Placebo Research Articles

Systematic Review and Meta-analysis: Placebo Response in Randomized Controlled Trials of Tourette’s Disorder Medications

To examine the magnitude of placebo response in randomized controlled trials (RCTs) of medications for Tourette's disorder. CENTRAL, Embase, PubMed, PsycInfo, Web of Science, WHO ICTRP, and ClinicalTrials.gov databases were searched to identify placebo-controlled RCTs assessing pharmacological interventions for Tourette's disorder. Standardized mean change and standardized mean difference were calculated for within-group (placebo, drug) and between-group (drug-placebo) change in tics. Data were pooled in random-effects meta-analysis. Meta-regressions were performed to identify study-level characteristics that could be differentially associated with placebo, drug, and drug-placebo response. Searchers identified 13,775 records, and 50 RCTs involving 1,566 participants were included in the placebo meta-analysis. Placebo response was medium to large (standardized mean change:-0.62; 95% CI:-0.75,-0.5; I2= 76%; τ2= 0.14). Several factors were associated with larger placebo responses (eg, non-US RCT, industry sponsorship, number of centers and participants). However, there was a moderate-to-high correlation between placebo and drug response (ρ= 0.66; 95% CI: 0.47, 0.79), and factors associated with larger placebo response were also generally associated with larger drug responses. There was not a significant correlation between placebo response and drug-placebo differences (ρ=-0.05; 95% CI:-0.32, 0.22), and factors associated with larger placebo response generally did not interfere in drug-placebo differences. The magnitude of placebo response in Tourette's disorder may be large, but similar to that in other child and adolescent psychiatric conditions. Clinical researchers may manipulate study-level factors to diminish placebo response (eg, carefully selecting study sites and keeping them at the minimum feasibility). However, drug-placebo differences may not increase as drug response will likely diminish as well. Comparative Efficacy, Tolerability, and Acceptability of Pharmacological Interventions for Chronic Tic Disorders Including Tourette's Syndrome in Children, Adolescents, and Adults: Protocol for a Systematic Review and Network Meta-analysis; https://www.crd.york.ac.uk; CRD42022296975. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science.

Benefit of Avasopasem Manganese on Severe Oral Mucositis in Head and Neck Cancer in the ROMAN Trial: Unplanned Secondary Analysis

IntroductionOral mucositis is a debilitating side effect of cisplatin and intensity-modulated radiation therapy (IMRT) in patients with head and neck cancer. The phase 3 ROMAN trial showed avasopasem manganese (AVA) significantly decreased individual endpoints of incidence and duration of severe oral mucositis (SOM, World Health Organization [WHO] grade 3-4), with nominal decrease in severity (WHO grade 4) and significant increase in the delay in onset of SOM. We sought to determine the Net Treatment Benefit (NTB) of AVA versus placebo (PBO) using the generalized pairwise comparisons (GPC) method. MethodsGPC is a statistical method that permits simultaneous analysis of several prioritized outcomes, comparing all possible pairs of a patient in the active (i.e., AVA) group and a patient from the control (i.e., PBO) group. NTB is the net benefit across all the outcomes for AVA compared to PBO. Key clinically relevant outcomes from ROMAN were prioritized: 1) WHO grade 4 OM incidence, 2) SOM incidence, 3) days of SOM, 4) days to SOM onset, with 7 days difference defined as the clinical relevance threshold for SOM days and SOM onset. ResultsGPC analysis of 407 patients (AVA = 241, Placebo = 166) stratified by cisplatin schedule and treatment setting resulted in 13,969 pairwise comparisons. AVA showed statistically significant net benefit on all four key outcomes with a 53.9% probability that AVA would benefit patients versus a 35.0% probability that PBO would; the difference between these probabilities was a NTB of 18.9% (p=0.0012), translating to an AVA number needed to treat of 5.3 patients. All outcomes contributed to NTB, reflecting improvements in SOM incidence, onset and duration, and in Grade 4 OM incidence seen in the original ROMAN analysis. ConclusionsThis GPC analysis shows compelling evidence from the ROMAN trial of AVA's clinical benefit across key parameters of SOM burden.

Effect of Esketamine Nasal Spray on Cognition in Patients With Treatment-Resistant Depression: Results From Four Phase 3 Studies.

While esketamine is effective in treatment-resistant depression (TRD), detailed information about the effect of esketamine on cognition is relatively scarce. This analysis assessed the effect of short-term (3 double-blind [DB] studies: DB1, DB2, and DB4) or long-term maintenance treatment (DB3) with esketamine nasal spray (ESK) compared with a placebo (PBO) combined withactive-comparator, on cognition in patients with TRD. Patients (DB1/DB2/DB3: [18-64 years, n = 747]; DB4: [65 years or older, n = 137]) with TRD received ESK (DB1/DB2/DB3: 56/84mg; DB4: 28/56/84mg) or PBO+newly initiated oral antidepressant (OAD) as per treatment schedules. Cognitive assessments-Cogstate battery and Hopkins Verbal Learning Test-Revised-were administered at baseline, Day 28/early withdrawal, and follow-up visits in DB1/DB2/DB4 and at 12-week intervals in the DB3 maintenance phase. Descriptive statistics were used to analyze ESK effects on cognition with effect sizes and 95% confidence intervals to express the nature andmagnitude of treatment effects relative to active-comparator+PBO. Correlation between depression severity (Montgomery-Ǻsberg Depression Rating Scale scores [MADRS]) and cognition was assessed at baseline and endpoint(s). At baseline, mild-to-moderate impairment in psychomotor function, attention, and memory (working andepisodic) were evident. For each DB1/DB2/DB4, group mean performance in Z-scores for ESK+OAD and OAD+PBO groups on all cognitive tests remained similar or slightly improved from baseline at endpoint (Day 28) and follow-up assessments. Similarly, in DB3 (maintenance phase), both groups generally showed improvement in cognitive performance at endpoint(s). Correlations between MADRSscores and performance on the cognitive test battery were small at baseline and endpoint(s). This analysis did not identify evidence of negative effects on cognition following short-term or long-term maintenance treatment with ESK+OAD in patients with TRD.

Acute acetaminophen ingestion improves the recovery of neuromuscular fatigue following simulated soccer match-play

ObjectiveThis study aimed to investigate the impact of acute acetaminophen (ACT) ingestion on the responses of neuromuscular function, biomarkers of muscle damage, and physical performance during the 72-h recovery period following simulated soccer match-play. DesignThe study followed a crossover randomized, double-blind, placebo-controlled trial design. MethodsDuring the two experimental sessions, thirteen semi-professional male soccer players completed a 90-min simulated soccer match, 60 min after oral ingestion of 1 g ACT or placebo (PL). Maximal voluntary contraction (MVC) and twitch responses of the knee extensors muscles, elicited through electrical femoral nerve stimulation, were utilized to evaluate both peripheral fatigue (potentiated twitch force, Qtw,pot) and central fatigue (voluntary activation, VA). Performance was assessed through countermovement jump (CMJ) and 20 m sprint tests. Creatine kinase (CK) and lactate dehydrogenase (LDH) were also measured. ResultsSmaller reductions were observed in MVC (−13.3 ± 7.5 % vs. -24.7 ± 11.1 %) and VA (−3.8 ± 4.4 % vs. -12.9 ± 5.4 %) in the ACT compared to the PL condition immediately after simulated soccer match-play (p < 0.05). Afterwards, these parameters were recovered 24 h earlier in the ACT session compared to the PL session. Furthermore, the 20 m sprint performance was significantly better throughout the recovery period in the ACT session compared to the PL session. ConclusionThe findings of this study showed that acute ingestion of 1 g of ACT (1 h before exercise) attenuated the decrease in MVC and VA levels after exercise, as well as improved 20 m sprint performance.

Cariprazine and Cognition in Patients with Schizophrenia and Bipolar Disorder: A Systematic Review.

Cariprazine (CAR), an antipsychotic with partial agonism at the D3 receptor and higher affinity than dopamine, has shown significant procognitive effects in preclinical animal studies. This study systematically reviews CAR's effects on cognitive measures in patients with schizophrenia and bipolar disorder. Two independent reviewers systematically searched PubMed, Web of Science, Scopus, and the Cochrane Library up to May 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Additional studies were found by hand searching the references of included studies. Eligible studies were randomized controlled trials (RCTs) in English that assessed CAR's effects on cognition in patients with schizophrenia or bipolar disorder. Quality was assessed using the Jadad scale. Out of 139 reports, 5 studies (involving 6,104 patients with schizophrenia or bipolar disorder) were included. In schizophrenia, CAR showed better cognitive outcomes (mainly indirect measures) than placebo (PBO) in both early and late stages. It also outperformed risperidone and aripiprazole in attention-related cognitive tests. In bipolar disorder, CAR improved cognition compared to PBO (also using indirect measures). Most studies found the greatest cognitive benefits with low doses of CAR (1.5-3 mg/d). CAR improved cognitive measures compared to PBO and other D2 antagonists or partial agonists in RCTs, especially in patients with greater baseline impairment. Thus, CAR may be a promising option for enhancing cognition in schizophrenic and bipolar patients; though, more trials using specific cognitive assessment tools are needed. PROSPERO CRD42023485028.

P150 Updated Overall Survival (OS) estimates leveraging long term extension data from TITAN study evaluating Apalutamide (APA) versus Placebo (PBO) in metastatic Hormone Sensitive Prostate Cancer (mHSPC) patients

P150 Updated Overall Survival (OS) estimates leveraging long term extension data from TITAN study evaluating Apalutamide (APA) versus Placebo (PBO) in metastatic Hormone Sensitive Prostate Cancer (mHSPC) patients

Subcutaneously transplanted xenogeneic protein recruits treg cells and M2 macrophages to induce browning of inguinal white adipose tissue.

To study whether subcutaneously embedding xenogeneic protein threads or synthetic polymer absorbable threads can improve obesity phenotypes and metabolic conditions, and to further explore its underlying mechanism. Thirty-six 8-week-old ob/ob mice were randomly allocated to three groups, respectively, receiving catgut embedding, PGA thread embedding or sham treatment bilaterally to the groin. Individual parameters including weight, food intake, and core temperature are recorded and metabolism assessment, energy expenditure analysis, and PET/CT scanning are also performed at fixed timepoints. After surgical incision, the inguinal white adipose tissue was histologically examined and its expression profile was tested and compared among groups 4 weeks and 12 weeks after operation. Catgut embedding reduced weight gain and improved metabolic status in ob/ob mice. Browning of bilateral inguinal WAT (white adipose tissue) was induced after catgut embedding, with massive infiltration of Treg cells and M2 macrophages in the tissue slices of fat pads. IL-10 and TGF-β released by Treg cells targeted macrophages and the induced M2 macrophages increased the expression of thermogenic and anti-inflammatory genes in fat. The secretion of catecholamines by polarized M2 macrophages led to the activation of β3-AR-related pathways in adipocytes and the browning of adipose tissue. Abdominal subcutaneous catgut embedding has the potential to combat obesity through the induction of WAT browning mediated by infiltrated Treg cells and macrophages.

Citrus supplementation in subjective cognitive decline: results of a 36-week, randomized, placebo-controlled trial

BackgroundDeveloping interventions for older adults with subjective cognitive decline (SCD) has the potential to prevent dementia in this at-risk group. Preclinical models indicate that Citrus-derived phytochemicals could benefit cognition and inflammatory processes, but results from clinical trials are still preliminary. The aim of this study is to determine the effects of long-term supplementation with Citrus peel extract on cognitive performance and inflammation in individuals with SCD.MethodsEighty participants were randomly assigned to active treatment (400 mg of Citrus peel extract containing 3.0 mg of naringenin and 0.1 mg of auraptene) or placebo at 1:1 ratio for 36 weeks. The primary endpoint was the change in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score across the 36-week trial period. Other cognitive outcomes included tests and scales evaluating verbal memory, attention, executive and visuospatial functions, and memory concerns. The secondary endpoint was the change of interleukin-8 (IL-8) levels over the 36-week trial period in a subsample of 60 consecutive participants. An Intention-to-treat approach with generalized linear mixed models was used for data analysis.ResultsThe RBANS total score showed significant improvement in both Citrus peel extract and placebo groups at 36 weeks (p for time < .001, d = 0.36, p time x treatment = .910). Significant time effects were also found in cognitive domains of short- and long-term verbal memory (p < .001) and scales of subjective memory (p < .01), with no significant time x treatment interaction. The largest effect sizes were observed in verbal memory in the placebo group (d = 0.69 in short-term, and d = 0.78 in long-term verbal memory). Increased IL-8 levels were found at 36-week follow-up in both Citrus peel extract and placebo groups (p for time = .010, d = 0.21, p time x treatment = .772). Adverse events were balanced between groups.ConclusionsIn this randomized clinical trial, long-term Citrus peel extract supplementation did not show cognitive benefits over placebo in participants with SCD, possibly due to high placebo response. These findings might have specific implications for designing future nutraceutical trials in individuals experiencing SCD.Trial registrationThe trial has been registered at the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 (https://www.clinicaltrials.gov/ct2/show/NCT04744922).

Effects of two carbonic anhydrase inhibitors on exercise performance in acute hypoxia.

Acute mountain sickness occurs due to rapid altitude ascents and/or insufficient acclimatization. Acetazolamide (AZ) is commonly prescribed for AMS prophylaxis but inhibits exercise performance. Methazolamide (MZ), an analogous drug, has similar prophylactic benefits but does not impair isolated muscle mass exercise performance in normoxia. We sought to compare whole-body exercise performance in acute hypoxia (FIO2 = 0.15) between AZ, MZ and placebo (PLA). Fifteen healthy participants completed 5 testing visits: day 1 maximal exercise test, day 2 a familiarization, and days 3-5 were the experimental visits. Each experimental visit involved a 5-km hypoxic cycling time trial performed after a 2-day dosing protocol of either AZ (250 mg t.i.d.), MZ (100 mg b.i.d.) or PLA (t.i.d.); the order was randomized and double-blinded. Prior to exercise, capillary blood samples were taken, and maximal voluntary contractions of quadriceps were performed. AZ and MZ resulted in a partially compensated metabolic acidosis at rest compared to PLA (capillary H+ 47±3, 43±2, 39±2 nmol for AZ, MZ and PLA respectively, p<0.01). Time to complete 5-km with PLA (562±32 seconds, p<0.01) was significantly faster than AZ and MZ (577±38 vs. 581±37s respectively), with no differences between AZ and MZ (p=0.96). There were no differences in average ventilation (124±27, 127±24, 127±19 l/min) and oxyhemoglobin saturation (87±2, 88±2, 88±3%) between AZ, MZ and PLA respectively (p>0.05). Overall, both AZ and MZ impair whole-body exercise performance in acute normobaric hypoxia.

A Pivotal Study on the Safety and Effectiveness of a Targeted Alkali Thermolysis Patch for Treatment of Primary Axillary Hyperhidrosis or Excessive Axillary Sweating.

One-third of US adults are bothered by excessive sweating, approximately 5% are diagnosed with hyperhidrosis. A topical patch using targeted alkali thermolysis (TAT) was developed for treatment of this condition. This study was intended to assess the efficacy and safety of the TAT-Patch for axillary sweat reduction. A randomized, multicenter, double-blind, sham-controlled, pivotal trial enrolled 120 subjects to a bilateral axillary treatment with a TAT patch (63 subjects) or sham patch (57 subjects). The primary end point was achieved; 64% of TAT-treated versus 44% of sham-treated subjects (p = .0332) improved from Hyperhidrosis Disease Severity Scale (HDSS) 3/4 to HDDS 1/2 at 4 weeks. Targeted alkali thermolysis treatment also showed a statistically significant improvement over sham treatment for all secondary end points, including gravimetric sweat production and subject-reported quality-of-life (QoL) assessments. The duration of effect is approximately 3 months, determined by the time to return to baseline HDSS. Mild-to-moderate treatment-site adverse events (AEs) were reported in 22% of TAT patch subjects. No serious or severe AEs were reported. HDSS, GSP, and QoL findings confirm clinically meaningful sweat reduction and a significant improvement in quality of life following a single TAT patch treatment. This device has potential to offer a new, noninvasive treatment option that is well tolerated with minimal downtime.

Effectiveness of Percutaneous Electrical Nerve Stimulation on Range of Motion, Pain Pressure Threshold in the Management of Myofascial Trigger Point: A Systemic Review

This review of randomized controlled trials sought to evaluate the efficacy of Percutaneous Electrical Nerve Stimulation (PENS) on range of motion, pain, and pain pressure threshold, as well as to investigate the specific factors influencing its effectiveness. The search for relevant studies published between 2017 and 2024 was conducted in PubMed, Scopus, The Cochrane Library, and the Physiotherapy Evidence Database. Fifteen studies met the inclusion criteria, with primary outcomes focusing on pain, range of motion, and quality of life. The findings indicate that percutaneous Electrical Nerve Stimulation (PENS) is effective in providing short-term pain relief, improving range of motion, and enhancing quality of life when compared to no intervention, sham, or placebo treatments. However, there is insufficient evidence regarding its impact on disability, analgesic medication intake, and sleep quality. In conclusion, while some evidence supports the short-term benefits of Percutaneous Electrical Nerve Stimulation (PENS), further high-quality randomized clinical trials with standardized procedures are necessary.

Transarterial Embolization for Musculoskeletal Pain Management: AJR Expert Panel Narrative Review.

Musculoskeletal embolization has emerged in recent years as a treatment for chronic joint pain, as the inflammatory cascade responsible for such pain has become better understood. Studies have demonstrated a complex interplay between joint inflammation and synovial hypervascularity that causes growth of new unmyelinated nerve fibers responsible for pain. Embolization targets joint hypervascularity, to disrupt the inflammatory cycle and provide pain relief. The standard treatment algorithm for chronic joint pain is well-established and entails escalating therapeutic options that include exercise, self-management programs, analgesic medications, intra-articular injections, and finally surgical replacement or release. Genicular artery embolization (GAE), targeting abnormal vasculature around the knee joint, is the most heavily studied musucloskeletal embolization procedure, reflecting the high worldwide prevalence and increasing incidence of knee osteoarthritis. GAE is now supported by multiple prospective studies, including randomized control trials comparing GAE versus sham treatment. Embolization has also extended outside of the knee joint to include the shoulder (treatment of adhesive capsulitis or secondary stiff shoulder), elbow (medial/lateral epicondylitis), hip (osteoarthritis, great trochanteric pain syndrome), and ankle (plantar fasciitis). This AJR Expert Panel Narrative Review discusses the current status of transarterial embolization for musculoskeletal pain management, focusing on treatment of knee osteoarthritis and chronic shoulder pain.

Effects of Ovariectomy on Kidney Injury in SDT Fatty Rats

Postmenopausal women are at a higher risk of developing diabetes, and estrogen can lower blood glucose levels. The purpose of this study was to investigate the effect of ovariectomy (OVX) on the pathology of diabetic nephropathy. Female SD rats and SDT fatty rat underwent bilateral OVX or sham treatment at 6 weeks of age, and their blood and kidneys were collected at 40 weeks of age for blood biochemical and histopathological analyses. OVX treatment resulted in a decrease in blood estradiol levels at 24 and 40 weeks of age. Histopathological analysis revealed that Sham-treated SDT fatty rats showed glomerular atrophy, adhesions, enlargement, mesangial cell proliferation, regenerated tubules, hyaline casts, Armani-Ebstein lesions, tubular dilatation, interstitial inflammatory cell infiltration, and fibrosis. OVX treatment slightly reduced glomerular atrophy and enlargement, renal tubular dilatation, and interstitial inflammatory cell infiltration, while slightly increased or exacerbated mesangial cell hyperplasia, tubular regeneration, and Armani-Ebstein lesions. The above findings suggest that SDT fatty rats are not a practical model to study postmenopausal diabetic nephropathy.

Relation of apolipoprotein C3 to risk of major adverse cardiovascular events and death after acute coronary syndrome on a background of optimized statin treatment

Abstract Background Apolipoprotein C3 (ApoC3), a component of triglyceride-rich lipoproteins and some low-density lipoprotein and high-density lipoprotein particles, has been shown to predict incident coronary heart disease (CHD) and major adverse cardiovascular events (MACE). However, it is unknown whether ApoC3 predicts risk in patients with acute coronary syndrome (ACS) receiving contemporary therapies including optimized statin treatment, and if any such association is independent of apolipoprotein B (ApoB) levels. Purpose We assessed the association of ApoC3 with first MACE (CHD death, nonfatal myocardial infarction, fatal or nonfatal ischaemic stroke, or hospitalization for unstable angina) and all-cause death in patients with recent ACS treated with high-intensity or maximum-tolerated statin and blinded PCSK9 inhibitor (alirocumab, ALI) or placebo (PBO). Methods ApoC3 was measured by mass spectrometry at baseline (n=11,956) and after 4 months (M4; n=11,176) of treatment with ALI or PBO in the ODYSSEY OUTCOMES trial (which had 18,924 total participants). In continuous and spline analyses adjusted for treatment group and ApoB, we assessed the association of baseline ApoC3 with risk of MACE and death. In the ALI group we determined association of change in ApoC3 from baseline to M4 with risk of MACE and death after M4 in a model adjusted for baseline ApoC3 and ApoB, and the change in ApoB from baseline to M4. Results Median (Q1, Q3) baseline ApoC3 concentration was in a normal range [85 (65, 113) mg/L]. Continuous ApoC3 was not related to MACE (p=0.50) or death (p=0.51); spline analysis showed a slight curvilinear association of baseline ApoC3 with risk of MACE and death, but no clinically meaningful relationship (Figure). Findings were similar in the PBO group alone, and without adjustment for ApoB (data not shown). At M4, the median (Q1, Q3) change from baseline in ApoC3 was -10 (-27, -5; p&amp;lt;0.0001) mg/L with ALI and 2 (-14, 18; P = NS) mg/L with PBO. Overall, ALI significantly reduced the incidence of MACE (10.1% vs 12.1%; p=0.0006) and death (3.5% vs 4.2%; p=0.045) compared with PBO among those with available baseline ApoC3. However, the change in ApoC3 on treatment with ALI did not predict the risk of MACE or death after M4. Findings were qualitatively similar without adjustment for ApoB or its change. Conclusion In a cohort with recent ACS receiving optimized statin therapy and with median baseline ApoC3 in a normal range, ApoC3 did not provide clinically meaningful prediction of cardiovascular events or death. A modest reduction of ApoC3 by ALI did not associate with subsequent risk of MACE or death. It remains uncertain whether targeted therapies producing larger reductions in ApoC3 from higher baseline levels will affect cardiovascular risk.

BMI shift and associated cardiometabolic risk factors in people with type 2 diabetes and obesity and/or overweight: a post hoc analysis from SURMOUNT-2

Abstract In SURMOUNT-2 (SM-2), treatment with once weekly GIP and GLP-1 receptor agonist tirzepatide (TZP) resulted in superior body weight reductions relative to placebo in people living with obesity and T2D. This post hoc analysis assessed whether participants with obesity (body mass index [BMI] ≥30 kg/m2) or overweight (BMI ≥27 kg/m2 with at least one weight-related comorbid condition) who shifted to a lower BMI category had improved cardiometabolic factors. Change in BMI category (&amp;lt;25 kg/m2, 25 to &amp;lt;30 kg/m2, 30 to &amp;lt;35 kg/m2, 35 to &amp;lt;40 kg/m2, and ≥40 kg/m2) from baseline to week 72 was assessed in participants from SM-2 treated with TZP 10 or 15 mg (N=623) or placebo (PBO)(N=315). BMI shifts were grouped into "improved" (shift to lower BMI category) or "non-improved" (stable or shift to a higher BMI category). Cardiometabolic parameters examined included waist circumference, fasting insulin, fasting glucose, HbA1c, blood pressure, and lipid profile. A mixed model with repeated measures was performed to estimate the mean change from baseline to week 72 for these parameters. In this post hoc analysis a total of 484 (52.1%) participants had improved BMI at week 72. For those whose BMI did not improve, most had stable BMI and only 11 (1.2%) had worsened BMI. Nine participants had no post-baseline BMI measurements and were excluded from analysis. Most participants demonstrated improved BMI with TZP treatment (N=418, 67%) vs PBO (N=66, 21%)(Table). Furthermore, 21% (N=129) of participants on TZP improved by ≥2 BMI categories compared to only 1 participant with PBO. Compared to those with non-improved BMI, participants with improved BMI demonstrated greater improvement in cardiometabolic risk factors, including decreases from baseline in waist circumference, fasting insulin, fasting glucose, HbA1c, systolic and diastolic blood pressure, triglycerides, and cholesterol (non-HDL-c, and LDL-c) and increases from baseline in HDL-c (Figure). Greater improvements to cardiometabolic risk factors were seen in participants on TZP vs PBO. Shifts to lower BMI categories were greater among TZP-treated people living with obesity or overweight and T2D in SM-2 and were associated with improved cardiometabolic risk factors, in this post hoc analysis. SURMOUNT-mortality and morbidity and cardiovascular outcome trials are ongoing to examine the impact of TZP treatment on CVD and mortality.

Preclinical characterisation and first-in-human results on the tolerability and pharmacodynamic effect of REGN9933, a monoclonal antibody targeting the factor XI/activated factor XI apple 2 domain

Abstract Background/Introduction Standard-of-care anticoagulants are associated with increased bleeding risk. Genetic/pharmacological data suggest coagulation factor XI (FXI) inhibition can prevent thrombosis with minimal increased bleeding risk. We present preclinical and first-in-human (FIH) data on REGN9933, a FXI-binding monoclonal Ab. Purpose To characterise REGN9933 epitope binding sites, affinities for FXI and activated FXI (FXIa), and effect on high molecular weight kininogen (HMWK)’s interaction with FXI. Also, to assess safety, tolerability and pharmacodynamics in healthy human participants (pts). Methods Epitope binding sites mapped with cryogenic electron microscopy, binding affinities determined with plasmon resonance techniques, effect on thrombin generation assessed with a thrombin generation assay, and impact on HMWK:FXI interaction analysed using ELISAs. In the FIH, Ph 1, randomised, double-blind, single-centre study, pts received a single dose of REGN9933 intravenously (IV; 3–300 mg) or subcutaneously (SC; 100 mg &amp; 300 mg), or placebo (PBO). Primary endpoint: incidence and severity of treatment-emergent AEs (TEAEs). Other endpoints: effect of REGN9933 on activated partial thromboplastin time (aPTT) and prothrombin time (PT) to assess intrinsic and extrinsic pathway-triggered coagulation, respectively; and FXI activity. Results REGN9933 was found to bind the FXI apple 2 domain, with subnanomolar binding affinities for FXI and FXIa at 37°C, resulting in reduced thrombin generation from the intrinsic (not extrinsic) pathway. REGN9933 competed with HMWK for FXI binding in a dose-related manner. In the Ph 1 study, 56 pts received REGN9933 (IV, n=30; SC, n=12) or PBO (n=14); 42.9% and 21.4% had ≥1 TEAE, respectively (most common with REGN9933: headache, 12%; oropharyngeal pain, 5%). No serious/severe TEAEs, or TEAEs of special interest (inc. moderate/severe bleeding) reported. Laboratory tests revealed no clinically meaningful differences in the number/type of treatment-emergent potentially clinically significant values with REGN9933 vs PBO. REGN9933 resulted in dose-dependent prolongation of aPTT; aPTT mean fold change from baseline was highest with IV 300 mg after 8 hrs (2.7) and remained &amp;gt;2 for 36 days (Fig 1). There was no detectable effect on PT or clinically meaningful effect on bleeding time. REGN9933 supressed FXI activity in a dose-dependent manner, with suppression to approx. the lower limit of assay quantification (5%) with IV ≥30 mg (Fig 2). Conclusion(s) REGN9933 binds the FXI apple 2 domain and inhibits HMWK:FXI interaction, preventing intrinsic pathway-triggered FXI activation. FIH data showed dose-dependent inhibition of the intrinsic coagulation pathway by REGN9933, without affecting the extrinsic or common pathways. Pharmacodynamic and safety findings support continued development of REGN9933 as an anticoagulant that may carry less bleeding risk than currently approved agents.

Survodutide, a glucagon receptor/GLP-1 receptor (GCGR/GLP-1R) dual agonist, improves cardiometabolic parameters in adults with obesity: analysis of a placebo-controlled, randomised phase 2 trial

Abstract Background Obesity increases the risk of cardiovascular (CV) disease and contributes to CV risk factors, such as hypertension (HTN) and dyslipidaemia. Survodutide is a GCGR/GLP-1R dual agonist in clinical development for obesity. In a phase 2 clinical trial in individuals with obesity without diabetes, survodutide elicited up to 18.7% mean reduction in body weight after 46 weeks (primary endpoint) according to actual treatment.1 Purpose We explored the effect of survodutide on cardiometabolic parameters in this trial cohort. Methods 387 people aged ≥18 to &amp;lt;75 years with body mass index (BMI) ≥27 kg/m2 without diabetes were randomised 1:1:1:1:1 to once-weekly subcutaneous survodutide (0.6, 2.4, 3.6, 4.8 mg) or placebo (PBO) for 46 weeks (wk), comprising an initial 20-wk escalation period when the dose could be adjusted for gastrointestinal (GI) tolerability, followed by a 26-wk maintenance period. We evaluated changes from baseline (BL) to wk 46 in waist circumference; lipid parameters (triglyceride [TG], high-density lipoprotein [HDL], very low-density lipoprotein [VLDL], low-density lipoprotein [LDL], total cholesterol [TC], and non-HDL cholesterol [non-HDL-C]); and blood pressure (BP) by presence/absence of HTN before and at screening. Data were analysed descriptively for all participants receiving ≥1 dose of study drug with data for ≥1 efficacy endpoint, i.e. full analysis set (FAS), according to doses received during the maintenance period (actual treatment) and according to doses assigned at randomization (planned treatment) using on-treatment data. Results In the FAS (n=384), BL demographic and clinical characteristics were similar across treatment groups: overall mean age 49.1 years, BMI 37.1 kg/m2, 262 (68.2%) female, 301 (78.4%) White, 40 (10.4%) Asian, and 37 (9.6%) Black. Before and at screening, 133 (34.6%) participants had hypertension and 108 (28.1%) had dyslipidaemia. Waist circumference was reduced in all survodutide doses vs PBO; the largest mean reduction was 16.6 cm (4.8 mg group; actual treatment). Survodutide was associated with reductions of up to 10.2 mmHg in SBP and 4.8 mmHg in DBP from BL to wk 46 by actual treatment; similar reductions were observed for planned treatment, and reductions were comparable with/without HTN before and at screening (Figure 1). A marked decrease in mean TG was observed in all survodutide groups by planned treatment (Figure 2). Mean HDL was relatively unchanged over the period. Small decreases occurred in mean VLDL (all survodutide doses) and mean LDL (2.4 and 3.6 mg doses). Mean TC and non-HDL-C decreased in 0.6, 2.4, and 3.6 mg groups. Conclusion In people living with obesity, the GCGR/GLP-1R dual agonist survodutide was associated with clinically meaningful reductions in waist circumference, BP (with/out HTN before and at screening), and TG.

Global deficiency in the inflammatory chemokine receptors 1,2,3 and 5 prevents vascular dysfunction in angiotensin II-induced hypertension and selectively modulates aortic myeloid cell phenotype

Abstract Background Leukocyte migration to the vasculature and the heart plays a critical role in hypertensive immune responses and is a carefully orchestrated process, regulated by the interactions of inflammatory chemokines with their receptors, notably CCR1, CCR2, CCR3, and CCR5 (collectively termed inflammatory chemokine receptors (iCCRs)). However, the inflammatory chemokine/receptor system is characterised by redundancy, ligand sharing and overlapping expression patterns. Consequently, our understanding of the specific and combinatory roles of chemokine receptors in cardiovascular inflammation remains incomplete, thus hindering the development of targeted therapies. To address this challenge, we have utilised two novel mouse models: iREP mice, carrying fluorescent reporters of inflammatory chemokine receptor expression, and TACKO mice, in which the entire iCcr locus containing Ccr1, Ccr2, Ccr3, and Ccr5 has been deleted. Purpose To evaluate the expression pattern of iCCRs in experimental hypertension and understand how the global deletion of iCCRs impacts disease progression. Methods We induced hypertension in mice by subcutaneously implanting osmotic minipumps administering angiotensin II (Ang II) for a duration of 14 days. Single-cell RNA sequencing was utilised for investigating iCCR expression in aortas during hypertension. Additionally, we employed flow cytometry and confocal microscopy to track iCCR expression and localization in aortas and hearts obtained from iREP mice. TACKO mice were utilised to assess the effect of global iCCr deficiency on hypertensive phenotypes. Blood pressure was measured via telemetry and vascular function was assessed using myography. Vascular and heart remodelling were evaluated through histology. Molecular mechanisms were analysed using Western Blotting and RT-qPCR, while immune cell changes in the aorta were evaluated through cytometry of time-of-flight (CyTOF). Results Ang II infusion induced higher iCCRs expression levels in both the aorta and the heart in comparison with sham treatment, particularly in fibrotic areas. After Ang II-treatment, global deletion of iCCRs in TACKO mice resulted in the prevention of endothelial dysfunction (n=5/group, P&amp;lt;0.05) and perivascular fibrosis (n=6-9, P&amp;lt;0.01), and a reduction in cardiomyocyte size (n=12-16, P&amp;lt;0.01) compared to wild type mice. However, no significant improvements were observed in other hypertensive phenotypes, including blood pressure, heart fibrosis, vascular NO synthase, and oxidative stress. CyTOF analysis revealed reductions in inflammatory monocytes and conventional type 2 dendritic cells in TACKO aorta, accompanied by a phenotypic switch in macrophages towards a less inflammatory phenotype. Conclusion Deficiency in iCCRs confers protective effects against vascular dysfunction in experimental hypertension, primarily by selectively reducing inflammatory myeloid cell homing to the aorta.

Conditional over-expression of heme-oxygenase 1 in myelomonocytic cells reduces AngII-induced hypertension and vascular inflammation in mice

Abstract Background Systemic arterial Hypertension is one of the most important risk factor responsible for morbidity and mortality world-wide. Angiotensin II (Ang II), a potent vasoconstrictor and key player in the renin-angiotensin-aldosterone system (RAAS) is responsible for vascular dysfunction, inflammation, and tissue damage. Heme oxygenase-1 (HO-1) overexpression may confer antioxidant and anti-inflammatory properties in Ang II-induced hypertension through its action on heme catabolism, generating carbon monoxide (CO), ferritin and biliverdin/bilirubin by the action of biliverdin reductase A (BLVRA). Methods and results Male 9–12-weeks-old HO-1indxLySMCre/wt and LySMCre/wt mice were infused with AngII (1mgAngII/Day/Kg) for 7 days to induce hypertension and compared to sham treatment. Blood pressure monitoring by tail-cuff method, and endothelium-dependent vasodilator studies via organ chamber system using acetylcholine (ACh) in isolated aortic segments (~4 mm), revealed that overexpression of HO-1 in myeloid cells resulted in decreased systolic blood pressure and improved endothelial function in AngII-infused HO-1indxLySMCre/wt mice compared to controls. Concurrently, increased BLVRA expression in liver tissue and elevated plasma bilirubin levels were detected by transcriptome analysis and high-performance liquid chromatography, respectively. These results were supported by a reduction in the expression of inducible cytokines and cell adhesion molecules (CAMs) in the aorta, assessed using qPCR. Bone marrow transplant experiments demonstrated that bone marrow from LysMcre mice in HO-1indxLySMCre/wt mice abrogated the protective effect of HO-1, resulting in endothelial damage and increased blood pressure, potentially due to decreased liver BLVRA expression and the accumulation of bone marrow-derived cells in the vessel wall in response to AngII. Additionally, adeno-associated viral vector (AAV) transfection targeting specifically BLVRA activity in liver lead to an increase in blood pressure values and worse endothelium relaxation, in parallel with higher oxidative stress and the blood neutrophils concentration, as assessed in whole blood by using oxidative burst method and blood count system respectively. Conclusion The overexpression of HO-1 in myeloid cells confers anti-inflammatory protection in AngII-induced arterial hypertension in mice. Myeloid cells bone marrow-derived overexpressing HO-1 regulate the differentiation and infiltration of pro-inflammatory immune cells in the vasculature. BLVRA expression and bilirubin levels downstream of HO-1 play a critical role in protecting against vascular damage by reducing leukocyte infiltration.

Hydroxychloroquine and Sjögren's disease: current evidences for its use

About 25–50% of patients with primary Sjögren's disease (SjD) take hydroxychloroquine (HCQ). Although it is widely prescribed, and recommended in international guidelines, its use is mostly based on expert opinion and personal experience. Our aim was to provide a comprehensive overview of the pathogenic mechanisms of HCQ, the current clinical evidence for its use, and its safety in primary SjD. HCQ plays an immunomodulatory and anti-inflammatory role, mainly by regulating some interferon proteins, chemokines, BAFF levels, and by modifying gut microbiota. It decreases immunoglobulins and ESR levels. In a Latin-American cohort, the main indications were arthritis, parotid gland enlargement and sicca-only symptoms. In the clinical setting, most studies showing a positive effect of HQC are open trials or retrospective cohorts. Some of these studies may be biased due to the use of non-validated outcomes, and a placebo response effect. To date, only 3 RCTs have investigated the benefits of HCQ, the JOQUER being the pivotal one. This study failed to improve oral/ocular symptoms or ESSDAI score. However, a re-analysis by symptomatology subgroups detected some differences in the ESSPRI. Recently, promising data from a small phase II RCT of the combination of HCQ/leflunomide was reported, but results should be replicated. Currently, the NECESSITY study is investigating treatment combinations that will provide new insights. In the meantime, HCQ plays a central role in the treatment of SjD due to its excellent benefit-risk profile. Data on damage accrual, quality of life, mortality and prevention of cardiovascular risks are also still lacking.