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IRCT20200128046294N1 IRCT 2020-02-22 Dr. Abidi Pharmaceuticals Sleeve Procedure vs Liraglutide vs Empagliflozin in NASH Disease and Obesity RCT (SPLENDOR) SPLENDOR A Prospective Randomized Controlled Trial Comparing Three Advanced Therapies in the Treatment of Non-Alcoholic Steatohepatitis 2024-03-02 anticipated 105 Complete https://irct.ir/trial/45518 interventional Randomization: Randomized, Blinding: Single blinded, Placebo: Not used, Assignment: Parallel, Purpose: Treatment, Randomization description: Patients will be randomized in a 1:1:1 ratio into one of the three treatment groups using computer generated randomization plan. The randomization will be stratified to ensure that there are equal numbers of patients with/without T2DM in each treatment group. Once eligibility is confirmed, the study coordinator will read the next letter in sequence to reveal the treatment assignment. Letters must be selected in sequence and not to be opened prior randomization. The date and time of randomization (reading letters) will be recorded, Blinding description: Patients and investigators will not be blinded to treatment assignment. The treatment assignment will remain unknown until the patient is randomized after meeting all eligibility requirements. Pathologists who report the liver biopsies (to assess the primary and end-point results of study) are blinded to treatment assignment. 3 Condition 1: Nonalcoholic Steatohepatits (NASH). Condition 2: Obesity. Intervention 1: Intervention group 1: Sleeve Gastrectomy - During laparoscopic SG, gastric resection starts within 3 to 6 cm of the pylorus along the greater curvature of stomach and ends with removal of the fundus, calibrated using a bougie. Intervention 2: Intervention group 2: Liraglutide - company: CinnaGen - prefilled multidose disposable pen with 18 mg liraglutide in 3 mL solution - dose: 1.8 mg once daily injection for 12 months - at any time of the day but at the same time each day - subcutaneous injection into the abdomen, thigh or upper arm. Intervention 3: Intervention group 3: Empagliflozin Tablet - company: Abidi - dose: 10 mg once every day -. Undecided - It is not yet known if there will be a plan to make this available Justification or reason for indecision in sharing IPD is There is no further information.
public Dr Anahita Sadeghi
Shariati Hospital, Kargar Street, Tehran
Tehran Iran (Islamic Republic of) 1411713135 +98 21 8241 5176 anahita825@gmail.com Tehran University of Medical Sciences scientific Prof. Reza Malekzadeh
Shariati Hospital, Kargar Street, Tehran
Tehran Iran (Islamic Republic of) 1411713135 +98 21 8241 5106 dr.reza.malekzadeh@gmail.com Tehran University of Medical Sciences Iran (Islamic Republic of) Iran (Islamic Republic of) Is a candidate for general anesthesia Is eligible for bariatric surgery (SG) Is ≥18 and ≤65 years old Have a BMI ≥30 and ≤45 kg/m2 Have a platelet count >150,000 and International Normalized Ratio (INR) ≤1.2 Have appropriate composite entry criteria on liver biopsy: NAFLD with activity score between 4 and 8, presence of hepatocyte ballooning, and fibrosis stage between 1 and 3, confirmed by independent reviews by 3 liver pathologists. In case of any discrepancies in histopathologic report, a joint review by 3 study pathologists will be performed. Have the ability and willingness to participate in the study and agree to any of the arms involved in the study. Able to understand the options and to comply with the requirements of each arm. Have a negative urine pregnancy test at screening and randomization visits for women of childbearing potential. Women, of childbearing age, must agree to use reliable method of contraception for 1 year. 11. Patients with and without T2DM are eligible for the study. Patients with T2DM should have been on a stable dose of anti-diabetic medication for at least 3 months prior to entry, with HbA1c ≤8.5%. ALT & AST > 35 in female and 45 in male 18 years 65 years Both 1. Known history of other chronic liver diseases (drug induced, viral hepatitis, autoimmune, and genetic): a.Hepatitis B as detected by presence of hepatitis B surface antigen (HBsAg), b.Hepatitis C as detected by presence of hepatitis C virus (HCV) RNA, c.Autoimmune liver disease as diagnosed by antibodies and compatible liver histology, d.Primary biliary cirrhosis as defined by the presence of at least 2 criteria (elevated alkaline phosphatase, presence of anti-mitochondrial antibody, and histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts), e.Primary sclerosing cholangitis, f.Wilson’s disease as diagnosed by low ceruloplasmin and compatible liver histology, g.Alpha-1-antitrypsin deficiency as diagnosed by alpha1-antitrypsin level and liver histology, h.Hemochromatosis as diagnosed by presence of 3+ or 4+ stainable iron on liver biopsy, i.Drug-induced liver disease as diagnosed by medical history, j.Known bile duct obstruction, k.Suspected or proven liver cancer Type 1 diabetes or autoimmune diabetes Known cases of human immunodeficiency virus infection Prior bariatric surgery of any kind Prior complex foregut surgery including any esophageal and gastric surgeries, anti-reflux procedures, splenectomy, biliary diversion, and trauma Thoracic, abdominal, pelvic and/or obstetric-gynecologic surgery within 6 months Any other surgery requiring general anesthesia within 6 weeks prior to signing the consent American Society of Anesthesiologists Class IV or V History of solid organ transplant Severe pulmonary disease defined as FEV1 < 50% of predicted value Cardiovascular conditions including significant known coronary artery disease, dysrhythmia, uncompensated congestive heart failure, history of stroke, or uncontrolled hypertension (defined as medically treated with the mean of 3 separate measurements systolic blood pressure > 180 mm Hg or diastolic blood pressure> 110 mm Hg) Chronic renal insufficiency with a eGFR is below 45 mL/min/1.73 m2, or being on dialysis Presence of moderate to severe GERD (Los Angeles classification B-D) Presence of moderate to large hiatal hernia (>3 cm) Presence of inflammatory bowel disease (Crohn’s disease or ulcerative colitis) Psychiatric disorders including dementia, active psychosis, severe depression requiring > 2 medications, history of suicide attempts, active alcohol or substance abuse within the previous 12 months Pregnancy Breastfeeding Diagnosis of malignancy within three years (except squamous cell and basal cell cancer of the skin) Anemia defined as hemoglobin less than 9 g/dL Any medical condition requiring anticoagulation therapy that cannot be temporarily discontinued for surgical procedure Known history of clotting disorders, including pulmonary embolus and deep vein thrombosis Use of any medications (prescription or over the counter), including herbal or other supplements for treatment of obesity or liver conditions (e.g. vitamin E or pioglitazone) during the last 3 months Use of investigational therapy or participation in any other clinical trial within 3 months prior to signing the consent History of pancreatitis (acute or chronic) or pancreatic carcinoma History of thyroid cancer Presence of concerning thyroid nodule Family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 Liver biopsies < 5 mm in length Absence of hepatocyte ballooning on liver biopsy Absence of fibrosis on liver biopsy NAFLD Activity Score between 1-3 on liver biopsy Presence of fibrosis stage 4 (cirrhosis) Evidence of ascites, hepatic encephalopathy, portal hypertension, esophageal varices, splenomegaly, low platelet counts, or prolonged INR Current or history of substantial alcohol consumption (>20 g/day for women or >30 g/day for men, on average) for a period of more than 3 consecutive months within 1 year prior to screening Poor glycemic control (HbA1c >8.5%) Use of steroids (oral or intravenous), methotrexate, or Amiodarone (potential promoters of hepatic Steatosis) ALT or AST >300 U/L Recurrent major hypoglycemia or hypoglycemic unawareness Patients with >20 lbs weight gain or loss in last 6 months Inability to safely obtain a liver biopsy Any condition or major illness that, in the investigator’s judgment, places the subject at undue risk by participating in the study Unable to understand the risks, benefits and compliance requirements of study Lack capacity to give informed consent Plans to move outside the primary location of study (Tehran) within the next 12 months K75.81 E66 Nonalcoholic steatohepatitis (NASH) Overweight and obesity Treatment - Surgery Treatment - Drugs Treatment - Drugs Intervention group 1: Sleeve Gastrectomy - During laparoscopic SG, gastric resection starts within 3 to 6 cm of the pylorus along the greater curvature of stomach and ends with removal of the fundus, calibrated using a bougie. Intervention group 2: Liraglutide - company: CinnaGen - prefilled multidose disposable pen with 18 mg liraglutide in 3 mL solution - dose: 1.8 mg once daily injection for 12 months - at any time of the day but at the same time each day - subcutaneous injection into the abdomen, thigh or upper arm Intervention group 3: Empagliflozin Tablet - company: Abidi - dose: 10 mg once every day - Liver Histopathology. Timepoint: before intervention and 12 months after intervention. Method of measurement: NAFLD activity score + hepatocellular ballooning + Fibrosis stage. Liver stiffness. Timepoint: before intervention and 12 months after intervention. Method of measurement: Fibroscan Score. Liver Enzyme Activity. Timepoint: Before intervention and 6, 12 months after intervention. Method of measurement: Blood Test (ALT , AST , ALK.Phosphatase , Bilirubin). Anthropometric changes. Timepoint: Before intervention and 1, 3, 6, 9, 12 months after intervention. Method of measurement: Waist Circumference + Weight and BMI. Metabolic Changes. Timepoint: Before intervention and 12 months after intervention. Method of measurement: Lab Lipid Profile (Chol, LDL, HDL, TG) + Blood Pressure (sphygmomonometer) + Lab (BS, HbA1C, HOMA-IR) + CRP. Quality of Life. Timepoint: Before intervention and 6, 12 months after intervention. Method of measurement: SF-36 questionnaire + chronic liver disease questionnaire (CLDQ) for NASH (CLDQ-NASH). Complications. Timepoint: 1, 3, 6, 9, 12 months after intervention. Method of measurement: Complications specifically related to NASH disease, as well as complications of liver biopsy, liraglutide, empagliflozin, and SG will be recorded and evaluated through history taking and physical examination. CinnaGen Digestive Disease Research Institute Behbood Sanat Darman co Dr. Abidi Pharmaceuticals CinnaGen Digestive Disease Research Institute Behbood Sanat Darman co Approved 2020-01-14 Ethics committee of Digestive Disease Research Institute - Tehran University of Medical Sciences Digestive Disease Research Institute, Shariati Hospital, Kargar Street, Tehran Tehran Tehran Iran (Islamic Republic of)