Trials In People Research Articles

Differences in uni-dimensional breathlessness measures and thresholds for clinical response in a randomised controlled trial in people with chronic breathlessness: an exploratory study

IntroductionOptimally measuring improvements in chronic breathlessness in clinical practice and research continues to evolve. The aim of this study was to consider the performance of uni-dimensional measures in chronic breathlessness...

Determinants of long‐term paramagnetic rim lesion evolution in people with multiple sclerosis

AbstractObjectiveBaseline paramagnetic rim lesion (PRL) load predicts disease progression in people with multiple sclerosis (pwMS). Understanding how PRLs relate to other known MS‐related factors, and the practical utility of PRLs in clinical trials, is crucial for informing clinical decision‐making and guiding development of novel disease‐modifying treatments (DMTs).MethodsThis study included 152 pwMS enrolled in a larger prospective, longitudinal cohort study who had 3T MRI scans and clinical assessments at baseline and 5‐ or 10‐year follow‐ups. PRLs were identified on baseline 3T quantitative susceptibility maps and classified as persisting, disappearing, or newly appearing at follow‐up. The relationships between PRL evolution and clinical, radiological, environmental, and genetic characteristics were assessed, and clinical trial sample sizes were estimated using PRL appearance or disappearance as outcome measures.ResultsDMT use was associated with lower odds of new PRL appearance (for high‐efficacy DMTs: odds ratio = 0.088, p = 0.024), but not disappearance. Current smoking status was associated with greater baseline PRL number (B = 0.527 additional PRLs, p = 0.013). A 24‐month clinical trial in people with progressive MS for a DMT that doubles the rate of PRL rim disappearance would require an estimated 118 people with progressive MS per group at 80% statistical power.InterpretationEarly MS diagnosis and subsequent DMT initiation may reduce new chronic active inflammation. However, the utility of PRL disappearance or new PRL appearance as outcome measures in clinical trials is limited by potentially large sample sizes that are needed for moderate efficacy drugs.

Basal insulin analogues in type 1 diabetes – Does one size fit all? Lessons from the HypoDeg trial based on single-patient outcomes

AimsIn the HypoDeg trial, a randomised crossover trial in people with type 1 diabetes prone to nocturnal severe hypoglycaemia, treatment with insulin degludec (IDeg) resulted in significantly reduced rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia compared to insulin glargine U100 (IGlar). We analysed HypoDeg data at a single-patient level to assess the proportion of participants to whom the overall result applied. MethodsPost hoc analysis using single-patient data (n = 133) on nocturnal symptomatic hypoglycaemia, all-day severe hypoglycaemia and HbA1c. The outcome was classified as superior with IDeg, superior with IGlar, or similar between treatments for the three outcomes. We also assessed a composite endpoint based on these outcomes to evaluate the overall superior treatment for each participant. ResultsA higher percentage (38 %) had IDeg as superior treatment compared to IGlar (15 %) for nocturnal symptomatic hypoglycaemia (p < 0.001). There was no difference between the treatments for all-day severe hypoglycaemia or HbA1c. A higher percentage (44 %) had a composite endpoint favouring IDeg compared to IGlar (16 %) (p < 0.001). ConclusionsThe superiority of IDeg was confirmed in many of the participants. However, a minority had IGlar as superior treatment, underscoring the need for individualised basal insulin therapy in clinical practice.

TNF-α inhibitors for type 1 diabetes: exploring the path to a pivotal clinical trial.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreas. This destruction leads to chronic hyperglycemia, necessitating lifelong insulin therapy to manage blood glucose levels. Typically diagnosed in children and young adults, T1D can, however, occur at any age. Ongoing research aims to uncover the precise mechanisms underlying T1D and to develop potential interventions. These include efforts to modulate the immune system, regenerate β-cells, and create advanced insulin delivery systems. Emerging therapies, such as closed-loop insulin pumps, stem cell-derived β-cell replacement and disease-modifying therapies (DMTs), offer hope for improving the quality of life for individuals with T1D and potentially moving towards a cure. Currently, there are no disease-modifying therapies approved for stage 3 T1D. Preserving β-cell function in stage 3 T1D is associated with better clinical outcomes, including lower HbA1c and decreased risk of hypoglycemia, neuropathy, and retinopathy. Tumor Necrosis Factor alpha (TNF-α) inhibitors have demonstrated efficacy at preserving β-cell function by measurement of C-peptide in two clinical trials in people with stage 3 T1D. However, TNF-α inhibitors have yet to be evaluated in a pivotal trial for T1D. To address the promising clinical findings of TNF-α inhibitors in T1D, Breakthrough T1D convened a panel of key opinion leaders (KOLs) in the field. The workshop aimed to outline an optimal clinical path for moving TNF-α inhibitors to a pivotal clinical trial in T1D. Here, we summarize the evidence for the beneficial use of TNF-α inhibitors in T1D and considerations for strategies collectively identified to advance TNF-α inhibitors beyond phase 2 clinical studies for stage 3 T1D.

Tirzepatide and blood pressure reduction: stratified analyses of the SURMOUNT-1 randomised controlled trial

BackgroundTreating obesity may be a pathway to prevent and control hypertension. In the SURMOUNT-1 trial in people with obesity or overweight with weight-related complications, 72-week tirzepatide treatment led to clinically...

Transcutaneous vagus nerve stimulation has no anti-inflammatory effect in diabetes

Chronic inflammation is associated with diabetes and contributes to the development and progression of micro- and macrovascular complications. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to reduce levels of circulating inflammatory cytokines in non-diabetics by activating the cholinergic anti-inflammatory pathway. We investigated the anti-inflammatory potential of tVNS as a secondary endpoint of a randomized controlled trial in people with diabetes (NCT04143269). 131 people with diabetes (type 1: n = 63; type 2: n = 68), gastrointestinal symptoms and various degrees of autonomic neuropathy were included and randomly assigned to self-administer active (n = 63) or sham (n = 68) tVNS over two successive study periods: (1) Seven days with four daily administrations and, (2) 56 days with two daily administrations. Levels of systemic inflammatory cytokines (IL-6, IL-8, IL-10, TNF-α, IFN-γ) were quantified from blood samples by multiplex technology. Information regarding age, sex, diabetes type, and the presence of cardiac autonomic neuropathy (CAN) was included in the analysis as possible confounders. No differences in either cytokine were seen after study period 1 and 2 between active and sham tVNS (all p-values > 0.08). Age, sex, diabetes type, presence of CAN, and baseline levels of inflammatory cytokines were not associated with changes after treatment (all p-values > 0.07). A tendency towards slight reductions in TNF-α levels after active treatment was observed in those with no CAN compared to those with early or manifest CAN (p = 0.052). In conclusion, tVNS did not influence the level of systemic inflammation in people with diabetes.

A randomized, placebo-controlled trial of purified anthocyanins on cognitive function in individuals at elevated risk for dementia: Analysis of inflammatory biomarkers toward personalized interventions

BackgroundDementia poses a significant global health challenge. Anthocyanins neutralize free radicals, modulate signaling pathways, inhibit pro-inflammatory genes, and suppress cytokine production and may thus have positive cognitive effects in people at increased risk of dementia. We aim to investigate the effects of purified anthocyanins on cognitive function in people at increased risk of dementia according to their inflammation status based on blood-based inflammatory biomarkers. MethodsThis is a secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial. Cluster analysis was performed to categorize two groups based on their individual inflammatory biomarker profile using multiplex sandwich ELISA for the quantitative measurement of cytokines. Descriptive statistics and longitudinal models assessed cognitive outcomes. The primary comparison was the group difference at week 24 based on a modified intention-to-treat analysis. ResultsCluster analysis revealed two distinct inflammatory biomarker profiles. In Cluster 1 (high levels of inflammation biomarkers), anthocyanin treatment showed a statistically significant improvement on cognitive function compared to placebo at 24 weeks. No significant differences were observed in Cluster 2 (low levels of inflammation biomarkers). The demographic characteristics, cognitive scores, and biomarker distributions were similar between treatment groups at baseline. However, cluster 1 exhibited higher BMI, diabetes prevalence, medication usage, and lower HDL cholesterol levels. ConclusionIndividuals with elevated levels of inflammation markers benefited from anthocyanin treatment to enhance cognitive performance, whereas those with lower levels did not. The anti-inflammatory and antioxidant properties of anthocyanins make them a promising intervention, and future prospective trials in people with increased inflammation are warranted.

Promotion of a Mediterranean Diet Alters Constipation Symptoms and Fecal Calprotectin in People with Parkinson's Disease: A Randomized Controlled Trial.

Parkinson's disease is associated with gastrointestinal (GI) dysfunction, including constipation symptoms and abnormal intestinal permeability and inflammation. A Mediterranean diet (MediDiet) may aid in disease management. This parallel, randomized, controlled trial in people with Parkinson's (PwP) and constipation symptoms compared a MediDiet against standard of care on change in constipation symptoms, dietary intake, and fecal zonulin and calprotectin concentrations as markers of intestinal permeability and inflammation, respectively. Participants were randomized to either standard of care for constipation (control; n = 17, 65.1 ± 2.2 years) or a MediDiet plus standard of care (n = 19, 68.8 ± 1.4 years) for 8 weeks. Constipation scores decreased with both interventions (p < 0.01), but changes from baseline were not different between groups (MediDiet, -0.5 [-1.0, 0]; control, -0.8 [-1.0, 0.2]; median [25th, 75th]; p = 0.60). The MediDiet group had a higher intake of dietary fiber at week 4 than the control group (13.1 ± 0.7 g/1000 kcal vs. 9.8 ± 0.7 g/1000 kcal; p < 0.001). No differences in fecal zonulin were observed between groups (p = 0.33); however, fecal calprotectin tended to be lower in the MediDiet group at week 8 (45.8 ± 15.1 µg/g vs. 93.9 ± 26.8 µg/g; p = 0.05). The MediDiet and standard interventions reduced constipation symptoms; however, the MediDiet provided additional benefit of increased dietary fiber intake and less intestinal inflammation.

O88 REDUCTION IN SYSTOLIC BLOOD PRESSURE FOLLOWING DIETARY FIBRE INTERVENTION IS DEPENDENT ON BASELINE GUT MICROBIOTA COMPOSITION

Background/Objective: Dietary interventions high in fibre have been shown to lower blood pressure (BP). This effect is via the gut microbiota, via fermentation of fibre and production of metabolites called short-chain fatty acids (SCFAs). Not all patients respond to dietary fibre interventions for unclear reasons. We aimed to determine if we can identify fibre-responders based on their gut microbiota and production of SCFAs. Methods: We performed a phase II cross-over placebo-controlled randomised clinical trial in untreated hypertensive patients. Twenty treatment-naive participants with hypertension received 40 g per day of fermentable fibre delivered as acetylated and butyrylated high amylose maize starch (HAMSAB) or the placebo for 3 weeks. Blood pressure was monitored at baseline and endpoint by ambulatory BP monitoring, with those experiencing a reduction of ≥2 mmHg in systolic BP classified as responders. The microbiota was determined by sequencing the V4-V5 region of the 16S rRNA gene in baseline stool samples. The relationship between baseline gut microbiota and response to dietary intervention was assessed with the MaAsLin2 package. Plasma SCFAs levels were quantified by mass spectrometry. Results: We observed a placebo-subtracted mean 24-hour systolic BP of –6.1 mmHg (p=0.03, reported in Jama et al., 2023 Nature Cardiovascular Research), with 14 (70%) individuals classified as responders and 6 (30%) as non-responders. Genera significantly enriched in responders included Dialister (β=1.29, q=1.921x10-134), Coprococcus (β=1.26, q=3.282x10-121), Bifidobacterium (β=1.67, q=1.11x10-81), Ruminococcus (β=0.161, q=1.11x10-8), and Roseburia (β=0.82, q=4.275x10-2). Responders also produced higher levels of the SCFAs butyrate (mean±SEM, non-responders 4.95±2.4 vs responders 51.15±14.7, p=0.0096), but no difference in other SCFAs. Conclusions: Participants who experienced a decrease in systolic BP following a dietary fibre intervention had increased bacterial genera known to contain species that produce SCFAs (Bifidobacterium, Roseburia, Ruminococcus) at baseline, and were able to produce more butyrate. These data suggest that baseline microbiota composition contributes to the response to dietary fibre intervention trials in people with hypertension, likely via increased capacity to produce butyrate.

Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis

BackgroundPositive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS). Objective: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation. Study design and settingsA randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial’s last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated. ResultsMean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL − RNS60 group; 3.3 years in low NfL − placebo group; 1.9 years in high NfL − RNS60 group; 1.8 years in high NfL − placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 − RNS60 group; 2.3 years in low MCP-1 − placebo group; 2.8 years in high MCP-1 − RNS60 group; 2.6 years in high MCP-1 − placebo group) levels at baseline. Conclusions and relevanceIn this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug’s effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival. Trial registrationStudy preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.

Trial to assess the tolerability of using felodipine to upregulate autophagy as a treatment of Huntington’s disease (FELL-HD): a phase II, single-centre, open-label, dose-finding trial protocol

IntroductionHuntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that presents with a progressive movement disorder along with cognitive and psychiatric problems. It is caused by a Cytosine-adenin-guanine (CAG) expansion...

Easing the way to achieving target serum urate in people with gout: protocol for a non-inferiority randomised strategy trial using an allopurinol dosing model in Aotearoa/New Zealand (the Easy-Allo Study)

IntroductionGout is one of the most common forms of arthritis worldwide. Gout is particularly prevalent in Aotearoa/New Zealand and is estimated to affect 13.1% of Māori men, 22.9% of Pacific...

Estimating risk of consequences following hypoglycaemia exposure using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials

Aims/hypothesisWhether hypoglycaemia increases the risk of other adverse outcomes in diabetes remains controversial, especially for hypoglycaemia episodes not requiring assistance from another person. An objective of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project was to create and use a dataset of pooled clinical trials in people with type 1 or type 2 diabetes to examine the association of exposure to all hypoglycaemia episodes across the range of severity with incident event outcomes: death, CVD, neuropathy, kidney disease, retinal disorders and depression. We also examined the change in continuous outcomes that occurred following a hypoglycaemia episode: change in eGFR, HbA1c, blood glucose, blood glucose variability and weight.MethodsData from 84 trials with 39,373 participants were pooled. For event outcomes, time-updated Cox regression models adjusted for age, sex, diabetes duration and HbA1c were fitted to assess association between: (1) outcome and cumulative exposure to hypoglycaemia episodes; and (2) outcomes where an acute effect might be expected (i.e. death, acute CVD, retinal disorders) and any hypoglycaemia exposure within the last 10 days. Exposures to any hypoglycaemia episode and to episodes of given severity (levels 1, 2 and 3) were examined. Further adjustment was then made for a wider set of potential confounders. The within-person change in continuous outcomes was also summarised (median of 40.4 weeks for type 1 diabetes and 26 weeks for type 2 diabetes). Analyses were conducted separately by type of diabetes.ResultsThe maximally adjusted association analysis for type 1 diabetes found that cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of neuropathy, kidney disease, retinal disorders and depression, with risk ratios ranging from 1.55 (p=0.002) to 2.81 (p=0.002). Associations of a similar direction were found when level 1 episodes were examined separately but were significant for depression only. For type 2 diabetes cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of death, acute CVD, kidney disease, retinal disorders and depression, with risk ratios ranging from 2.35 (p<0.0001) to 3.00 (p<0.0001). These associations remained significant when level 1 episodes were examined separately. There was evidence of an association between hypoglycaemia episodes of any kind in the previous 10 days and death, acute CVD and retinal disorders in both type 1 and type 2 diabetes, with rate ratios ranging from 1.32 (p=0.017) to 2.68 (p<0.0001). These associations varied in magnitude and significance when examined separately by hypoglycaemia level. Within the range of hypoglycaemia defined by levels 1, 2 and 3, we could not find any evidence of a threshold at which risk of these consequences suddenly became pronounced.Conclusions/interpretationThese data are consistent with hypoglycaemia being associated with an increased risk of adverse events across several body systems in diabetes. These associations are not confined to severe hypoglycaemia requiring assistance.Graphical

Visceral fat mass dynamics in a 2-year randomized STrength versus ENdurance training trial in people with obesity.

To compare the effectiveness of strength versus endurance training on reducing visceral fat in individuals with obesity. For the STrength versus ENdurance (STEN) 24-month randomized clinical trial, we assigned 239 participants with abdominal obesity to either strength or endurance training (two to three times a week, 60 min/training session) in addition to standard nutritional counselling to promote a healthy diet. Changes in abdominal visceral adipose tissue (VAT) area quantified by magnetic resonance imaging after 12 months were defined as a primary endpoint. Participants (aged 44 years, 74% women, body mass index: 37 kg/m2, mean VAT volume: 4050 cm3) had an approximately 50% retention rate and a 30% good training programme adherence at 12 months. There was no difference between strength and endurance training in VAT volume dynamics after 12 and 24 months (p = .13). Only in the good adherence group did we find a trend for reduced VAT volume in both training regimens. Independently of the exercise programme, there was a continuous trend for moderate loss of abdominal subcutaneous AT volume, body fat mass, body mass index and improved parameters of insulin sensitivity. Although parameters of physical fitness improved upon both exercise interventions, the dynamics of resting energy expenditure, glucose and lipid metabolism parameters were not different between the intervention groups and did not significantly improve during the 2-year trial (p > .05). Despite heterogeneous individual training responses, strength and endurance training neither affected VAT volume nor key secondary endpoints differently.

Once-weekly semaglutide in people with HIV-associated lipohypertrophy: a randomised, double-blind, placebo-controlled phase 2b single-centre clinical trial

HIV-associated lipohypertrophy, which is characterised by an abnormal accumulation of abdominal visceral adipose tissue, remains problematic in people with HIV. Effective interventions are lacking, despite HIV-associated lipohypertrophy carrying a substantial risk of cardiometabolic comorbidity. The primary aim of this trial was to investigate effects of the GLP-1 receptor agonist, semaglutide, on adipose tissue in HIV-associated lipohypertrophy. This randomised, double-blind, placebo-controlled phase 2b clinical trial was conducted at a single US site. Key inclusion criteria included people with HIV aged 18 years or older with controlled HIV-1, a BMI of 25 kg/m2 or more, and lipohypertrophy but without type 1 or type 2 diabetes. Participants were randomly assigned 1:1 to receive 32 weeks of once-weekly subcutaneous semaglutide (8-week dose titration and 24 weeks at 1·0 mg) or placebo; all research personnel and participants remained masked to treatment assignment. Primary outcomes were changes at 32 weeks in adipose tissue quantity by body compartment. Analyses, including safety, were performed using intention-to-treat principles. This trial was registered ClinicalTrials.gov (NCT04019197) and is complete. Between June 10, 2019, and July 28, 2022, 108 participants were randomly assigned to receive semaglutide (n=54) or placebo (n=54). Eight (15%) in each group withdrew prematurely. Significant effects of semaglutide were seen over the 32-week study period in sex-adjusted multiplicative regression analyses for the primary outcome, abdominal visceral adipose tissue (β -30·82 cm2, 95% CI -50·13 to -11·51; % change -30·6%). Decreases were also seen in other key measures, including abdominal subcutaneous adipose tissue (β -42·01 cm2, 95% CI -75·49 to -8·52; % change -11·2%) and total body fat (natural logarithmic -0·21 kg, 95% CI -0·33 to -0·08; % change -18·9%). There were no statistically significant differences in possibly related or related adverse events (absolute risk difference 0·1111, 95% CI -0·0727 to 0·2869); however, one semaglutide-related grade 4 elevated lipase and two possibly related cases of cholelithiasis (grades 1 and 2) were observed. Semaglutide holds promise as an effective treatment for HIV-associated lipohypertrophy. The potential risk of serious adverse events deserves further scrutiny in large trials in people with HIV. National Institutes of Health.

BREATHE DMD: boosting respiratory efficacy after therapeutic hypoxic episodes in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disorder, characterised by progressive decline in skeletal muscle function due to the secondary consequences of dystrophin deficiency. Weakness extends to the respiratory musculature, and cardiorespiratory failure is the leading cause of death in men with DMD. Intermittent hypoxia has emerged as a potential therapy to counteract ventilatory insufficiency by eliciting long-term facilitation of breathing. Mechanisms of sensory and motor facilitation of breathing have been well delineated in animal models. Various paradigms of intermittent hypoxia have been designed and implemented in human trials culminating in clinical trials in people with spinal cord injury and amyotrophic lateral sclerosis. Application of therapeutic intermittent hypoxia to DMD is considered together with discussion of the potential barriers to progression owing to the complexity of this devastating disease. Notwithstanding the considerable challenges and potential pitfalls of intermittent hypoxia-based therapies for DMD, we suggest it is incumbent on the research community to explore the potential benefits in pre-clinical models. Intermittent hypoxia paradigms should be implemented to explore the proclivity to express respiratory plasticity with the longer-term aim of preserving and potentiating ventilation in pre-clinical models and people with DMD.

#2496 Effect of semaglutide on kidney outcomes in people with overweight or obesity and established cardiovascular disease in the SELECT trial

Abstract Background and Aims Obesity is an important risk factor for declining kidney function and albuminuria. Secondary analyses of cardiovascular outcome trials in people with type 2 diabetes suggest that the glucagon-like peptide-1 receptor agonist semaglutide has the potential to reduce kidney function deterioration. Semaglutide reduced the primary endpoint of major adverse cardiovascular events by 20% in the randomised controlled SELECT trial in people with overweight or obesity without diabetes. The present report is the prespecified analysis on secondary and exploratory kidney outcomes in SELECT. Method The main kidney endpoint was the time from randomisation to first occurrence of a 5-component nephropathy composite comprising: death from kidney causes; initiation of chronic kidney replacement therapy (dialysis or transplantation); onset of persistent estimated glomerular filtration rate (eGFR) &amp;lt;15 mL/min/1.73 m2; persistent ≥50% reduction in eGFR compared with baseline; or onset of persistent macroalbuminuria. Persistence was defined as at least two measures at least 4 weeks apart. Patients were randomised to once-weekly subcutaneous semaglutide 2.4 mg or placebo. Blood and urine samples for eGFR and urinary albumin-to-creatinine ratio (UACR) were collected at screening, at 20, 52, 104, 156, 208 weeks of follow-up and at the end of treatment. Analyses were of in-trial data and used Cox regression and mixed models for repeated measures. Results A total of 8803 patients were assigned to semaglutide and 8801 to placebo. The median follow-up was 182 weeks. The main composite nephropathy endpoint occurred in fewer of those assigned semaglutide (1.8% [155/8803]) than placebo (2.2% [198/8801]): hazard ratio 0.78 [95% confidence interval (CI) 0.63, 0.96]; p = 0.02 (Fig. 1). This effect on the main endpoint was driven by the treatment effect on onset of macroalbuminuria and, to a lesser extent, persistent ≥50% reduction in eGFR. At the prespecified 104-week time point, eGFR had declined less in the semaglutide than placebo arm, giving a treatment effect of 0.75 mL/min/1.73 m2 [95% CI 0.43, 1.06]; p &amp;lt; 0.001 (Fig. 2A). The treatment effect on eGFR at 104 weeks was 0.57 mL/min/1.73 m2 [95% CI 0.26, 0.89] among those with eGFR ≥60 mL/min/1.73 m2 (N = 15 638) at baseline and was 2.19 mL/min/1.73 m2 [95% CI 1.00, 3.38] in those with eGFR &amp;lt;60 mL/min/1.73 m2 (N = 1908) at baseline. At 104 weeks the proportionate increase in UACR was less in the semaglutide than the placebo arm, with a treatment effect of –10.7% [95% CI –13.2, –8.2]; p &amp;lt; 0.001 (Fig. 2B). The treatment effect on UACR at 104 weeks was –8.1% [95% CI –10.6, –5.6], –27.2% [95% CI –35.3, –18.1] and –31.4% [95% CI –54.9, 4.3] in those with normo- (N = 14 848), micro- (N =1968) and macroalbuminuria (N = 325) at baseline, respectively. Semaglutide was not associated with any excess of acute kidney injury, regardless of baseline eGFR. Conclusion These prespecified secondary analyses suggest a beneficial effect of once-weekly subcutaneous semaglutide 2.4 mg on a composite kidney endpoint in people with overweight or obesity and established cardiovascular disease. Significant benefits for both eGFR and UACR were found, including clinically relevant lesser eGFR decline in those with baseline eGFR &amp;lt;60 mL/min/1.73 m2.

Lifestyle intervention for metabolic dysfunction-associated fatty liver disease: a 24-h integrated behavior perspective

IntroductionThe prevalence, health and socioeconomic burden of metabolic dysfunction-associated fatty liver disease (MAFLD) is growing, increasing the need for novel evidence-based lifestyle approaches. Lifestyle is the cornerstone for MAFLD management and co-existing cardiometabolic dysfunction. The aim of this review was to evaluate the evidence for lifestyle management of MAFLD, with a specific lens on 24-hour integrated behaviour and provide practical recommendations for implementation of the evidence. ResultsWeight loss ≥ 7–10% is central to lifestyle management; however, liver and cardiometabolic benefits are attainable with improved diet quality and exercise even without weight loss. Lifestyle intervention for MAFLD should consider an integrated ‘24-h’ approach that is cognisant of diet, physical activity/exercise, sedentary behavior, smoking, alcohol intake and sleep. Dietary management emphasises energy deficit and improved diet quality, especially the Mediterranean diet, although sociocultural adaptations to meet preferences should be considered. Increasing physical activity and reducing sedentary behavior can prevent MAFLD, with strongest evidence in MAFLD supporting regular structured moderate–vigorous aerobic exercise for 150–240 min/week. Resistance training in addition to aerobic exercise should be considered and prioritised for those who are losing body mass via diet and/or pharmacological approaches and those with sarcopenia, to minimise bone and lean mass loss. Limited evidence suggests that sleep is important for MAFLD prevention. Emerging novel approaches to diet and exercise may address some of the key barriers to behaviour change (e.g. lack of time, access to resources and social support).Future DirectionsLarge-scale multidisciplinary trials in people with MAFLD with long-term follow-up, that can be scaled up into mainstream healthcare, are required. Future management guidelines should consider the heterogeneity of MAFLD and specialised models of care that coordinate the health workforce to manage the increased and growing MAFLD population.

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV.

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.

Effects and long-term outcomes of endurance versus resistance training as an adjunct to standard medication in patients with stable COPD: a multicenter randomized trial

BackgroundComparisons between endurance training (ET) and resistance training (RT) have produced equivocal findings in chronic obstructive pulmonary disease (COPD) patients. The purpose of our study is to investigate the effectiveness and long-term outcomes of adding ET and RT to conventional medical treatment in patients with COPD. A secondary objective is to investigate the clinical improvements resulting from exercise training in patients with different disease severities.MethodsThe study was a multicenter, prospective trial in people with stable COPD. The cohort was randomized to three groups: individualized medical treatment group (MT), MT + endurance training group (MT + ET) and MT + resistance training group (MT + RT). Exercise was performed 3 times weekly over a 12-week period. The endpoints of exercise capacity, health-related quality of life, COPD symptoms, lung function, and anxiety and depression questionnaires were re-evaluated at baseline, at the completion of the intervention and at 6 and 12-month follow-up. According to the COPD assessment tool offered by GOLD guidelines, patients were stratified into GOLD A and B groups and GOLD C and D groups for further subgroup analysis.ResultsThe intention-to-treat (ITT) population included 366 patients, 328 of them completed the study protocol over 12 months (the PP-population). There were no significant differences in the primary outcome, quality of life, between patients who underwent medical treatment (MT) alone, MT + endurance training (MT + ET), or MT + resistance training (MT + RT) at the completion of the intervention, 6-, or 12-month follow-up. Additionally, no significant differences were observed between MT, MT + RT, or MT + ET groups concerning the primary outcome, exercise capacity (3MWD), after initial 3 months of intervention. However, a small statistically significant difference was noted in favor of MT + ET compared to MT + RT at 12 months (ITT: Δ3MWD in ET vs RT = 5.53 m, 95% confidence interval: 0.87 to 13.84 m, P = 0.03) (PP: Δ3MWD in ET vs RT = 7.67 m, 95% confidence interval: 0.93 to 16.27 m, P = 0.04). For patients in the GOLD C and D groups, improvement in quality of life following ET or RT was significantly superior to medical intervention alone. Furthermore, upon completion of the exercise regimen, RT exhibited a greater improvement in anxiety compared to ET in these patients (ITT: ΔHAD-A at 3-month: RT = -1.63 ± 0.31 vs ET = -0.61 ± 0.33, p < 0.01) (PP: ΔHAD-A at 3-month: RT = -1.80 ± 0.36 vs ET = -0.75 ± 0.37, p < 0.01).ConclusionsOur study presents evidence of the beneficial effects of ET and RT in combination with standard medical treatment, as well as the long-term effects over time after the intervention. While the statistically significant effect favoring ET over RT in terms of exercise capacity was observed, it should be interpreted cautiously. Patients in severe stages of COPD may derive greater benefits from either ET or RT and should be encouraged accordingly. These findings have implications for exercise prescription in patients with COPD.Trial registrationChiCTR-INR-16009892 (17, Nov, 2016).