A Prospective Randomized Double-Blind Sham-Controlled Multi-Center Pivotal Study to Evaluate the Efficacy and Safety of Duodenal Mucosal Resurfacing Using the Revita System in Subjects with Type 2 Diabetes on Insulin therapy
The Revita® System is an endoscopic treatment consisting of a single catheter and console designed to lift the duodenal mucosa with saline followed by controlled circumferential hydrothermal ablation of the mucosa.The exclusion of the duodenum from the passage of nutrients by surgical diversion appears to result in weight-independent improvements in glycemia associated with a reduction in insulin resistance. This effect is also notable in being almost immediate in its onset (within days) and durable over time (years). The gastrointestinal tract is now recognized to be the largest endocrine organ in the body. It releases gastrointestinal hormones in a finely tuned pattern to help the body achieve glucose homeostasis in the fasting and post-prandial states, with the gastro-intestinal mucosa playing the role as a critical sensing and secreting interface. Bypass of the proximal small bowel appears to modify the secretion of certain key gastrointestinal hormones that in turn lead to improvements in glucose homeostasis. This occurs without calorie malabsorption. Rather, these changes restore the ability of the liver to suppress endogenous glucose production in response to insulin, a physiologic process that is otherwise impaired in diabetes.There are two main theories on how the bypass of the proximal small bowel exerts such a strong anti-diabetic effect, both of which may explain the role of the small bowel in glucose homeostasis.29 First, some believe that the delivery of excess nutrients to the distal small bowel leads to enhanced secretion of GLP-1 (and perhaps additional related insulin-secreting hormones) from the GLP-1-rich entero-endocrine cells of the terminal ileum. Enhanced GLP-1 release into the bloodstream after an ingested meal has a number of beneficial effects on glucose homeostasis30.A second theory is that individuals with Type 2 Diabetes acquire mucosal alterations in their proximal small bowel that contribute to insulin resistance and glucose intolerance and that bypass of this segment is beneficial. Data from rats and humans suggest that prolonged exposure to a Western diet leads to an increase in enteroendocrine cell numbers and a subsequent gastric inhibitory peptide (GIP) after a meal.Other studies have demonstrated hypertrophy of the mucosa of the small bowel in subjects with diabetes.In this way, the insulin resistance of the body may arise from hormones produced by the proximal small bowel as a consequence of these mucosal alterations. The hypothesis is that bypass of the duodenum by nutrients prevents the release of these hormones and therefore immediately leads to an improvement in glucose tolerance after surgery.Moreover, it is now becoming increasingly recognized that the upstream surgical perturbation of the gastrointestinal tract, resulting in the exclusion of the duodenum, does indeed manifest a compelling anti-diabetic effect but the diabetes state of the patient is also a key determinant of outcome. Studies have now reported that the potency of the anti-diabetic effect manifested with metabolic surgery is contingent on or influenced by innate endogenous beta-cell reserve or insulin secretory capacity. In other words, surgery elicits powerful anti-diabetic effects but more notably in the presence of sufficient endogenous beta-cell secretory capacity. This raises important questions concerning a more targeted use of such interventions in individuals that have certain beta-cell reserve characteristics and/or certain companion pharmacological agents that augment beta-cell secretory function (e.g. GLP-1-receptor agonists) to best optimize outcome.A model of type 2 diabetes pathogenesis emerges from these observations. Namely, a life of excess fat and sugar ingestion in genetically prone individuals can lead to changes in the mucosa of the proximal small bowel. These mucosal changes, in turn, are associated with alterations in signals emanating from the proximal gut (including hormone secretion). This altered proximal gut signal exerts an effect that worsens insulin resistance, could negatively affect insulin secretion and may well drive the pathogenesis of T2D. In this context, duodenal exclusion through surgery or a medical device may reduce the abnormal signal emanating from the proximal gut, and thus improves glucose homeostasis.Duodenal mucosal resurfacing (DMR), using the Revita® System, is designed to mimic the metabolic benefit of the duodenal exclusion component of bariatric surgery, thereby eliciting an insulin-sensitizing effect. Duodenal Mucosal Resurfacing (DMR) consists of a highly controlled mucosal lift and ablation procedure of the post papillary duodenum using the Revita® System over the guided wire placed using a standard endoscope.The Revita® clinical data indicates that DMR exerts insulin-sensitizing like effects as evidenced by a lowering of HOMA-IR40, by an insulin-sensitizing metabolic signature by metabolomics testing (e.g., lowering of a-hydroxybutyrate, diacylglycerol, and peroxidase activity), and by other related insulin-sensitizing biomarker effects (including lowered hepatic transaminases and urinary microalbumin).Unlike bariatric surgery, which involves an anatomical bypass of the duodenum and therefore no exposure of ingested nutrients to the surface of that portion of the GI tract, DMR is designed to ablate and re-epithelialize the duodenal mucosal surface, thus allowing nutrients to be exposed to a newly regrown and normalized local mucosa. This infers that the duodenal mucosa surface is in some way abnormal in insulin resistant T2D subjects and is, therefore, emanating a potential ‘insulin resisting’ effect. This notion is supported by multiple lines of evidence: the duodenum undergoes a maladaptive hypertrophic response when exposed to unhealthy nutrients (i.e., fat, simple sugars); this change appears to be associated with an augmented insulin-resistant signal emanating from this portion of the bowel.This signal appears to be persistent and reversible in T2D, as revealed in post-bariatric surgery: in those individuals in whom metabolic improvement has been established after surgery, the acute re-exposure of the bypassed duodenum to nutrients quickly restores the insulin resistant, hyperglycemic, dysmetabolic condition that had existed pre-surgery ; and ablation technology applied to other tissue surfaces has shown that the natural tissue response to ablation is re-growth of a healthy tissue surface.Taken together, there is a strong rationale that the duodenal mucosa of T2D subjects is abnormal and that subjects would likely reap a metabolic benefit if the local duodenal mucosa is resurfaced through an ablation technique.In addition to the glycemic benefits previously seen, data has also indicated liver benefits after ablating abnormal duodenal mucosa in T2D. The C-20000 study, which did not require a NAFLD diagnosis at baseline, showed that approximately 85% of patients had fatty liver even in the presence of normal liver transaminases, confirming prior evidence of the growing epidemiologic overlap with T2D.Patients with NAFLD (liver MRI-PDFF > 5%)at baseline showed a large magnitude and a clinically meaningful reduction in liver fat content at week 12, confirming earlier findings of reductions in ALT through 2 years. These data provide insight into a potential therapeutic opportunity for DMR to favorably impact both T2D and NAFLD/NASH in a manner that can modify the natural history of these chronic and progressive diseases.
A randomised double-blind placebo-controlled multicentre Phase 3 study evaluating efficacy and safety of lanifibranor followed by an active treatment extension in adult patients with non-cirrhotic non-alcoholic steatohepatitis (NASH) and fibrosis 2 (F2)/fibrosis 3 (F3) stage of liver fibrosis
The 3 peroxisome proliferator-activated receptors (PPAR) isoforms play an important role in several components of NASH, from hepatic triglyceride accumulation to fibrosis. Lanifibranor, a pan-PPAR agonist, has demonstrated significant improvement in histological endpoints of NASH in the previous Phase 2b study in patients with highly active NASH. A positive effect of lanifibranor on glucose and lipid metabolism was also demonstrated. This suggests that lanifibranor has the potential to address histological and metabolic aspects of NASH and may be a promising candidate for its treatment.Primary ObjectiveThis Phase 3 study is conducted to evaluate Lanifibranorin adults with NASH and liver fibrosis stage 2 or 3 and consists of 2 parts: Part 1 and Part 2, with the following primary objectives:Part 1To assess the effect of Lanifibranorcompared to placebo on NASH resolution and improvement of fibrosis assessed by liver histology.Part 2To assess the effect of Lanifibranorcompared to placebo on delaying NASH disease progression measured by a composite endpoint that includes progression to cirrhosis, liver-related clinical outcome events, or all-cause death.
A Randomized Comparative Effectiveness Study of Staged Complete Revascularization with Percutaneous Coronary Intervention to Treat Coronary Artery Disease vs Medical Management Alone in Patients with Symptomatic Aortic Valve Stenosis undergoing Elective Transfemoral Transcatheter Aortic Valve Replacement: The COMPLETE TAVR Study
This study is being conducted in Aortic Stenosis patients who have undergone successful TAVR with a balloon expandable heart valve who also have coronary artery disease (CAD) or narrowing of the heart arteries.The study will compare:1. opening all suitable stenosis or blockages with an additional procedure (either during the same hospitalization as the TAVR or as a separate procedure) called percutaneous coronary intervention (PCI). This procedure opens or widens the stenosis with a stent thereby allowing blood to flow to the heart muscle. This procedure will happen within 45 days of your TAVR procedure. You will also receive optimal medical therapy.OR2. treating these additional stenosis or blockages with medication only and not opening them with an additional PCI procedure.
A Randomized controlled study of a health literacy-informed technology-based approach to support safe medication use by parents after discharge of infants from the neonatal intensive care unit
This is a randomized controlled study of parents of children to be discharged from the neonatal intensive care unit at Bellevue and Elmhurst hospitals. A total of 425 subjects will be recruited across two sites over preparatory phases and two primary study phases. Subjects will be assigned to 1 of 3 intervention groups: usual care, HELPix (health literacy-informed written materials and verbal counseling in addition to usual care), or HELPix + TECH (a health literacy-informed web application in addition to HELPix and usual care). Phase A is a pilot study, in which 120 parents will be enrolled at Bellevue Hospital and randomly assigned to usual care or HELPix + TECH. Phase B will take place at both Bellevue and Elmhurst Hospitals, and 225 subjects will be randomly assigned to usual care, HELPix, or HELPix + TECH. Parents will be screened and recruited, written informed consent will be obtained, and a brief survey will be administered on the day of the child’s expected discharge from the neonatal intensive care unit Subjects will then receive usual care followed by the intervention if randomized to one of those groups (Visit 1, Day 0). Medication knowledge, dosing, and adherence will be assessed in-person at a subsequent follow-up visit (Visit 2, Day ~1-7). Adverse events will be assessed via phone call (Visit 3, Day ~30-45). Additional data will be assessed using a chart review. There will be a preparatory phase before each of the 2 phases. For the preparatory phase before Phase A: 10 cognitive interviews will be conducted to assess parent comprehension/ acceptability of HELPix followed by 20 parent interviews focused on HELPix app usability.For the preparatory phase before Phase B: 12 cognitive interviews will be conducted to assess parent comprehension/ acceptability of HELPix. In addition to the cognitive interviews, 3 rounds of feedback with 6 parents per round will be conducted to iteratively refine the HELPix digital app. Once adapted, 20 parents will be asked about HELPix app usability.
A RANDOMIZED CONTROLLED TRIAL OF MAGNESIUM SULFATE AS AN ADJUNCTIVE ANALGESIC IN PROSTATE SURGERY
We will randomize prostate surgery patients to receive magnesium sulfate or not in the context of a standardized anesthetic. Postoperative pain scores and analgesic dose will be measured, in addition to the presence of shivering, quantitative neuromuscular blockade monitoring, drugs administered during anesthesia, and postoperative disposition (home or admission to hospital). We anticipate 110 subjects will give us 90% power to detect a 2 point difference in a 10 point pain score 30 minutes after awakening.
A Randomized Double-blind Placebo-controlled Phase 2a Study to Evaluate the Safety and Efficacy of Zetomipzomib (KZR-616) in Patients with Autoimmune Hepatitis
This is a Phase 2a, multi-center, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of zetomipzomib in patients with AIH who have failed standard-of-care treatment, had an incomplete biochemical response to =3 months of standard-of-care treatment, or had a disease flare after standard-of-care treatment.Zetomipzomib or placebo will be administered weekly for a 24-week treatment period, followed by a 4-week off-treatment safety follow-up period. A screening period of up to 4 weeks will precede Day 1. Efficacy will be assessed at Weeks 12, 16, 20, and 24; assessments are discussed in Section 7.2.2. Safety will be assessed throughout the study by monitoring of vital signs, clinical laboratory tests, and physical examinations, and by recording and analyzing all adverse events (AEs) and serious AEs (SAEs).Eligible patients will be randomized in a 2:1 ratio on Day 1 (Visit 2) to receive either standard-of-care (glucocorticoids) with zetomipzomib (Active Treatment group), or standard-of-care with Placebo (Control group). Zetomipzomib and placebo (ie, sterile water for injection [sWFI] in an equivalent volume to the reconstituted zetomipzomib dose), will be administered subcutaneously (SC) once weekly. The first dose of investigational medicinal product (IMP) will be 30 mg zetomipzomib or placebo, followed by weekly doses of 60 mg zetomipzomib or placebo for the remaining 23 weeks of the treatment period.
A Randomized Double-blind Placebo-controlled Phase 3 Study to Evaluate the Effect of Resmetirom on Liver-related Outcomes in Patients with Well-compensated (Child-Pugh A) Non-alcoholic Steatohepatitis (NASH) Cirrhosis
This is a multi-national, multicenter, double-blind, randomized, placebo-controlledstudy in patients with well-compensated NASH cirrhosis (CP-A, see Child-PughClassification, Appendix 6). Study subjects must have at least three metabolic riskfactors for NASH cirrhosis, as defined in Section 6.1 Pre-Screening Criteria. Thediagnosis of histologic NASH cirrhosis is defined as one of the following: (A) NASHcirrhosis on most recent biopsy (within last 5 years). This group is estimated to beapproximately 70% of the study population. (B) Historical biopsy shows NASH withsignificant fibrosis, now with progression to cirrhosis based on clinical diagnosis. Thisgroup is estimated to be approximately 20% of the study population. (C) Historicalbiopsy shows NASH with steatosis, now with progression to cirrhosis based on clinicaldiagnosis. This group is estimated to be approximately 10% of the study population (seeSection 6.2 for additional details). To be eligible for this study, patients must have adiagnosis of well-compensated NASH cirrhosis (CP-A) with either normal liverfunction or mild hepatic impairment, and no history of a hepatic decompensation event.A CP-A (score of 5 to 6) is considered well-compensated disease.Patients who qualify for study inclusion will be randomized 3:1 in a blinded manner toreceive 80 mg resmetirom or matching placebo given orally once daily in the morningfor the duration of the study (until the required number of events are achieved,approximately 3 years). The randomization will be stratified by 3 factors: (1) baselineType 2 diabetes (T2D) status (presence/absence); (2) MRI-PDFF (=5%, >5%) or, whenMRI-PDFF is unavailable/contraindicated, CAP (
A Randomized Double-Blind Placebo-Controlled Phase 3 Study to Evaluate the Efficacy and Safety of Fazirsiranin the Treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease with METAVIR Stage F2 to F4 Fibrosis
This is a phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of fazirsiran (TAK-999, previously called ARO-AAT) in the treatment of subjects aged 12 to 75 years (inclusive) with AATD-LD moderate to advanced fibrosis and compensated cirrhosis.The study will enroll subjects with PiZZ AATD-LD with METAVIR stage F2, F3, or F4 liver fibrosis. Approximately 126 up to 140 subjects are planned to be randomized 1:1 to receive either placebo or fazirsiran administered subcutaneously (SC). Subject randomization will be stratified according to METAVIR stage (F2 or F3 vs F4). The F4cc population will be capped at 25% of the total subjects with the remaining 75% being comprised of F2 and F3 subjects.
A randomized double-blind placebo-controlled study of ALPN-101 in systemic lupus erythematosus.
Subjects will be evaluated during a screening period of 42 days. Screening laboratory evaluations and disease activity assessments will be performed by the Investigator and reviewed by the sponsor to determine eligibility. Subjects will return for the Baseline visit to undergo assessment and confirmation of disease activity by the Investigator. Subjects who are eligible will be randomized to receive blinded study drug every 2 weeks for a totalof 12 doses of 3mg/kg ALPN-101 or placebo.
A Randomized Double-Blind Placebo-Controlled Study to Evaluate the Efficacy and Safety of Volixibat in the Treatment of Cholestatic Pruritus in Patients with Primary Sclerosing Cholangitis (VISTAS)
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, single, inferentially seamless, adaptive design clinical study that will be conducted in 3 parts.The primary and secondary objectives and endpoints will be evaluated in participants with PSC who have a baseline score of =4 on the Adult Itch-Reported Outcome (ItchRO), as assessed during the single-blind placebo run-in period during the core study.