Placebo-controlled Research Articles

Preliminary results from a multicenter, randomized trial using fecal microbial transplantation to induce remission in patients with mild to moderate Crohn's disease.

Fecal microbial transplantation (FMT) has shown promise at inducing remission in ulcerative colitis. This study is the first of its kind to evaluate the efficacy and safety of FMT at inducing remission in Crohn's disease (CD). This double-blind, placebo-controlled trial was conducted in three Canadian academic centers; randomized patients with mild to moderate CD received FMT or placebo. The first treatment was administered by colonoscopy followed by weekly fecal capsules for 7 weeks. Primary endpoint was clinical and endoscopic remission at week 8. Secondary outcomes included clinical and endoscopic response, adverse events, and health-related quality of life using generic and disease-specific instruments. From July 2017 to June 2021, 21 and 13 patients were randomized to FMT and placebo groups, respectively. The trial terminated early due to futility. At week 8, 0% (0/15) of patients in the FMT group versus 8.3% (1/11) in the placebo group reached the primary endpoint of combined clinical and endoscopic remission as per protocol analysis. There were no differences between the groups in clinical or endoscopic responses. One participant in each group had worsening of CD. Although both groups experienced statistically significant improvements in health-related quality of life, only the FMT group had a significant decrease in activity impairment. Although there were no significant changes in microbial diversity or composition, participants who achieved clinical response became more similar to their donors in stool microbial composition. FMT was not effective at inducing clinical and endoscopic remission in CD using the FMT regimen in this study. Future studies may use other strategies to enhance treatment response, including longer intervention, antibiotic pretreatment, optimized donor-recipient pairing, and concomitant anti-inflammatory diet, biologic or small molecule therapies.

Abstract 4135443: A Phase 1, Single Ascending Dose Study to Evaluate ALN-TTRsc04, a Next-Generation RNA Interference Therapeutic, in Healthy Participants for Potential Treatment of Transthyretin Amyloidosis

Introduction: Transthyretin amyloidosis (ATTR) is a progressive, debilitating, fatal disease caused by deposition of misfolded toxic transthyretin (TTR) amyloid fibrils in multiple organs and tissues. Major ATTR manifestations include polyneuropathy and cardiomyopathy. Ongoing amyloid deposition drives rapid progression of ATTR, leading to morbidity and mortality. ALN-TTRsc04 is an investigational small interfering RNA that targets hepatic TTR mRNA to reduce circulating TTR protein levels. Hypothesis: ALN-TTRsc04 rapidly knocks down serum TTR and is well tolerated. Aims: Describe safety, pharmacokinetics, and pharmacodynamics of single ascending ALN-TTRsc04 doses. Methods: This ongoing, Phase 1, randomized, double-blind, placebo-controlled study (NCT05661916) enrolled healthy adults (18–65 yrs; 18.0–30 kg/m 2 ) sequentially included in 6 cohorts receiving subcutaneous single ascending doses of ALN-TTRsc04 (5, 25, 100, 300, 600, or 900 mg) or placebo (randomized 3:1). Urine and plasma concentrations were measured on Days 1–2 and 1–4, respectively; change from baseline (BL) in serum TTR and AEs will be assessed over 12 months. Results: Overall, 36 and 12 adults (of similar age/sex distribution) were randomized to 1 of the 6 ALN-TTRsc04 groups or placebo, respectively. ALN-TTRsc04 plasma concentrations declined below lower limit of quantification within 24–48 hrs; mean (SD) plasma half-life ranged from 4.5 (1.5) hrs (300 mg dose) to 7.6 (3.2) hrs (100 mg dose). ALN-TTRsc04 was minimally excreted by renal route (<20%) after 24 hrs. Rapid and sustained knockdown in serum TTR occurred following all ALN-TTRsc04 doses ( Figure ). Mean (SD) serum TTR was 236.2 (47.4) µg/mL and 290.1 (73.3) µg/mL at BL and 22.2 (1.8) µg/mL and 289.0 (59.1) µg/mL at Day 15, for ALN-TTRsc04 300 mg and placebo, respectively. Mean percent knockdown at Day 15 was 90.3% vs 1.8%, respectively. Robust mean serum TTR knockdown of >90% from BL was seen with ALN-TTRsc04 doses ≥300 mg at Day 29 and sustained until Day 90 (or Day 180 with 300 mg dose, 92.6% reduction). Majority of AEs across doses were mild; none were considered related to treatment. No injection-site reactions or safety signals, including liver-related signals, were identified. Conclusion: A single ALN-TTRsc04 dose led to a rapid and sustained knockdown in serum TTR; a reduction >90% from BL was sustained until Day 180 with the 300 mg dose. All ALN-TTRsc04 doses have been well tolerated to date; data through 12 months will be assessed.

Nutritional intervention to enhance recovery after arthroscopic knee surgery in adults: a randomized controlled pilot trial.

Essential amino acid (EAA) and omega-3 fatty acid ingestion independently attenuate leg skeletal muscle disuse atrophy in uninjured persons. However, no data exist regarding the effectiveness of combined EAA and omega-3 fatty acid ingestion to mitigate skeletal muscle disuse atrophy in response to anterior cruciate ligament reconstruction (ACLR) surgery. This pilot trial will explore the feasibility of recruitment and retention of ACLR outpatients from a single center across 18 months to consume either a combination of omega-3 fatty acids and EAAs, or a placebo control, for 4 weeks before and 2 weeks after surgery. Thirty adult (≥ 18 years old) ACLR outpatients will be recruited for this single center, double-blind, two-arm randomized controlled feasibility pilot trial. Participants will consume either 5 g⋅day-1 of omega-3 fatty acids (fish oil) and 40 g⋅day-1 of EAAs or 5 g⋅day-1 of a control fatty acid mixture (safflower oil) and 40 g⋅day-1 of non-essential amino acids (NEAAs). Fatty acid supplements will be consumed 4 weeks before and for 2 weeks after ACLR surgery, whereas the EAAs and NEAAs will be consumed 1 week before and for 2 weeks after ACLR surgery. The primary outcomes are feasibility of recruitment and retention, with the goal to recruit 30 outpatients across 18 months and retain 22 participants upon completion of the study protocol following 12 weeks of data collection. These results will be reported using descriptive statistics, along with reasons and timepoints for study dropout. Secondary exploratory outcomes will be reported using inferential statistics for purposes of hypothesis generation and elucidation of mechanistic targets for future work; no inferences to clinical efficacy will be made. These outcomes include integrated rates of skeletal muscle protein synthesis, skeletal muscle protein content and expression of translation factors, skeletal muscle and erythrocyte phospholipid composition, and measures of skeletal muscle mass, strength, and power. This work will set the foundation for a future randomized controlled trialpowered to detect an effect of EAA + omega-3 fatty acid intake on skeletal muscle size or function in response to ACLR surgery. ClinicalTrials.gov, NCT06233825. Registered 31 January 2024. https://clinicaltrials.gov/study/NCT06233825?term=NCT06233825&rank=1.

Randomized Clinical Trials Demonstrate the Safety Assessment of Alkalihalobacillus clausii AO1125 for Use as a Probiotic in Humans

(1) Background: Alkalihalobacillus clausii AO1125 is a Gram-positive, motile, spore-forming bacterium with potential as a probiotic due to its broad-spectrum antimicrobial activity, inhibiting pathogens like Listeria monocytogenes, Staphylococcus aureus, and Clostridium difficile, as well as anti-rotavirus activity. Its resilience in gastrointestinal conditions suggests benefits for gut health. This study evaluates the safety and probiotic potential of A. clausii AO1125. (2) Methods: Genome annotation identified genes linked to probiotic traits such as stress resistance, gut colonization, immune modulation, and antimicrobial production. The genome was screened for antibiotic resistance genes using CARD, bacteriocin clusters using BAGEL4, and virulence factors via VFDB. Cytotoxicity was assessed on Vero cells and erythrocytes, and a Phase I, double-blind, placebo-controlled clinical trial was conducted with 99 healthy volunteers (50 AO1125, 49 placebo). (3) Results: Genomic analysis confirmed minimal antibiotic resistance genes and the absence of virulence factors, supporting safety. A. clausii AO1125 showed no pathogenicity, cytotoxicity, or hemolytic activity and was well-tolerated in clinical settings, with mild, transient abdominal gas as the most common adverse event. (4) Conclusions: The safety profile and genetic basis for probiotic and antimicrobial properties support A. clausii AO1125 as a promising probiotic candidate for gastrointestinal health, warranting further clinical research.

Abstract 4135480: Effect of Time Since Heart Failure Diagnosis or Hospitalization on the Cost-effectiveness of Dapagliflozin in Patients with Heart Failure with Mildly Reduced or Preserved Ejection Fraction

Background: Previous studies have shown dapagliflozin, a sodium-glucose co-transporter-2 inhibitor (SGLT2i), to be a cost-effective treatment option for patients with heart failure (HF) with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF) in multiple European settings. Research question: Is the cost-effectiveness of dapagliflozin treatment in HFpEF/HFmrEF modified by either the time since HFpEF/HFmrEF diagnosis or the time since the last hospitalization for heart failure (HHF) event? Methods: A Markov cohort transition model was built for the UK setting, informed by patient-level data from the randomized, placebo-controlled DELIVER trial. The patient population was subset according to categories of time since last HHF event (including no prior HHF) and time since HF diagnosis (further subset to those with no prior HHF). For each subgroup, disease evolution was characterized by transitions among health states defined by quartiles of the Kansas City Cardiomyopathy Questionnaire Total Symptom Scale. The risk of fatal (cardiovascular and non-cardiovascular) and non-fatal events of worsening HF were modelled, adjusting for baseline characteristics and time-updating health state. Incremental costs and quality-adjusted life-years (QALYs) were calculated for each subgroup to yield incremental cost-effectiveness ratios (ICERs). Results: The lowest ICERs were observed for subgroups with the shortest time from HF diagnosis (with and without prior HHF) or last HHF event (Figure 1). Across all subgroups, the calculated ICERs were below the UK willingness-to-pay (WTP) threshold of £20,000/QALY gained. Conclusions: In patients with HFpEF/HFmrEF, the cost-effectiveness of dapagliflozin improved (via lower ICERs) in the subgroups corresponding to earliest disease (least time since an HHF event or HF diagnosis) compared with groups of later disease and potentially delayed treatment initiation. These findings suggest early optimization of HF therapy with implementation of guideline-directed medical therapy, including SGLT2is, may improve economic value.

Rocatinlimab Improves Patient-Reported Outcomes in Adults with Moderate-to-Severe Atopic Dermatitis: Results from a Double-Blind Placebo-Controlled Phase2b Study.

In adults with moderate-to-severe atopic dermatitis (AD), rocatinlimab demonstrated significant and progressive improvement in clinical measures of disease severity compared with placebo. This post hoc analysis of a phase2b study was undertaken to understand the disease burden and to assess the impact of rocatinlimab on patient-reported outcomes (PROs). This analysis used baseline data from a multicenter, randomized, double-blind study of adults with moderate-to-severe AD, who completed a Worst Pruritus numerical rating scale (NRS), Sleep Disturbance NRS, and the Dermatology Life Quality Index (DLQI). A mixed model for repeated measures was used to estimate changes in PRO scores from baseline; scores were also compared with clinically meaningful change benchmarks. The analysis included 267 subjects, mean (SD) age 37.9 (14.7) years, 40.8% female; 55.1% grade3 and 44.9% grade4 Investigator Global Assessment for AD. Mean (SD) scores were: Worst Pruritus NRS 7.5 (1.9), Sleep Disturbance NRS 5.5 (2.9), DLQI total score 12.6 (7.1). Worst Pruritus and Sleep NRS scores had low positive correlations with SCORing AD (SCORAD) score (r = 0.44, r = 0.45 respectively) and negligible correlations with Eczema Area and Severity Index (EASI) score and area affected (r < 0.30). DLQI score varied by sex, study country, race, age, longer disease duration, disease severity (EASI and SCORAD), presence of asthma, and Worst Pruritus NRS, Sleep disturbance NRS, and DLQI scores. Rocatinlimab showed benefit on all three PROs, with significant improvements from baseline at the end of the double-blind period (week18) and active treatment extension (week36). Benefits were maintained over 20weeks' post-treatment follow-up. The benefit of rocatinlimab treatment on PROs is rapid and maintained for at least 20weeks following treatment completion. This analysis demonstrates the importance of characterizing the burden of moderate-to-severe AD from the patient's perspective, alongside clinical disease measures, to develop a fuller picture of treatment benefit. ClinicalTrials.gov identifier, NCT03703102.

Enhanced Bioavailability and Immune Benefits of Liposome-Encapsulated Vitamin C: A Combination of the Effects of Ascorbic Acid and Phospholipid Membranes

The bioavailability of vitamin C, or ascorbic acid, depends on limiting transport mechanisms that may be bypassed by liposome-encapsulation. The goal for this study was to evaluate the uptake, antioxidant, and immune-modulating effects of liposome-encapsulated vitamin C (LEC) using Lypo-Spheric® technology, compared to three controls: ascorbic acid (AA), the phospholipid fraction composing the liposome, and placebo. A double-blinded placebo-controlled cross-over study design involved twelve healthy participants attending four clinic visits. At each visit, a baseline blood draw was performed, followed by consumption of 1 g LEC, 1 g AA, the phospholipid component of LEC, or placebo. Additional blood draws were performed at 2, 4, and 6 h. Consuming LEC and AA increased blood levels of vitamin C; the levels were significantly higher after consuming LEC at all timepoints when compared to AA (p &lt; 0.01). LEC consumption increased serum antioxidant capacity (p &lt; 0.01 at 2 h) and protection. Consuming LEC increased IFN-γ levels at 6 h, while consuming the phospholipid fraction rapidly decreased inflammatory cytokines IL-6, MCP-1, and MIP-1α at 2 h. Consuming LEC provided enhanced vitamin C bioavailability and antioxidant protection compared to AA. Consuming the phospholipids had anti-inflammatory effects. The results suggest that LEC provides antioxidant and immune benefits above AA, useful in preventive medicine.

Weight Loss Induces Changes in Vitamin D Status in Women with Obesity but not in Men: a Randomized Clinical Trial.

Obesity is associated with low vitamin D and recent studies have suggested a difference in vitamin D metabolism between females and males. The aim of this study was to investigate the effects of weight loss on vitamin D status in individuals with obesity, and secondarily, whether vitamin D metabolism differs between women and men. Secondary analysis from a randomized placebo-controlled trial, designed to investigate the efficacy of 52 weeks of treatment with either liraglutide, exercise or combined, compared with placebo on weight loss maintenance after an 8-week low-calorie diet-induced weight loss in 195 individuals with obesity (BMI 32-43 kg/m2). The low-calorie diet-induced weight loss resulted in an increase in serum 25(OH)D in both women and men (12 nmol/L (95%CI 9-15) and 13 nmol/L (95%CI 8-17); p < 0.001 for both). Women who experienced a further weight loss during the 52 weeks of intervention had an increase in serum 25(OH)D compared with women regaining weight (14 nmol/L (95%CI 6-22); p = 0.001). Interestingly, women experiencing further weight loss at week 52 had a lower serum 25(OH)D at baseline compared with women regaining weight (54 nmol/L (SD 19) vs. 70 nmol/L (SD 25); p < 0.001). Weight loss induced by a low-calorie diet resulted in an increase in serum 25(OH)D in both women and men. Only in women, further weight loss had an additional beneficial impact on vitamin D. Additionally, initial low serum 25(OH)D was associated with successful weight loss maintenance in women, but not men.

The potential for improving cardio-renal outcomes in chronic kidney disease with the aldosterone synthase inhibitor vicadrostat (BI 690517): a rationale for the EASi-KIDNEY trial.

Patients with chronic kidney disease (CKD) are at risk of progressive loss of kidney function, heart failure, and cardiovascular death despite current proven therapies, including renin-angiotensin system inhibitors (RASi), sodium glucose co-transporter-2 inhibitors (SGLT2i), and statin-based regimens. RASi and SGLT2i reduce risk of CKD progression irrespective of primary cause of kidney disease, suggesting they target final common pathways. Targeting aldosterone overactivity with a nonsteroidal mineralocorticoid receptor antagonist (MRA) also reduces cardiorenal risk in patients with albuminuric diabetic kidney disease already treated with RASi. Together, these observations provide the rationale for trials to assess effects of inhibiting the aldosterone pathway in a broader range of patients with CKD, including those with non-diabetic causes of CKD or low albuminuria. Aldosterone synthase inhibitors (ASi) have emerged as an alternative to MRAs for aldosterone pathway inhibition. Phase II data from 586 patients with albuminuric CKD have shown that 10 mg of an ASi, vicadrostat (BI 690517), reduced urine albumin-to-creatinine ratio by ∼40% compared to placebo with or without concurrent empagliflozin treatment. MRA and ASi increase risk of hyperkalaemia. Combining their use with an SGLT2i may mitigate some of this risk, improving tolerability, and allowing a wider range of patients to be treated (including those with higher levels of blood potassium than in previous trials). The EASi-KIDNEY (NCT06531824) double-blind placebo-controlled trial will test this approach by assessing the safety and cardiorenal efficacy of vicadrostat in combination with empagliflozin in ∼11,000 patients with CKD. It will be sufficiently large to assess effects in patients with and without diabetes separately.

Abstract 4114406: Galectin-3 and Progression of Kidney Disease in Patients With Type 2 Diabetes Mellitus: Analyses From the DECLARE-TIMI 58 Trial

Background: Galectin-3 (Gal-3) is a circulating biomarker of fibrosis, with higher levels having been associated with an increased risk of progression of kidney disease. Patients with type 2 diabetes mellitus (T2DM) are at increased risk for kidney disease with fibrosis. Aims: To study the association of Gal-3 with chronic kidney disease progression, and the effect of the SGLT2-inhibitor dapagliflozin in pts with T2DM. Methods: DECLARE-TIMI 58 was a randomized, placebo-controlled trial of dapagliflozin in pts with T2DM with or at high risk for atherosclerotic cardiovascular (CV) disease and creatinine clearance ≥60ml/min. In a nested biomarker substudy, Gal-3 was measured at baseline (Alinity, Abbott Diagnostics) in the TIMI Clinical Trials Laboratory (Boston, MA). The prespecified kidney-specific composite endpoint (Kidney-EP) was a sustained ≥40% decrease in eGFR to &lt;60 mL/min, initiation of renal replacement therapy or confirmed sustained eGFR &lt;15 mL/min, or adjudicated renal death. Cox models were adjusted for baseline eGFR, urine albumin-creatinine ratio (UACR), patient characteristics, CV risk factors, NTproBNP and hs-cTnT. Results: Among 14,530 pts, median Gal-3 was 14.9 ng/mL [IQR, 11.9, 18.4]. Gal-3 was weakly associated with UACR (r = 0.098, p &lt; 0.0001) and eGFR (r = -0.27, p&lt;0.001) at baseline. Gal-3 was independently associated with the incidence of the Kidney-EP (adj-HR 1.15 [95% CI 1.03, 1.28] per 1-SD log(Gal-3), p = 0.013). Upon stratification by quartiles, there was a gradient of higher adjusted risk of the Kidney-EP with higher Gal-3 ( Fig., A ; p-trend &lt;0.0001). There were 111 (1.5%) and 203 (2,8%) Kidney-EPs in the dapagliflozin and placebo groups, respectively. Dapagliflozin significantly and similarly reduced the relative risk of the Kidney-EP across quartiles of Gal-3 (overall HR 0.45 [95%CI 0.23, 0.85], p&lt;0.0001; p-interaction = 0.97, Fig., B ). However, there was greater absolute benefit of dapagliflozin with higher Gal-3 (ARR Q4 1.9 [95% CI 0.6, 3.2] vs. Q1 0.6% [-0.1, 1.3], ARR p-trend 0.048). Conclusion: Plasma Gal-3 is associated with progression of kidney dysfunction in patients with T2DM independently of patient characteristics, including baseline kidney function. Moreover, Gal-3 identified an increasing gradient of absolute benefit of dapagliflozin for reducing kidney disease progression.

Abstract 4140102: Changes in EQ-5D-5L with Aficamten in Obstructive Hypertrophic Cardiomyopathy (oHCM): the SEQUOIA-HCM Trial

Introduction: In patients with obstructive hypertrophic cardiomyopathy (oHCM), the SEQUOIA-HCM trial demonstrated that aficamten, a next-in-class cardiac myosin inhibitor, improved exercise capacity, heart failure symptoms and hemodynamics compared with placebo. Aficamten’s impact on overall quality-of-life (QoL) in oHCM has not been reported. Hypothesis: Aficamten, compared with placebo, improves QoL as assessed by the EQ-5D-5L. Aims: To describe EQ-5D-5L changes in patients enrolled in SEQUOIA-HCM. Methods: SEQUOIA-HCM (NCT05186818) is a phase III, placebo-controlled trial of adults with symptomatic oHCM randomized to aficamten (n=142) or placebo (n=140) on top of standard-of-care medical therapy. Participants underwent blinded dose escalation over 6 weeks and were treated for 24 weeks followed by a 4-week washout. EQ-5D-5L (ranges from 0 to 1) and overall QoL using the Visual Analogue Scale (VAS; from 0 to 100) was measured at baseline through week 28 with higher scores indicating better QoL. Aficamten treatment effect on EQ-5D-5L was estimated using linear regression (study visits) and mixed effects regression (overall treatment effect) using all follow-up data with model adjustments for baseline EQ-5D-5L score and randomization stratification variables. Results: Mean age (n=282) was 59.1±12.9 years (40.8% women; 79.1% white). Aficamten baseline EQ-5D-5L index and VAS scores were 0.8±0.19 and 71.2±17.9 (placebo: 0.78±0.2; 68.9±18.6), respectively. Aficamten improved the EQ-5D-5L by 0.026 (95% CI: -0.001, 0.052; p=0.056) and the VAS by 2.8 points (95% CI: 0.8, 4.8; p=0.006) versus placebo with significant differences as early as 8 weeks after treatment initiation (p=0.005). After treatment withdrawal at 24 weeks, QoL benefits in aficamten-treated patients decreased compared with placebo (Figure: Index, p&lt;0.001; VAS, p=0.003), with hemodynamic parameters returning to baseline. Conclusions: Aficamten yielded early, sustained and significant improvement in overall QoL compared with placebo. Withdrawal of aficamten was associated with the loss of treatment benefits and perhaps an increased perception of pre-treatment symptoms. These data support a role of aficamten in improving QoL among patients with oHCM.

Abstract 4144501: Effect of the Cardiac Myosin Activator Omecamtiv Mecarbil on Risk of Ventricular Arrhythmias in Heart Failure with Reduced Ejection Fraction: the GALACTIC-HF Trial

Introduction: The selective cardiac myosin activator, omecamtiv mecarbil (OM), has been shown to benefit individuals with HFrEF but the clinical experience of cardiac myosin activators and incidence of ventricular arrhythmias (VA) is limited. We investigated the prognostic role of VA and the associations between OM, VA occurrence, and outcomes in the GALACTIC-HF trial. Methods: GALACTIC-HF was a placebo-controlled trial testing the efficacy and safety of OM in participants with symptomatic chronic HF and LVEF≤35%. VA were captured based on safety adverse event reporting. Severe HF was defined according to the ESC-HFA criteria. Poisson regression models using restricted cubic splines model were used to assess the association between baseline LVEF and incidence rates of VA. Associations between incident VA and subsequent clinical outcomes were evaluated using time-updated Cox proportional hazard models. Results: Over a median follow-up of 21.8 months, 594 out of the 8,232 individuals randomized in the GALACTIC-HF trial experienced VA, with no statistically significant differences between study arms. Individuals with lower LVEF values were at greater risk of incident VA (per 10% decline: HR 1.37; 95% CI 1.21-1.55; p&lt;0.001) with no significant differences between study arms ( Figure, panel A ). Following VA occurrence, participants were at higher risk of the primary endpoint of CV death or HF events (adj HR 1.67; 95% CI 1.42-1.97; p&lt;0.001) and all-cause mortality (adj HR 2.07; 95% CI 1.77-2.42; p&lt;0.001). The treatment effects of OM on clinical outcomes were consistent in patients not experiencing VA and after VA events. Among the 2,258 participants with severe HF, OM did not affect the risk of VA (adj HR 0.95; 95% CI 0.70-1.29) and this was consistent across the range of LVEF; Figure, panel B . Conclusions: The occurrence of VA among patients with HFrEF is associated with a substantially higher risk of subsequent fatal and non-fatal events. OM did not increase the risk of VA and the beneficial treatment effects were maintained irrespective of VA occurrence. These findings reinforce the safety of OM use among individuals with HFrEF who are at risk of arrhythmic events.

Abstract 4116298: Once Weekly Utreglutide (GL0034), a Glucagon-like Peptide-1 Receptor Agonist, at 4 × 450 µg Doses Reduces Blood Pressure, Lipids, and Body Weight in Post-menopausal Females: A Phase I Study

Background: Utreglutide (GL0034), a novel, once weekly glucagon-like peptide-1 receptor agonist (GLP-1RA), previously demonstrated significant reductions in body weight (BW) after a single dose ascending study in individuals with obesity . BW reductions after pharmacological treatment of obesity with GLP-1RA is associated with blood pressure (BP) lowering effects. Aim: This phase I study assessed the safety, tolerability, and cardio-metabolic effects of utreglutide after multiple ascending doses in post-menopausal female volunteers with overweight and obesity. Methods: In this randomized, double-blind, placebo-controlled study 12 post-menopausal female volunteers with overweight/obesity, aged 18 to 65 years old with a body mass index (BMI) ≥26 kg/m 2 were randomized (9:3) to subcutaneous utreglutide fixed doses (4 × 450 µg); or placebo once weekly for four weeks. Safety, tolerability, and key cardio-metabolic parameters were assessed. Biomarker measurements included oral glucose tolerance test (OGTT) insulin and glucose area under the curve (AUC), systolic- and diastolic BP, lipid profile (triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL), creatinine, potassium, BW and leptin. Results: Utreglutide was generally well tolerated and related adverse effects were mainly gastrointestinal with dose-dependent nausea, vomiting and decreased appetite. Reductions in OGTT AUCs of insulin ( p &lt;0.05) and glucose ( p &lt;0.01) were noted on Day 23 after four weeks treatment with Utreglutide. This was accompanied by a decrease ( p &lt;0.001) in mean systolic and diastolic BP on Day 23 from baseline (BL). On Day 23, significant reductions in TC ( p &lt;0.01), LDL ( p &lt;0.05) and non-HDL ( p &lt;0.05) were observed. BW reduction versus BL ( p &lt;0.001) was 2.0 kg and 1.8 kg respectively on Day 29 and End of Study (EoS). Leptin levels significantly reduced from BL on Day 23 ( p&lt; 0.01) and EoS ( p &lt;0.001). No significant changes were observed for TG, creatinine and potassium (Table). Conclusions: Once weekly utreglutide dosing for four weeks at a dose of 450 µg in post-menopausal females with overweight and obesity, demonstrated clinically relevant reductions of systolic and diastolic BP. This was associated with improved performance of OGTT AUC of insulin and glucose, lipids, BW and leptin with an overall good tolerability and with potential to demonstrate cardio-metabolic benefits.

Efficacy and safety of balovaptan for posttraumatic stress disorder: A randomized, placebo-controlled trial.

Posttraumatic stress disorder (PTSD) has a significant impact on quality of life and affects more than 13 million individuals in the United States, with limited treatments available. EXUVIA (NCT05401565) was a Phase 2, randomized, placebo-controlled, double-blind trial, conducted across eight sites in the United States. The study aimed to assess the efficacy, safety, and pharmacokinetics of balovaptan, a highly selective vasopressin 1a receptor antagonist, in adults with PTSD. Between August 2022 and October 2023, a total of 57 adult participants (aged 18-60 years) were screened, and 29 participants were randomly allocated (1:1) to receive either balovaptan (13/29 [44.8%]) or placebo (16/29 [55.2%]). No meaningful differences were observed for balovaptan (-17.2 [± 10.7]) versus placebo (-15.6 [± 10.7]) as measured by the primary endpoint of change from baseline at Week 12 in Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition total symptom severity score. No meaningful differences for balovaptan versus placebo were observed at Week 12 for any secondary endpoints. Balovaptan was well tolerated with no new safety findings. The number of participants with at least one adverse event of any intensity was 9/13 (69.2%) in the balovaptan group and 7/16 (43.8%) in the placebo group. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The cerebral and cognitive changes after intermittent theta burst stimulation (iTBS) treatment for depression: study protocol for a randomized double-blind sham-controlled trial.

The therapeutic use of intermittent theta burst stimulation (iTBS) delivered to the left dorsolateral prefrontal cortex (LDLPFC) is a relatively new but promising treatment option for depression. There is a need for more knowledge on the mechanisms involved in its antidepressant effects. This is a single-centre, prospective, randomized, double-blind, placebo-controlled trial with two arms, iTBS and sham iTBS. Adult outpatients with unipolar major depressive disorder of at least moderate severity will undergo cognitive assessment with an N-back task (0-back and 2-back), functional and structural magnetic resonance imaging and assessment of depression severity before and after brain stimulation. Neuronavigated iTBS or sham stimulation will be targeted at the LDPFC once a day for 10 consecutive workdays. ITBS will be delivered with the parameters 120% of resting motor threshold, triplet 50Hz bursts repeated at 5Hz; 2s on and 8s off, 600 pulses per session with a total duration of 3min 9s. The severity of depression will be measured with the Montogomery Aasberg Depression Rating Scale and the Beck Depression Inventory - second edition. In the iTBS group relative to sham, we expect significant antidepressant effects and improved N-back performance, associated with increased integrity in white matter tracts functionally connected with the LDLPFC and emotion regulation areas within the rostral anterior cingulate cortices, alongside potential increases in cortical thickness in these regions. On functional imaging, we expect to observe increased brain activity in the LDPFC during the performance of the N-back condition with higher cognitive load (2-back) in the iTBS group relative to sham. iTBS is a promising, time-efficient, and considered a safe treatment option for depression according to existing evidence. This trial aims to assess the neurocognitive impact of a 2-week, once-daily iTBS compared to sham iTBS, targeting the LDLPFC in depressed adult outpatients. The study investigates the relationships between changes in cerebral measures and cognitive performance on an N-back task in relation to the antidepressant effect following iTBS. This trial delves into the neurocognitive mechanisms of iTBS in depression, potentially offering novel scientific insights into its treatment effects and mechanisms of action. ClinicalTrials.gov NCT06534684. Retrospectively registered on August 1st 2024.

CTIM-14. EARLY SAFETY DATA FROM A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PHASE 2B STUDY OF IGV-001, AN AUTOLOGOUS CELL IMMUNOTHERAPY, VERSUS PLACEBO, IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)

Abstract Standard of care (SOC) for ndGBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. IGV-001 is an autologous biologic-device combination immunotherapy for the treatment of ndGBM that consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA, irradiated and administered via biodiffusion chambers implanted in the abdomen. In a phase 1b study, IGV-001 was well tolerated without unexpected adverse events in subjects with ndGBM. Multiple efficacy signals were observed, including significant improvements in progression-free survival (PFS), overall survival (OS), radiographic evidence of tumor response, and changes in immune response biomarkers. Here, we present early safety data from the phase 2b randomized, multicenter, double-blind, placebo-controlled study (NCT04485949) designed to assess efficacy and safety of IGV-001 in subjects with ndGBM across 20 sites in the United States. After surgical resection, subjects were randomized 2:1 and treated with IGV-001 or placebo followed by SOC. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include OS, defined as the time from randomization to death due to any cause, and safety. As of May 22, 2024, 99 subjects were randomized and 95 implanted with IGV-001 or placebo plus SOC. A total of 39/45 (86.7%) subjects had sufficient follow-up time after initiated treatment with concurrent radiation and temozolomide. Nine of 72 randomized (12.5%) discontinued treatment, including 7 who stopped during the SOC treatment period. None ceased treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized subjects discontinued the study after randomization. A review of blinded safety data did not show any emerging risk and supports no change to the benefit-risk profile of IGV-001 versus placebo. Updated data will be presented.

CTNI-18. RESULTS FROM A PHASE 1 STUDY OF SONODYNAMIC THERAPY WITH WHOLE HEMISPHERIC LOW INTENSITY NON-ABLATIVE ULTRASOUND IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA

Abstract We report the first use of a novel device that delivers non-ablative low intensity diffuse ultrasound (LIDU) across the entire hemisphere in combination with the oral sonosensitizing agent 5-ALA for the treatment of recurrent high grade glioma. LIDU in combination with 5-ALA focally targets tumor cells with sonodynamic therapy (SDT), causing selective tumor cell death across the entire hemisphere via 1) direct tumor targeting and 2) stimulation of immunogenic cell death. In this 3x3 clinical trial designed for safety (n=12, NCT05362409), two patients were enrolled after multiple recurrences and seven patients had multifocal or multicentric disease. Treatments were delivered monthly for a minimum of four sessions. A treatment duration of 120 minutes was established after dose escalation and expansion. SDT delivered via a novel device and in conjunction with 5-ALA was well tolerated, with no duration-limiting toxicities or serious related adverse events. Compared to historical data, we observed a significant increase in overall survival (mOS of 14.0+ months, with 7 of 12 patients still alive at the time of this submission and final median OS not yet achieved). A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been planned to commence in 2025 to assess the safety and efficacy of LIDU with sonosensitization in patients with newly diagnosed GBM.

The effect of caffeine dose on caffeine and paraxanthine changes in serum and saliva and CYP1A2 enzyme activity in athletes: a randomized placebo-controlled crossover trial.

Although caffeine (CAF) supplementation has been shown to improve exercise performance, its dose-dependent effect on CAF metabolism has not been sufficiently investigated. The aim of this study was to evaluate the effects of 3, 6 and 9mg of CAF/kgBM on changes of CAF and paraxanthine (PRX) in the serum and saliva at four time-points. In a randomized, double-blind, placebo-controlled crossover design, acute pre-exercise supplementation in 26 moderately-trained athletes, participating in high-intensity functional training (HIFT), was examined. The study protocol involved CAF/PRX biochemical analyses of serum and saliva with respect to CYP1A2 polymorphism and CYP1A2 enzyme activity. Despite significant differences between the serum and saliva levels of CAF and PRX, there was no difference in the PRX/CAF ratio. The interaction effect of dose and time-points for PRX concentration was revealed. The main effects of dose were observed for CAF and the PRX/CAF ratio. The main effect of time-points was registered only for serum CAF. Dose- and time-dependent effect of CAF supplementation on CAF and PRX in the serum and saliva of athletes was confirmed, but there was no effect of the CAF dose on CYP1A2 enzyme activity, nor was there an interaction of CYP1A2 with enzyme inducibility. The CAF/PRX correlation indicated the possibility of interchangeable use of serum and/or saliva analyses in exercise studies. This trial was registered prospectively at ClinicalTrials.gov (NCT03822663, registration date: 30/01/2019).

Effects of Nigella sativa on disease activity, T lymphocytes and inflammatory cytokine profiles in pediatric systemic lupus erythematosus: A randomized controlled trial

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with diverse manifestations, requiring long-term treatment that can have side effects, particularly in pediatric patients. Nigella sativa (NS) has shown potential for improving SLE symptoms due to its anti-inflammatory and immunomodulatory effects. The aim of this study was to investigate the immunomodulatory effect of N. sativa oil (NSO) on disease activity, T lymphocyte activity and inflammatory cytokine profiles in pediatric SLE patients. A randomized, double-blinded, placebo-controlled clinical trial was conducted at Saiful Anwar Hospital in Malang, Indonesia, from January 2022 to January 2023. Pediatric patients with SLE were randomly assigned to receive either one gram of NSO or a placebo containing starch in capsule form as adjunct therapy alongside their SLE primary treatment. Blood samples were collected before treatment and after eight weeks of daily capsules. Disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K); flow cytometry was used to identify T helper lymphocytes, and serum cytokine levels were measured using ELISA. The statistical analysis tests were performed to compare the outcomes between groups at baseline or after the treatment, and within-group comparisons before and after the study period, as appropriate. A total of 32 patients were included in the study. A significant decrease in the SLEDAI-2K score was observed at post-treatment in both the NSO and placebo groups (p&lt;0.001 and p=0.025, respectively). The percentage of T helper 17 (Th17) cells was significantly reduced in both the NSO and placebo groups post-treatment compared to pre-treatment (p=0.026 and p=0.034, respectively). Conversely, the post-treatment percentage of regulatory T (Treg) cells increased significantly in both groups. A significant reduction in interleukin (IL)-2 levels was observed in the NSO and placebo groups at post-treatment compared to pre-treatment (p=0.006 and p=0.046, respectively). Additionally, there were increases in IL-4 and IL-6 serum levels in both groups at post-treatment compared to pre-treatment (p&lt;0.05). This study highlights that although disease activity was not significantly different between NSO and placebo groups, NSO could affect the inflammatory cytokine profiles in pediatric SLE patients.

CTIM-11. LONG-TERM SURVIVORS FROM A PHASE 1B STUDY OF IGV-001 IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed glioblastoma (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers (BDCs) implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM (Andrews et al., 2021), including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. The Phase 1b study enrolled 33 patients in four different cohorts implanted with 10 or 20 BDCs for 24 or 48 hours. Here we report on 6 subjects with survival beyond 4 years, including 5 subjects who survived 5 years or more (15.2%). There were 4 male and 2 female subjects, with a median age of 52 years (range 32-75). At diagnosis the MGMT promoter was methylated in 4 of 5 subjects that survived 5 years or more. We also report on T cell receptor Vβ CDR3 region sequencing of peripheral blood mononuclear cells and tissue infiltrated lymphocytes that was performed in a subset of 9 patients, including 3 subjects who survived beyond 4 years. Immune correlates of IGV-001 suggest an association between peripheral T cell clonal expansion and PFS/OS outcomes. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949) has completed enrollment and results are expected to be available in 2025.