-083 and placebo for CMV and change in ankle dorsiflexion strength. Fat fraction and all other functional outcomes were not significantly improved by ACE-083. Moderate to mild injection-site reactions were the most common TEAEs. Despite significantly increased TMV and CMV, patients with CMT receiving ACE-083 in tibialis anterior muscles did not demonstrate greater functional improvement compared with those receiving placebo. Clinical Trials Registration: NCT03124459. This study provides Class II evidence that intramuscular ACE-083 is safe and well tolerated and increases total muscle volume after 6 months of treatment in adults with CMT1 or CMTX.

Use of a Liquid Supplement Containing 2 Human Milk Oligosaccharides: The First Double-Blind, Randomized, Controlled Trial in Pre-term Infants.

There is growing evidence supporting the benefit of human milk oligosaccharides (HMOs) on reducing risk of illnesses and improving immune function in newborn infants, but evidence in pre-term infants is lacking. This randomized, double-blind, placebo-controlled trial (NCT03607942) of pre-term infants evaluated the effects of HMO supplementation on feeding tolerance, growth, and safety in 7 neonatal units in France. Pre-term infants (27–33 weeks' gestation, birth weight <1,700 g) were randomized early after birth to receive HMO supplement (n = 43) [2′-fucosyllactose (2′FL) and lacto-N-neotetraose (LNnT) in a 10:1 ratio (0.374 g/kg body weight/day)] or an isocaloric placebo (n = 43) consisting of only glucose (0.140 g/kg/day) until discharge from the neonatal unit. Anthropometric z-scores were calculated using Fenton growth standards. Primary outcome was feeding tolerance, measured by non-inferiority (NI) in days to reach full enteral feeding (FEF) from birth in HMO vs. placebo group (NI margin = 4+ days). Mean number of days on intervention prior to FEF was 8.9 and 10.3 days in HMO and placebo, respectively. Non-inferiority in time to reach FEF in HMO (vs. placebo) was achieved [LS mean difference (95% CI) = −2.16 (−5.33, 1.00); upper bound of 95% CI < NI margin] in full analysis set and similar for per protocol. Adjusted mean time to reach FEF from birth was 2 days shorter in HMO (12.2) vs. placebo (14.3), although not statistically significant (p = 0.177). There was no difference in weight-for-age z-scores between groups throughout the FEF period until discharge. Length-for-age z-scores were higher in HMO at FEF day 14 [0.29 (0.02, 0.56), p = 0.037] and 21 [0.31 (0.02, 0.61), p = 0.037]. Head circumference-for-age z-score was higher in HMO vs. placebo at discharge [0.42 (0.12, 0.71), p = 0.007]. Occurrence of adverse events (AEs) was similar in both groups and relatively common in this population, whereas 2.3 and 14.3%, respectively, experienced investigator-confirmed, related AEs. HMO supplementation is safe and well-tolerated in pre-term infants. After 9 days of supplementation, the HMO group reached FEF 2 days earlier vs. placebo, although the difference was not statistically significant. In addition, HMO supplementation supports early postnatal growth, which may have a positive impact on long-term growth and developmental outcomes.

Reduced asthma morbidity during COVID-19 in minority children: is medication adherence a reason?

Objectives Asthma control improved during the COVID-19 pandemic. This study examined objectively measured medication adherence, asthma morbidity and quality of life (QoL) outcomes in Black and Latinx children by month for January-June 2019 (pre-COVID) compared to January-June 2020 (including first peak of COVID). Methods Secondary analyses of 94 children with asthma (ages 10–17 years, 64% Latinx, 36% Black) and their caregivers assigned to the comparison group of a longitudinal RCT intervention trial. Outcomes included mean aggregate electronic adherence for controller medications, oral steroid bursts, acute healthcare utilization, caregiver asthma QoL, and the Asthma Control Test. Repeated measures analyses were conducted due to multiple observations. Results Adherence to controller medications declined 48% from 2019 to 2020 (LS Mean = 33.9% vs. 17.6%, p=.0004, f=.92) with levels reaching a low in May 2020. A reduction in steroid bursts was observed over the same timeframe, 1.29 vs. 0.61, p = 0.006, f=.63. Caregiver QoL increased from 2019 to 2020 on total score (5.18 vs. 5.85, p = 0.002, f=.72), activity limitations (5.04 vs. 5.95), and emotional functioning (5.26 vs. 5.80). Although not statistically significant, a clinically meaningful 62% reduction in acute healthcare visits (p = 0.15) was reported in 2020. Children reported better asthma control (OR = 1.47, 95% CI 1.24, 1.73, p < 0.0001) in 2020 versus 2019 driven by improvements from May to June 2020. Conclusions Decreased asthma morbidity in minority children during COVID was coupled with decreased adherence to controller medications. This observed decrease in morbidity is not explained by improvements in adherence.

PREFUL MRI Depicts Dual Bronchodilator Changes in COPD: A Retrospective Analysis of a Randomized Controlled Trial.

PurposeTo assess whether dynamic ventilation and perfusion (Q) biomarkers derived by phase-resolved functional lung (PREFUL) MRI can measure treatment response to 14-day therapy with indacaterol-glycopyrronium (IND-GLY) and correlate to clinical outcomes including lung function, symptoms, and cardiac function in patients with chronic obstructive pulmonary disease (COPD), as determined by spirometry, body plethysmography, cardiac MRI, and dyspnea score measurements.Materials and MethodsThe cardiac left ventricular function in COPD (CLAIM) study enrolled patients aged 40 years or older with COPD, stable cardiovascular function, and hyperinflation (residual volume > 135% predicted). Dynamic MRI data of these patients were retrospectively analyzed using the PREFUL technique to assess the effect of 14-day IND-GLY treatment versus placebo on regional measurements of ventilation dynamics. After manual segmentation of the lung parenchyma, flow-volume loops of each voxel were correlated to an individualized reference flow-volume loop, creating a two-dimensional flow-volume loop correlation map (FVL-CM) as a measure of ventilation dynamics. Ventilation-perfusion match (VQM) was evaluated in combination with perfusion and regional ventilation (VQMRVent) and with perfusion and the FVL-CM measurement (VQMCM). For image and statistical analysis, the lung parenchyma was segmented as a region of interest by manually delineating the lung boundary and excluding the large (central) vessels for each section. Differences in ventilation, perfusion, and VQM between IND-GLY and placebo were compared using analysis of variance, with study treatment, patient, and period included as factors.ResultsFifty patients (mean age, 64.3 years ± 7.65 [SD]; 35 men) were included in this analysis. IND-GLY significantly increased mean correlation as measured with FVL-CM versus that of placebo (least squares [LS] means treatment difference: 0.05 [95% CI: 0.03, 0.07]; P < .0001). Compared with placebo, IND-GLY increased mean Q (LS means treatment difference: 9.27 mL/min/100 mL [95% CI: 0.05, 18.49]; P = .049) and improved both VQMCM and VQMRVent (LS means treatment difference: 0.06 [95% CI: 0.03, 0.08]; P < .0001 and 0.05 [95% CI: 0.02, 0.08]; P = .001, respectively).ConclusionRegional ventilation dynamics and VQM measured by PREFUL MRI show treatment response in COPD. Supplemental material is available for this article. Clinical trial registration no. NTR6831Keywords: MRI, COPD, Perfusion, Ventilation, Lung, PulmonaryPublished under a CC BY 4.0 license

123 Selection for Post-weaning Fecal Egg Count Estimated Breeding Value Is Associated with Greater Antibody Production After Clostridial Vaccination in Katahdin Sheep

Abstract In a previous study, Katahdin lamb survivability to weaning was affected by sire post-weaning fecal egg count estimated breeding values (PFEC EBV) where lambs sired by low PFEC rams had greater survivability than high-PFEC-sired lambs. Therefore, selection for PFEC may also select for improved generalized immunity. The aim of this study was to compare effects of divergent PFEC mating on antibody production in purebred Katahdin lambs in response to vaccination. Katahdin dams with a PFEC value of greater than zero were bred to positive (high-PFEC) FECEBV rams, likewise, dams with a PFEC value of less than zero were bred to negative (low-PFEC) FECEBV rams. All lambs were managed as one cohort until approximately 105 days of age. During this time on pasture, a natural helminth infection was established, blood samples were taken weekly, and fecal samples were collected bi-weekly. Lamb FEC corresponded to sire/dam genotype (943 epg high-PFEC vs. 455 epg low-PFEC; P &amp;lt; 0.001). Serum samples were taken weekly for 3 wks after initial vaccination for Clostridium perfringens type C&amp;D and C. perfringens type A and for 4 wks after booster vaccination, which occurred 3 wk following primary vaccination. Total circulating IgG was measured used an ovine-specific enzyme-linked immunosorbent assay (ELISA). To evaluate lamb IgG differences, data were analyzed using the General Linear Model (GLM) procedure of SAS with fixed effects of genotype, time, and genotype X time interactions. Means comparisons were performed on LS means of fixed affects or interactions, using Bonferroni adjustment. A genotype by time interaction revealed that IgG response to boostering favored LoPFEC lambs (1679.91 vs 1153.08 ug/mL, respectively; P &amp;lt; 0.001). When averaged across time, LoPFEC lambs generated greater IgG concentration than HiPFEC lambs (886.79 ug/mL vs 465.15 ug/mL, respectively; P &amp;lt; 0.001). These data indicate that PFEC breeding values in Katahdin sheep may predict immunological fitness outside the context of parasitic infections and has implications for use in selection of individuals less prone to disease.

The New Island-Wide LS Factors of Taiwan, with Comparison with EU Nations

Soil erosion is a global environmental challenge that the United Nations Sustainable Development Goal (UN SDG) #15 wants to address, and the topographic factor, according to the RUSLE (Revised Universal Soil Loss Equation) model, is one of the most critical factors causing soil erosion. In this study, we employed three separate digital elevation models of Taiwan, with horizontal resolution ranging from 20 to 90 m, to compute the LS factors based on the upslope contributing areas and multiple flow directions, utilizing the methodologies used by the European Soil Data Centre. This is the first study to create a map of Taiwan’s island-wide LS factors without using a fixed slope length of 40 m. To compare European Union countries with Taiwan, we also calculated their LS means, standard deviations, and coefficients of variation of LS factors. As a result, Taiwan’s high LS values are readily noticeable as compared to the EU. Taiwan’s LS factor is greater than that of any EU country and the United Kingdom, at 2.69 times the EU average. To put it another way, while all other erosive factors are held equal, Taiwan’s average soil erosion is about 2.69 times that of the EU. With an LS factor of 6.95, Austria has the highest average LS in the EU, yet it is 91 percent of Taiwan’s. The findings demonstrate that Taiwan has a far higher mean LS factor than any EU country or the United Kingdom, which helps to partially explain why soil erosion in Taiwan is substantially higher than in the EU.

Effectiveness and Safety of Secukinumab for Psoriasis in a Real-World Clinical Setting in the Asia-Pacific and Middle East Regions: Results from the REALIA Study.

IntroductionSecukinumab has demonstrated sustained long-term efficacy with a favourable safety profile in various manifestations of psoriatic disease. We investigated effectiveness and safety of secukinumab, other biologics and conventional systemic therapies in patients with chronic plaque psoriasis in a real-world setting.MethodsREALIA was a non-interventional, multicentre, prospective, parallel group study. Eligible patients were ≥ 18 years old with chronic plaque psoriasis commencing a new treatment with a biologic agent or conventional systemic therapies.ResultsAt baseline, 541 patients were divided into three cohorts based on treatment initiated: conventional systemics (173), secukinumab (184) and other biologics (184). A significantly higher proportion of patients achieved almost clear to clear skin based on physician’s judgement in secukinumab versus conventional systemics at month 3 (64.7% versus 22.8%, P < 0.001) and month 6 (61.8% versus 20.8%, P < 0.001). At month 12, clear to almost clear skin was achieved by 52.1% of the patients in secukinumab versus 35.8% in conventional systemics (P = 0.066). The proportion of patients achieving Psoriasis Area Severity Index (PASI) 90 on conventional systemics, secukinumab and other biologics was 18.8%, 59.7% and 40.0% at month 3 and 35.3%, 60.8% and 50.0% at month 12, respectively. Secukinumab patients showed significantly higher change in PASI total score from baseline versus conventional systemics at month 3 {least squares [LS] mean [standard error (SE)]: −14.49 [0.648] versus −8.48 [1.149], P < 0.001} and numerically higher [LS mean (SE): −13.60 (0.475) versus −10.84 (1.733), P = 0.122] at month 12. The proportion of patients with Dermatology Life Quality Index 0/1 score on conventional systemics, secukinumab and other biologics was 22.6%, 65.0% and 41.6% at month 3 and 32.0%, 63.5% and 41.3% at month 12, respectively. Safety profile was comparable across cohorts.ConclusionsSecukinumab is effective and well tolerated in patients with chronic plaque psoriasis in a real-world setting in an Asia-Pacific and Middle East population, and these results are in agreement with clinical outcomes of secukinumab reported in randomised clinical trials.Trial registration number170803-001645.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00675-w.