Placebo-treated Subjects Research Articles

Efficacy of Radicava® IV (intravenous edaravone) in subjects with differing trajectories of disease progression in amyotrophic lateral sclerosis: Use of a novel statistical approach for post hoc analysis of a pivotal phase 3 clinical trial

IntroductionSubjects with amyotrophic lateral sclerosis (ALS) treated with Radicava® (edaravone) IV (intravenous; Mitsubishi Tanabe Pharma America [MTPA], hereafter “MTPA IV edaravone”) in Study MCI186–19 had a significantly slower physical functional decline vs placebo-treated subjects as measured by the revised ALS Functional Rating Scale (ALSFRS-R) and analyzed by the linear mixed model for repeated measures (MMRM). This Study 19 post hoc analysis of MTPA IV edaravone–treated and placebo-treated subjects evaluated linear and nonlinear latent class mixed models defining trajectories based on identifying the model with the lowest Bayesian information criterion. The best model differentiated 4 nonlinear trajectories in ALS subjects. ALSFRS-R total score in MTPA IV edaravone–treated and placebo-treated subjects was evaluated for these 4 nonlinear latent class trajectory groups. MethodsDisease trajectories of MCI186–19 MTPA IV edaravone–treated or placebo-treated ALS subjects who completed the double-blind period were investigated using latent class analysis (LCA) statistical models to identify potential unique nonlinear ALSFRS-R disease trajectories. ResultsALSFRS-R trajectories revealed 4 unique nonlinear trajectory latent classes per treatment group in MTPA IV edaravone–treated and placebo-treated ALS subjects completing the MCI186–19 double-blind period. Latent classes 2–4 had statistically significant slowing of ALSFRS-R total score decline in the predicted nonlinear trajectories of MTPA IV edaravone–treated vs placebo-treated ALS subjects. ConclusionsThis post hoc analysis suggests MTPA IV edaravone treatment results in slower ALSFRS-R decline vs placebo in most predicted nonlinear trajectories. LCA is a novel approach that may benefit future trial analyses.

Reversal of Pharmacologically Induced Mydriasis with Phentolamine Ophthalmic Solution

Evaluate safety and efficacy of 0.75% phentolamine ophthalmic solution (POS), an alpha-1 antagonist, in reversal of pharmacologically induced mydriasis. Two Phase 3, multicenter, placebo-controlled, randomized, double-masked clinical trials in healthy subjects. 553 healthy 12 to 80 year old subjects were randomized 1:1 (MIRA-2) and 2:1 (MIRA-3) to receive either POS or placebo eye drops OU. Subjects received POS or placebo administered 1 hour after mydriasis, induced by instillation of either 2.5% phenylephrine, 1% tropicamide, or Paremyd (1% hydroxyamphetamine / 0.25% tropicamide). Primary endpoint was percent of subjects returning to ≤0.2 mm greater than baseline pupil diameter in study eye at 90 minutes after POS administration. Safety measures included treatment-emergent adverse events (TEAEs) and tolerability measures, including conjunctival hyperemia. In MIRA-2, 185 subjects were randomized to treatment with placebo (94) or POS (91). In MIRA-3, 368 subjects were randomized to treatment with placebo (124) or POS (244). A statistically significant greater percentage of subjects treated with POS had study eyes that showed reversal of mydriasis at 90 minutes (primary endpoint) compared with the placebo treatment (48.9% vs 6.6% for MIRA-2; p<0.0001 and 58% VS 6% for MIRA-3; p<0.0001) and as early as 60 minutes (24.5% vs 5.5% for MIRA-2; p<0.0003 and 42% VS 2% for MIRA-3; p<0.0001). Between 28 to 34% of placebo-treated subjects had not returned to baseline PD at 24 hours following pharmacological dilation compared to 8 to 11% treated with POS (p<0.0001). POS treatment had a rapid onset in reducing PD within 60- to 90-minutes, with a statistically significant time savings of 3 to 4 hours to return to baseline PD compared to placebo. One or 2 drops of POS rapidly reversed mydriasis in all subjects regardless of mydriatic agent or iris color. More subjects receiving POS reported a perceived benefit in the resolution of visual symptoms caused by pharmacologically induced mydriasis compared to placebo, with statistically significant differences noted as early as 1 hour. The safety profile was favorable, with the most common adverse effects being mild transient conjunctival hyperemia (11.2%), instillation site discomfort (10.9%), and dysgeusia (3.6%).

A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFβ3 Antibody, in Healthy Volunteers.

Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs). This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50mg, 150mg, 240mg) or subcutaneously (SC; 240mg, 675mg, 1200mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations. The study enrolled 49 HVs, with a median age of 39 (range 18-73)years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (Cmax) and area under the concentration-timecurve from time 0 to infinity (AUC0-inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50mg IV) tested positive for ADAs at a single time point (day15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition. RO7303509 was well tolerated at single SC doses up to 1200mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy. ISRCTN13175485.

Composite Plot for Visualizing Aminotransferase and Bilirubin Changes in Clinical Trials of Subjects with Abnormal Baseline Values.

On-treatment excursions of liver laboratory test values in clinical trials involving subjects with underlying liver disease are relevant for the efficacy and safety assessment of drug products and biologics. Existing visualization and analysis tools do not efficiently provide an integrated view of these excursions when baseline liver tests are abnormal. The aim of this study was to develop a composite plot that enables visualization of on-treatment changes in liver test results both as multiples of the upper limit of normal defined by each laboratory's reference population (×ULN) and multiples of the subjects' baseline (×BLN) values. The composite plot approach combines biochemical evaluation for drug-induced severe hepatotoxicity (eDISH) plots sequentially applied to subjects' baseline and peak on-treatment liver test results normalized by ULN and integrates them into a four-panel shift plot of peak on-treatment values normalized by BLN. The composite plot enabled efficient assessment of improvement in liver test values during treatment compared with pretreatment in subjects treated with the investigational drug (or the natural history of placebo-treated subjects) and identified outlier subjects for potential drug-induced liver injury. For studies in subjects with abnormal baseline values, the composite plot has potential application in the assessment of beneficial and concerning on-treatment modifications in liver test values in reference to the individual subject's baseline and population threshold values.

Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis

Telazorlimab is a humanized anti-OX40 monoclonal antibody being studied for treatment of T-cell-mediated diseases. This randomized, placebo-controlled, phase 2b dose-range finding study investigated efficacy, safety, pharmacokinetics, and immunogenicity of telazorlimab in subjects with atopic dermatitis. In this 2-part study (NCT03568162), adults (≥18 years) with moderate-to-severe disease were randomized to various regimens of subcutaneous telazorlimab or placebo for 16 weeks' blinded treatment, followed by 38 weeks' open-label treatment and 12 weeks' drug-free follow-up. Telazorlimab treatment groups (following a loading dose) in part 1 were 300 mg every 2 weeks; 300 mg every 4 weeks; or 75 mg every 4 weeks. Part 2 evaluated telazorlimab 600 mg every 2 weeks. The primary end point was percentage change from baseline in Eczema Area and Severity Index (EASI) at week 16. Safety assessments included incidence of treatment-emergent adverse events. The study randomized 313 subjects in part 1 and 149 in part 2. At 16 weeks, the least squares mean percentage change from baseline in EASI was significantly greater in subjects receiving telazorlimab 300 mg every 2 weeks (part 1) and 600 mg every 2 weeks (part 2) versus placebo (-54.4% vs -34.2% for part 1 and -59.0% vs -41.8% for part 2, P= .008 for both). Telazorlimab was well tolerated, with similar distribution of adverse events between telazorlimab- and placebo-treated subjects in both part 1 and part 2. Telazorlimab, administered subcutaneously at 300 mg every 2 weeks or 600 mg every 2 weeks following a loading dose, was well tolerated and induced significant and progressive clinical improvement in adults with moderate-to-severe atopic dermatitis.

Proinflammatory islet antigen reactive CD4 T cells are linked with response to alefacept in type 1 diabetes.

Variation in the preservation of β cell function in clinical trials in type 1 diabetes (T1D) has emphasized the need to define biomarkers to predict treatment response. The T1DAL trial targeted T cells with alefacept (LFA-3-Ig) and demonstrated C-peptide preservation in ~30% of new onset T1D subjects. We analyzed islet antigen reactive (IAR) CD4 T cells in PBMC samples collected prior to treatment from alefacept- and placebo-treated subjects using flow cytometry and single cell RNA-sequencing. IAR CD4 T cells at baseline had heterogenous phenotypes. Transcript profiles formed phenotypic clusters of cells along a trajectory based on increasing maturation and activation, and T cell receptor (TCR) chains showed clonal expansion. Notably, the frequency of IAR CD4 T cells with a memory phenotype and a unique transcript profile (Cluster 3) were inversely correlated with C-peptide preservation in alefacept-, but not placebo-treated subjects. Cluster 3 cells had a proinflammatory phenotype characterized by expression of the transcription factor BHLHE40 and the cytokines GM-CSF and TNF-α, and shared TCR chains with effector memory-like clusters. Our results suggest IAR CD4 T cells as a potential baseline biomarker of response to therapies targeting the CD2 pathway and warrant investigation for other T cell-related therapies.

OR25-06 The Effect of Testosterone Replacement Therapy on NAFLD in Elderly Hypogonadal Men

Abstract Disclosure: H. Lee: None. S. Han: None. R.S. Swerdloff: None. Y. Pak: None. M.J. Budoff: None. C.C. Wang: None. The Effect of Testosterone Replacement Therapy on NAFLD in Elderly Hypogonadal Men Background: Aging increases body weight, visceral fat, insulin resistance and metabolic syndrome, leading to increased prevalence of nonalcoholic fatty liver disease(NAFLD) in elderly. Testosterone deficiency, more prevalent in elderly men, is associated with metabolic syndrome and increased visceral fat. The T Trials evaluated the effect of testosterone treatment on sexual function, physical function, and vitality. A substudy on the effect of testosterone on cardiovascular markers showed decrease in total cholesterol, LDL cholesterol, HDL cholesterol, fasting insulin level and HOMA-IR in testosterone treatment group compared to placebo. We hypothesized that testosterone replacement in elderly male with hypogonadism will improve NAFLD. Methods: Data from the T Trial was used to evaluate prevalence of NAFLD using 3 clinical scores in testosterone treatment group and placebo group; Lipid accumulation product (LAP) index, hepatic steatosis index (HSI) and NAFLD-MS score. A randomized sub-group of the placebo and testosterone treated subjects had cardiac CT (Computed tomography) that includes liver and spleen. Liver Hounsfield unit (HU) and spleen HU were obtained to evaluate NAFLD by CT criteria. Clinical liver fat scores and CT findings were evaluated at baseline and 12 months post treatment. Correlation between each liver fat score (LAP index, HSI and NAFLD-MS score) and liver CT findings were analyzed. Results: 502 male of age 65 and over with total testosterone &amp;lt;275ng/dL were analyzed (testosterone group n= 246, placebo group n=233). Baseline testosterone levels were not different between the two groups at baseline. Testosterone level was increased by 285.5±266.4ng/dL in the treatment group compared to 1.98±73.6ng/dL in the placebo group (p= 0.0001). Prevalence of NAFLD in elderly hypogonadal men by LAP index, HSI and NAFLD-MS were 89.77%, 88.93% and 3.96% respectively. 30% of subjects had liver HU&amp;lt;40, 21.36% had liver-to-spleen HU ratio (LSR)&amp;lt;1. There were no statistically significant changes in liver fat scores and CT findings in each arm at baseline and after 12 months treatment. Subgroup analysis on subjects with NAFLD defined by LAP index, liver HU or LSR did not show improvement of NAFLD after 12 months of testosterone replacement. Among the 3 liver fat scores, only LAP index showed inverse correlation with liver HU. Conclusion: Our study did not show improvement of NAFLD in elderly hypogonadal male after 12 months of testosterone replacement compared to placebo, assessed by lipid accumulation product index, hepatic steatosis index, NAFLD-MS score, liver HU and liver-to-spleen ratio. Future studies with longer treatment duration and additional modalities to define NAFLD as primary outcome may be warranted. Presentation Date: Saturday, June 17, 2023

OR18-03 Peripheral But Not Hepatic Insulin Resistance Associates With Adverse Vascular And Metabolic Health In Type 1 Diabetes: A Possible Target For Adjunctive Therapy

Abstract Disclosure: J.R. Snaith: None. N. Olsen: None. G. Kowalski: None. C. Bruce: None. J. Holmes-Walker: None. J.R. Greenfield: None. Insulin resistance in type 1 diabetes (T1D) is a cardiometabolic risk factor that is potentially targetable with adjunctive therapy. Prior studies of metformin in T1D have yielded mixed results. Whether liver and/or muscle insulin resistance is a prerequisite for metformin’s action in adults with T1D is unknown. The INTIMET study recruited 40 adults with T1D (age 37.4±8.8 years, HbA1c 7.5±0.9%, diabetes duration 22.9±8.8 years, BMI 26.4±0.9 kg/m2) and 20 age- and BMI-matched controls without diabetes. Subjects with T1D were randomized to metformin extended-release 1500mg daily or placebo for 26 weeks. Two-step hyperinsulinemic euglycemic clamps (low-dose 20 mU/m2/min, high-dose 60 mU/m2/min insulin) using 6,6-2H2-glucose tracers assessed liver (basal glucose rate of appearance [B-Ra] and low-dose endogenous glucose production [L-EGP]; primary outcomes) and muscle (high-dose glucose infusion rate [GIR]; secondary outcome) insulin resistance at t=0 in all subjects and at t=26 weeks in T1D. Dual-energy x-ray absorptiometry was used to measure fat free mass and visceral adipose tissue (VAT). Applanation tonometry was used to measure arterial stiffness (AIx, augmentation index). Adults with T1D and controls had similar B-Ra (18.2±5.1 vs 18.3±2.2 mmol/kgFFM/min; p=0.87). However, T1D were insulin-resistant at the liver (L-EGP 5.9±2.2 vs 3.6±1.7 mmol/kgFFM/min; p&amp;lt;0.001) and at muscle (GIR 62±20 vs 88±18 µmol/min·kgFFM; p&amp;lt;0.001). Despite these differences, VAT was comparable. In all subjects, baseline GIR correlated with L-EGP (r=-0.343; p=0.008), VAT (r=-0.269; p=0.039) and BMI (r=-0.304; p=0.019). In contrast, baseline L-EGP did not relate to VAT (r=0.060; p=0.653) or BMI (r=0.173; p=0.189). Adults with T1D had borderline higher AIx than controls (11.2±11.4 vs 4.7±13.1%, p=0.05). In the whole group, GIR was associated with LogAIx (r=-0.258, p=0.048), but L-EGP was not (r=0.154; p=0.246). In T1D, HbA1c correlated with GIR (r=-0.329; p=0.041) but L-EGP did not (r=0.307; p=0.057). After 26 weeks, there was no difference between metformin vs placebo-treated T1D subjects in HbA1c and weight, or B-Ra, L-EGP or GIR using generalised linear regression adjusted for age and baseline B-Ra, L-EGP and GIR. In these models, baseline GIR inversely predicted L-EGP (p=0.027) and directly predicted GIR (p&amp;lt;0.001) at 26 weeks. Adults with T1D exhibited greater liver and muscle insulin resistance, and higher arterial stiffness, which was not improved with metformin. Muscle but not liver insulin resistance related to BMI, VAT, HbA1c and AIx. Baseline muscle insulin resistance predicted muscle and hepatic insulin resistance at 26 weeks, irrespective of metformin treatment. This study highlights 1) the importance of muscle but not liver insulin resistance in T1D and 2) the need to identify muscle insulin resistant T1D individuals to enable interventions that improve vascular and metabolic outcomes. Presentation: Saturday, June 17, 2023

FRI076 Colchicine Treatment Effects On The Gut Microbiome In Adults With Metabolic Syndrome, Insulin Resistance, And High C-reactive Protein (CRP): A Secondary Analysis Of A Randomized, Placebo-controlled Clinical Trial

Abstract Disclosure: C.M. Kisimba: None. J.L. Donahue: None. K.K. Chivukula: None. P. Subramanian: None. S.D. Mistry: None. A. Wolska: None. A.T. Remaley: None. J.A. Yanovski: None. A.P. Demidowich: None. Background: Obesity-induced inflammation plays a substantial role in the development of insulin resistance and type 2 diabetes. The altered gut flora in obesity can also contribute to metabolic dysregulation and systemic inflammation. However, it remains unclear how dysregulation of systemic inflammation in obesity affects the gut microbiome. We hypothesized that colchicine’s systemic anti-inflammatory effects in obesity would be associated with improvements in gut microbial diversity. Methods: This study was a secondary analysis of a double-blind randomized placebo-controlled trial, in which 40 adults with obesity, high CRP (≥ 2.0 mg/L), insulin resistance (HOMA-IR ≥ 2.6 mg/L), and metabolic syndrome (MetS) were randomized to three months of colchicine 0.6mg or placebo tablets twice daily. Serum and stool samples were collected at baseline and final visit. Gut microbiota composition was characterized from stool DNA by dual-index amplification and sequencing of 16S ribosomal RNA. Results: Pre- and post-intervention stool samples were available for 15 colchicine- and 12 placebo-treated subjects. Circulating hsCRP, interleukin-6, resistin, white blood count, and neutrophils were significantly decreased in the colchicine arm as compared to placebo. However, changes in stool microbiome alpha diversity, as assessed by the Chao1, Shannon, and Pielou indices, were not significant between groups. Sequence variant counts were unchanged among all examined phyla or families. Oscillibacter was the only genus to demonstrate even a nominally significant change. Conclusion: Among adults with obesity and MetS, colchicine significantly improved systemic inflammation. However, this anti-inflammatory effect was not associated with significant changes in the gut microbiome. Further studies are warranted to investigate this relationship. Presentation: Friday, June 16, 2023

β-Carotene Supplementation Increases Antioxidant Capacity of Plasma in Older Women , ,

The antioxidant effect of dietary beta-carotene supplementation on the peroxidation potential of plasma was investigated in a randomized double-blind, placebo-controlled study. Twelve healthy women (62-80 y) supplemented their usual daily diet with 90 mg of beta-carotene (n = 6) or placebo (n = 6) capsules for 3 wk. Plasma concentrations of beta-carotene, alpha- and gamma-tocopherol, ascorbate, urate, bilirubin and in vitro production of phosphatidylcholine hydroperoxides (PC-OOH) and utilization of plasma antioxidants in the presence of 50 mmol/L 2,2'-azobis (2-aminopropane) hydrochloride (AAPH), a free radical generator, at 37 degrees C were measured before and after dietary treatment. Plasma beta-carotene increased from 0.76 +/- 0.16 to 6.45 +/- 1.16 micromol/L (P < 0.05) in supplemented but not placebo-treated subjects. The plasma concentrations of other antioxidants did not change significantly in either group. beta-Carotene supplementation did not affect basal levels of plasma PC-OOH as measured by HPLC post-column chemiluminescence but did affect AAPH-induced production of PC-OOH. Before supplementation, the induction period of plasma PC-OOH production was 2.4 +/- 0.4 h, with levels reaching 5.39 +/- 1.50 micromol/L after 6 h of incubation. After supplementation, the induction period increased significantly to 4.2 +/- 0.4 h (P < 0.01), with a lower PC-OOH production of 2.16 +/- 0.90 micromol/L after 6 h (P < 0.05). In this system, plasma ascorbate concentrations were depleted first, followed by loss of bilirubin and alpha-tocopherol and then by the sequential loss of gamma-tocopherol, urate and beta-carotene. These results indicate that beta-carotene supplementation increases the plasma antioxidant capacity of older women.

A Novel 3-Point Injection Technique for OnabotulinumtoxinA in the Upper Depressor Anguli Oris.

To evaluate the efficacy and safety of onabotulinumtoxinA (ONA) injections to the depressor anguli oris (DAO) to improve downturned mouth. This prospective, placebo-controlled, study enrolled subjects aged 18 to 65 years. Injections were performed using a novel 3-point technique in the upper DAO (1.5 U/injection site). The primary end point was a DAO contraction scale 1-grade improvement. Subjective evaluation was performed using the Global Aesthetic Improvement Scale (GAIS). Ten subjects received ONA and 10 placebo (saline) injections. In ONA-treated subjects, DAO scores showed significant improvements at Weeks 4 and 12 ( p < .001) compared with baseline. No significant difference between visits was observed for placebo-injected subjects. Global Aesthetic Improvement Scale scores showed that 100% of subjects were improved compared with baseline at Week 4% and 90% at Week 12. By contrast, 90% and 80% of placebo-treated subjects had "no change" in their DAO appearance at Weeks 4 and 12. Subject GAIS assessments matched the live evaluator at Week 4; 60% continued to report improvement at Week 12. Treatment was well tolerated. OnabotulinumtoxinA injections to the DAO using a 3-point technique provide clinically meaningful improvements in appearance. Treatment was well tolerated and in most individuals lasted at least 12 weeks. ClinicalTrials.gov NCT04240535.

Colchicine effects on the gut microbiome in adults with metabolic syndrome.

Obesity-induced inflammation plays a substantial role in the development of insulin resistance and type 2 diabetes. The altered gut flora in obesity can also contribute to metabolic dysregulation and systemic inflammation. However, it remains unclear how dysregulation of systemic inflammation in obesity affects the gut microbiome. We hypothesized that colchicine's systemic anti-inflammatory effects in obesity would be associated with improvements in gut microbial diversity. We conducted a secondary analysis of a double-blind randomized placebo-controlled trial, in which 40 adults with obesity, high C-reactive protein (CRP) (≥2.0 mg/L), insulin resistance (homeostatic model of insulin resistance: HOMA-IR ≥2.6 mg/L), and metabolic syndrome (MetS) were randomized to three months of colchicine 0.6 mg or placebo tablets twice daily. Serum and stool samples were collected at baseline and final visit. Gut microbiota composition was characterized from stool DNA by dual-index amplification and sequencing of 16S ribosomal RNA. Pre- and post-intervention stool samples were available for 15 colchicine- and 12 placebo-treated subjects. Circulating high sensitivity CRP (hsCRP), interleukin-6, resistin, white blood count, and neutrophils were significantly decreased in the colchicine arm as compared to placebo. However, changes in stool microbiome alpha diversity, as assessed by the Chao1, Shannon, and Pielou indices, were not significant between groups. Amplicon sequence variant counts were unchanged among all examined phyla or families. Oscillibacter was the only genus to demonstrate even a nominally significant change. Among adults with obesity and MetS, colchicine significantly improved systemic inflammation. However, this anti-inflammatory effect was not associated with significant changes in the gut microbiome. Further studies are warranted to investigate this relationship.

A secondary analysis of depression outcomes from a randomized controlled trial of adjunctive sertraline for HIV-associated cryptococcal meningitis

Background: Depression is a risk factor for worse HIV outcomes in persons living with HIV/AIDS, including engagement-in-care, HIV medication adherence, and retention-in-care. Depression has a prevalence of more than three times as high as in the general population. Despite this, there are few randomized studies of antidepressants in HIV-infected Africans, including those with opportunistic infections. Methods: We enrolled 460 HIV-infected Ugandans with cryptococcal meningitis into a randomized clinical trial of adjunctive sertraline vs placebo (2015-2017). We defined depression using the Center for Epidemiologic Studies Depression Scale (CES-D) score of &gt;15, and severe depression as &gt;26 at one and three months after meningitis diagnosis and initiation of treatment. We evaluated the relationship between sertraline and depression, as well as associations with persistent depression, at three months. Results: At one- and three-months post meningitis diagnosis, 62% (108/174) and 44% (74/169) of all subjects had depression (CES&gt;15), respectively. At three months, sertraline-treated subjects had consistent risk for depression as placebo-treated subjects but were significantly less likely to have severe depression (CES&gt;26) (OR 0.335; 95%CI, 0.130-0.865). Of those with depression at one month, sertraline-treated subjects were less likely than placebo-treated subjects to be depressed at three months (p=0.05). Sertraline was the only factor we found significant in predicting persistent depression at three months among those with depression at one month. Conclusions: Depression is highly prevalent in HIV-infected persons who have survived cryptococcal meningitis. We found that sertraline is associated with a modest reduction in depression in those with depression at baseline and a significant decrease in severe depression.

Effects of Omega-3 and Antioxidant Cocktail Supplement on Prolonged Bed Rest: Results from Serum Proteome and Sphingolipids Analysis.

Physical inactivity or prolonged bed rest (BR) induces muscle deconditioning in old and young subjects and can increase the cardiovascular disease risk (CVD) with dysregulation of the lipemic profile. Nutritional interventions, combining molecules such as polyphenols, vitamins and essential fatty acids, can influence some metabolic features associated with physical inactivity and decrease the reactive oxidative and nitrosative stress (RONS). The aim of this study was to detect circulating molecules correlated with BR in serum of healthy male subjects enrolled in a 60-day BR protocol to evaluate a nutritional intervention with an antioxidant cocktail as a disuse countermeasure (Toulouse COCKTAIL study). The serum proteome, sphingolipidome and nitrosoproteome were analyzed adopting different mass spectrometry-based approaches. Results in placebo-treated BR subjects indicated a marked decrease of proteins associated with high-density lipoproteins (HDL) involved in lipemic homeostasis not found in the cocktail-treated BR group. Moreover, long-chain ceramides decreased while sphingomyelin increased in the BR cocktail-treated group. In placebo, the ratio of S-nitrosylated/total protein increased for apolipoprotein D and several proteins were over-nitrosylated. In cocktail-treated BR subjects, the majority of protein showed a pattern of under-nitrosylation, except for ceruloplasmin and hemopexin, which were over-nitrosylated. Collectively, data indicate a positive effect of the cocktail in preserving lipemic and RONS homeostasis in extended disuse conditions.

Efficacy and safety of SER-109, an investigational microbiome therapeutic for recurrent clostridioides difficile infection: Data from ECOSPOR III, a phase 3 randomized trial.

12113 Background: Patients with malignancies are at increased risk for recurrent Clostridioides difficile infection (rCDI) due to their immunosuppressed state and frequent exposure to antibiotics and chemotherapy. These factors disrupt the gut microbiome creating an environment conducive to C. difficile colonization. Patients with cancer have higher rates of rCDI and worse outcomes than those without malignancy. SER-109, an investigational microbiome therapeutic, was superior to placebo in reducing rCDI at 8 weeks compared with placebo (12% vs 40%, respectively) in ECOSPOR III, a Phase 3 randomized, double-blind trial of subjects with a history of rCDI [NEJM 2022; 386:220-9]. Here, we report secondary endpoints of rCDI rates at 4, 12 and 24 weeks. Methods: Adults with rCDI (≥3 episodes in 12 months) were screened at 56 US/Canadian sites. After standard-of-care antibiotics (vancomycin or fidaxomicin per investigator discretion), subjects were randomized 1:1 to SER-109 (4 capsules x 3 days) or matching placebo. The primary endpoint was rCDI (recurrent toxin + diarrhea requiring treatment) at 8 weeks; secondary endpoints included rCDI at 4, 12 and 24 weeks. Safety was evaluated through week 24. Results: 281 subjects were screened and 182 (intention-to-treat population; ITT) were randomized (59.9% female; mean age 65.5 years). The most common comorbidities were respiratory disease (36.3%) and cardiovascular disease (32.4%). A total of 28.6% and 18.1% had a history of immunocompromise and malignancy, respectively. Significantly fewer SER-109 vs. placebo treated subjects had rCDI posttreatment compared with placebo recipients at Weeks 4, 8, 12 and 24 (Table). The absolute risk reduction between placebo and SER-109 arms ranged from 22.1% to 28.3% across the 4 timepoints. The safety profile of SER-109 through week 24 was comparable to placebo. Most adverse events (AEs) were mild to moderate gastrointestinal occurrences. More placebo-treated vs SER-109-treated subjects experienced serious AEs through week 8, while comparable proportions of subjects in both arms reported serious AEs from 8 through 24 weeks. Conclusions: In this population of subjects with comorbidities, including malignancy and immunosuppression, SER-109 significantly reduced rCDI rates through week 24 with an observed safety profile comparable to placebo. Clinical trial information: NCT03183128. [Table: see text]

Baseline GP2 immune response as an independent prognostic factor in a phase IIb study evaluating HER2/neu peptide GP2 (GLSI-100) versus. GM-CSF alone after adjuvant trastuzumab in HER2-positive women with breast cancer.

e12519 Background: Delayed type hypersensitivity (DTH) skin tests to GP2 were conducted in the randomized, active-controlled, single-blinded, multicenter Phase IIb trial investigating GLSI-100 (GP2+GM-CSF) administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2. Previously it has been reported that subjects with baseline response to GP2 by DTH were more likely to experience a recurrence sooner than those without a positive baseline response. It was of interest to determine if this response was independent of other known prognostic factors. Methods: Patients were randomized and received GLSI-100 (500 mcg GP2: 125 mcg GM-CSF) or control (GM-CSF only) via 6 intradermal injections every 3-4 weeks as part of the Primary Immunization Series (PIS) for 6 months and 4 booster injections every 6 months thereafter. GP2 DTH skin tests were placed at baseline and after the 6th dose. After 48-72 hours, the largest perpendicular diameters of induration were measured and the orthogonal mean was calculated. Induration of over 5mm was considered a positive response. The relationship between prognostic factors such as demographic and disease characteristics and the baseline DTH response were investigated by logistic regression. Results: The study enrolled 180 patients who were HER2 3+ positive and low HER2 expressors (1-2+). After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GLSI-100, if completing the PIS, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 patients treated with GM-CSF (p = 0.0338). Just under 23% of subjects experienced an immune response to GP2 by DTH at baseline. The incidence was similar in patients who were HER2/neu positive and those considered low expressors and was equally distributed across GLSI-100 and placebo-treated subjects. Known prognostic factors such as hormone receptor status, stage at presentation, node status, etc. were evenly distributed across subjects that experienced a baseline DTH response to GP2 and those who did not. Each prognostic factor was investigated in a logistic model to determine if it predicted baseline DTH immune status. The prognostic factors did not predict baseline DTH immune response in the logistic models. There appears to be no correlation between baseline immune response to GP2 and known prognostic factors. Conclusions: Baseline GP2 immune response as measured by the delayed-type hypersensitivity test may be an independent prognostic factor for recurrence. Knowledge of this GP2 immune response may identify a patient with increased risk of rapid recurrence. Clinical trial information: 00524277.

Long-Term GAD-alum Treatment Effect on Different T-Cell Subpopulations in Healthy Children Positive for Multiple Beta Cell Autoantibodies.

Objective The objective of this study was to explore whether recombinant GAD65 conjugated hydroxide (GAD-alum) treatment affected peripheral blood T-cell subpopulations in healthy children with multiple beta cell autoantibodies. Method The Diabetes Prevention–Immune Tolerance 2 (DiAPREV-IT 2) clinical trial enrolled 26 children between 4 and 13 years of age, positive for glutamic acid decarboxylase autoantibody (GADA) and at least one other autoantibody (insulin, insulinoma antigen-2, or zinc transporter 8 autoantibody (IAA, IA-2A, or ZnT8A)) at baseline. The children were randomized to two doses of subcutaneously administered GAD-alum treatment or placebo, 30 days apart. Complete blood count (CBC) and immunophenotyping of T-cell subpopulations by flow cytometry were performed regularly during the 24 months of follow-up posttreatment. Cross-sectional analyses were performed comparing lymphocyte and T-cell subpopulations between GAD-alum and placebo-treated subjects. Results GAD-alum-treated children had lower levels of lymphocytes (109 cells/L) (p = 0.006), T-cells (103 cells/μL) (p = 0.008), T-helper cells (103 cells/μL) (p = 0.014), and cytotoxic T-cells (103 cells/μL) (p = 0.023) compared to the placebo-treated children 18 months from first GAD-alum injection. This difference remained 24 months after the first treatment for lymphocytes (p = 0.027), T-cells (p = 0.022), T-helper cells (p = 0.048), and cytotoxic T-cells (p = 0.018). Conclusion Our findings suggest that levels of total T-cells and T-cell subpopulations declined 18 and 24 months after GAD-alum treatment in healthy children with multiple beta-cell autoantibodies including GADA.

The Efficacy and Safety of Probiotics for Allergic Rhinitis: A Systematic Review and Meta-Analysis.

BackgroundProbiotics have proven beneficial in a number of immune-mediated and allergic diseases. Several human studies have evaluated the efficacy and safety of probiotics in allergic rhinitis; however, evidence for their use has yet to be firmly established.ObjectiveWe undertook a systematic review and meta-analysis aiming to address the effect and safety of probiotics on allergic rhinitis.MethodsWe systematically searched databases [MEDLINE (PubMed), Embase, and the Cochrane Central Register of Controlled Trials] from inception until June 1, 2021. Qualified literature was selected according to inclusion and exclusion criteria, the data were extracted, and a systematic review and meta-analysis was conducted.ResultsTwenty-eight studies were included. The results showed that probiotics significantly relieved allergic rhinitis symptoms (standardized mean difference [SMD], −0.29, 95% confidence interval (CI) [−0.44, −0.13]; p = 0.0003, I 2 = 89%), decreased Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores compared with the control group (SMD, −0.64, 95% CI [−0.79, −0.49], p < 0.00001, I 2 = 97%), and increased T helper cell 1(Th1)/Th2 ratio (mean difference [MD], −2.47, 95% CI [−3.27, −1.68], p < 0.00001, I 2 = 72%). There was no significant change in overall or specific IgE levels between probiotic-treated and placebo-treated subjects (SMD, 0.09, 95% CI [−0.16, 0.34], I 2 = 0%, and SMD, −0.03, 95% CI [−0.18, 0.13], p = 0.72, I 2 = 0%, respectively).ConclusionsTo sum up, probiotic supplement seems to be effective in ameliorating allergic rhinitis symptoms and improving the quality of life, but there is high heterogeneity in some results after subgroup analysis and clinicians should be cautious when recommending probiotics in treating allergic rhinitis.Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/, PROSPERO (CRD42021242645).

Interactions Between Statins, Exercise, and Health: A Clinical Update

Interactions Between Statins, Exercise, and Health: A Clinical Update

Effects of Regular Low-Level Alcohol Consumption in Healthy Individuals: A Randomized, Double-Blind, Placebo-Controlled Crossover Study.

The effects of alcohol consumption on health are suggested to depend on the amount of alcohol consumed. We investigated the objective and subjective health effects of the daily consumption of a small amount of alcohol in healthy individuals using a randomized, double-blind, placebo-controlled crossover study. Accordingly, 15 male and 27 female Japanese adults with average or lower general well-being schedule (GWBS) scores were asked to consume a beverage with 0.5% (v/v) alcohol (~4 g of alcohol a day; test beverage) and a placebo beverage two times daily for 4 weeks each. Regular low-level alcohol consumption significantly decreased the serum liver function indexes (aspartic aminotransferase, alanine aminotransferase, and lactate dehydrogenase) before and after consumption (p = 0.034, 0.033, and 0.013, respectively). The small amount of alcohol did not affect the participants’ GWBS scores; however, a stratified analysis with poor subjective well-being revealed that these changes differed significantly between low-level alcohol consumption and placebo-treated subjects (16.0 vs. 11.5, p = 0.041). In addition, changes in serum testosterone levels demonstrated a higher trend in the group that received the test beverage compared with the group that received the placebo beverage (p = 0.051). Daily low-level alcohol consumption may have positive effects on liver function and subjective well-being.