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IRCT20200209046427N3 IRCT 2026-06-22 Shahid Beheshti University of Medical Sciences Effect and Safety of Tirzepatide on Improving Functional Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Obesity Evaluation of the Efficacy and Safety of Tirzepatide, a Dual glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide (GLP-1/GIP) Agonist, on Functional capacity in Reduced Ejection Fraction Heart Failure Patients with obesity: A Double-Blinded Randomized Controlled Trial 2026-07-18 anticipated 60 Recruiting https://irct.ir/trial/89992 interventional Randomization: Randomized, Blinding: Triple blinded, Placebo: Used, Assignment: Parallel, Purpose: Treatment, Randomization description: The randomization method is based on block randomization, in which participants are equally allocated to the intervention and control groups. Participants are assigned in a 1:1 ratio (intervention to control) and enrolled in the study using random blocks of four generated by online software https://www.sealedenvelope.com. The investigators ensure the unpredictability of the allocation sequence and concealment of the allocation process using a computer-generated randomization procedure. In other words, through this centralized randomization method, the random allocation sequence remains concealed from the individuals enrolling participants into the study, Blinding description: The study is designed as a triple-blinded trial. In this study, participants, principal investigators, healthcare and research personnel responsible for patient care, data collectors, outcome assessors, and members of the Data Safety and Monitoring Board (DSMB) will be blinded to the allocation of participants to the intervention or control groups. The randomization and allocation process will be performed by an independent individual who is not involved in patient treatment, outcome assessment, or data analysis. Allocation codes will be kept in confidential sealed envelopes and will not be accessible to the research team, participants, or outcome assessors until completion of the final data analysis, except in emergency situations related to patient safety. Participants in the intervention group will receive tirzepatide, while participants in the control group will receive placebo. The placebo will contain all inactive ingredients and excipients of the active drug formulation except for the active ingredient tirzepatide. Placebo pens will be identical to the active drug pens in appearance, color, volume, odor, packaging, storage conditions, and method of administration. In addition, placebo pens will be prepared in visual dose presentations corresponding to 2.5, 5, 7.5, and 10 milligrams in order to maintain an identical dose-escalation process in both groups and prevent identification of treatment allocation. Administration of the active drug and placebo in both groups will be performed subcutaneously once weekly, on a fixed day and time, by a trained nurse. All participants in both groups will undergo identical administration procedures, follow-up visits, and outcome assessments in order to maintain blinding throughout all stages of the study. 3 Condition 1: patients with reduced ejection fraction heart failure. Condition 2: Overweight and obesity. Intervention 1: Intervention group: Participants in the intervention group, in addition to receiving standard treatment for heart failure, will receive tirzepatide as a subcutaneous injectable pen. Tirzepatide is a dual agonist of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors. The study drug will be administered as prefilled injection pens containing doses of 2.5, 5, 7.5, and 10 milligrams manufactured by Sinagen (Spartina).Drug administration will be performed once weekly, on a fixed day and time, by a trained and experienced nurse at the treatment center. Subcutaneous injections will be administered in the abdomen, thigh, or upper arm, and the injection site will be rotated at each administration to reduce the risk of local adverse reactions.The initial tirzepatide dose will be 2.5 milligrams once weekly for four weeks. If tolerated without significant gastrointestinal adverse effects, the dose will be increased to 5 milligrams once weekly at week five. Thereafter, based on patient tolerance and clinical assessment, the dose will be gradually escalated up to a maximum dose of 10 milligrams once weekly and continued until the end of the sixth month. The dose will not exceed 10 milligrams per week.In the event of significant adverse effects or drug intolerance, the dose will be reduced to the last tolerated dose or treatment will be temporarily discontinued. All participants will be regularly monitored throughout the study for adverse effects, treatment adherence, and clinical response. Intervention 2: Control group: Participants in the control group, in addition to receiving standard treatment for heart failure, will receive placebo as a subcutaneous injectable pen. The placebo will consist of prefilled injection pens containing all inactive ingredients and excipients of the active drug formulation except for the active ingredient tirzepatide. The placebo pens will be identical to the active drug pens in appearance, color, volume, odor, packaging, and storage conditions and will be manufactured by Sinagen (Spartina) to prevent identification of treatment allocation by participants or study personnel. In addition, placebo pens will be prepared and packaged in dose presentations visually corresponding to 2.5, 5, 7.5, and 10 milligrams in order to maintain a dose-escalation process identical to the intervention group and preserve study blinding.Placebo administration will be performed once weekly, on a fixed day and time, by a trained and experienced nurse at the treatment center. Subcutaneous injections will be administered in the abdomen, thigh, or upper arm, and the injection site will be rotated at each administration to reduce the risk of local adverse reactions.Participants in the control group will receive placebo with the same administration schedule, frequency of injections, administration conditions, and dose-escalation pattern as the intervention group in order to maintain blinding throughout the study. The duration of intervention in the control group will also be six months. All participants in this group will be regularly monitored throughout the study for adverse effects, treatment adherence, and clinical status. Yes - There is a plan to make this available What will be shared: All potentially shareable data will be available after de-identification of patient information. When: The access period starts after publication of the results To whom: Academic researchers will be granted access to the data upon providing an explanation for the need to access the information. Conditions: Applicants are required to clearly explain the reason for requesting access to the data. Where to obtain: Documents would be available according to cause of request from Dr Shadi Shafaghi Email: shafaghishadi@yahoo.com How to obtain: Applicants are required to submit a written request by email, including the reason for requesting access to the data. If approved, the requested information will be provided within a maximum of one week. Comments:
public Shadi Shafaghi
Masih Daneshvari Hospital, Darabad, Shahid Bahonar Street
Tehran Iran (Islamic Republic of) 1956944413 +98 21 2712 3810 shafaghishadi@yahoo.com Shahid Beheshti University of Medical Sciences scientific Babak Sharif Kashani
Masih Daneshvari Hospital, Darabad, Shahid Bahonar Street
Tehran Iran (Islamic Republic of) 1956944413 +98 21 2712 3810 Babaksharifkashani@Yahoo.Com Shahid Beheshti University of Medical Sciences Iran (Islamic Republic of) Iran (Islamic Republic of) Iran (Islamic Republic of) Iran (Islamic Republic of) Iran (Islamic Republic of) Iran (Islamic Republic of) Iran (Islamic Republic of) Heart Failure with Reduced Ejection Fraction (HFrEF) with Ejection Fraction (EF) less than or equal to 40 percent based on recent echocardiography (performed within the previous 3 months) Body Mass Index (BMI) greater than or equal to 30 kilograms per square meter (kg/m²) BMI greater than or equal to 27 kg/m² and the presence of at least one obesity-related comorbidity, including hypertension, diabetes mellitus, or hyperlipidemia. Steady heart failure treatment for more than or equal to 4 weeks prior to enrollment (beta-blockers, renin–angiotensin system inhibitors/angiotensin receptor–neprilysin inhibitor (ARNI), and sodium-glucose cotransporter-2 (SGLT2) inhibitors if prescribed) Obtained Written informed consent 18 years no limit Both Acute heart failure decompensation within the past 4 weeks or recent cardiac hospitalization Uncontrolled blood pressure (Systolic Blood Pressure (SBP) less than 90 or greater than or equal to 180 millimeters of mercury (mmHg) Advanced renal failure (Estimated Glomerular Filtration Rate (eGFR) less than 30 milliliters per minute per 1.73 square meters) Severe hepatic impairment (Elevation of liver enzymes to three times the baseline level) Active pancreatitis History of medullary thyroid tumor or Multiple Endocrine Neoplasia Type 2 (MEN 2) in the patient or first-degree relatives Pregnancy or breastfeeding Known hypersensitivity to glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide (GLP-1/GIP) receptor agonists Concurrent use of weight-loss medications I50 E66 Heart failure Overweight and obesity Treatment - Drugs Placebo Intervention group: Participants in the intervention group, in addition to receiving standard treatment for heart failure, will receive tirzepatide as a subcutaneous injectable pen. Tirzepatide is a dual agonist of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors. The study drug will be administered as prefilled injection pens containing doses of 2.5, 5, 7.5, and 10 milligrams manufactured by Sinagen (Spartina).Drug administration will be performed once weekly, on a fixed day and time, by a trained and experienced nurse at the treatment center. Subcutaneous injections will be administered in the abdomen, thigh, or upper arm, and the injection site will be rotated at each administration to reduce the risk of local adverse reactions.The initial tirzepatide dose will be 2.5 milligrams once weekly for four weeks. If tolerated without significant gastrointestinal adverse effects, the dose will be increased to 5 milligrams once weekly at week five. Thereafter, based on patient tolerance and clinical assessment, the dose will be gradually escalated up to a maximum dose of 10 milligrams once weekly and continued until the end of the sixth month. The dose will not exceed 10 milligrams per week.In the event of significant adverse effects or drug intolerance, the dose will be reduced to the last tolerated dose or treatment will be temporarily discontinued. All participants will be regularly monitored throughout the study for adverse effects, treatment adherence, and clinical response. Control group: Participants in the control group, in addition to receiving standard treatment for heart failure, will receive placebo as a subcutaneous injectable pen. The placebo will consist of prefilled injection pens containing all inactive ingredients and excipients of the active drug formulation except for the active ingredient tirzepatide. The placebo pens will be identical to the active drug pens in appearance, color, volume, odor, packaging, and storage conditions and will be manufactured by Sinagen (Spartina) to prevent identification of treatment allocation by participants or study personnel. In addition, placebo pens will be prepared and packaged in dose presentations visually corresponding to 2.5, 5, 7.5, and 10 milligrams in order to maintain a dose-escalation process identical to the intervention group and preserve study blinding.Placebo administration will be performed once weekly, on a fixed day and time, by a trained and experienced nurse at the treatment center. Subcutaneous injections will be administered in the abdomen, thigh, or upper arm, and the injection site will be rotated at each administration to reduce the risk of local adverse reactions.Participants in the control group will receive placebo with the same administration schedule, frequency of injections, administration conditions, and dose-escalation pattern as the intervention group in order to maintain blinding throughout the study. The duration of intervention in the control group will also be six months. All participants in this group will be regularly monitored throughout the study for adverse effects, treatment adherence, and clinical status. Distance covered during the Six-Minute Walk Test (6MWT). Timepoint: Before the intervention and 6 months after initiation of the intervention. Method of measurement: The Six-Minute Walk Test (6MWT) will be performed according to the standardized protocol of the American Thoracic Society (ATS) using a straight 30-meter corridor. Participants will be instructed to walk as far as possible at their maximum tolerated pace for six minutes and will be allowed to stop and rest if necessary. At the end of the test, the total distance walked will be recorded in meters. The 6MWT is a standardized, valid, and reproducible tool widely used for the assessment of functional capacity and exercise tolerance in patients with heart failure. New York Heart Association (NYHA) functional class. Timepoint: Before the intervention and 6 months after initiation of the intervention. Method of measurement: According to the criteria of the New York Heart Association classification system. Fasting Blood Sugar. Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Venous blood sampling after at least 8 hours of fasting and measurement of Fasting Blood Glucose using a standard laboratory assay kit based on the enzymatic glucose oxidase method. Glycated Hemoglobin (HbA1c). Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Biochemical assay kit for measurement of Glycated Hemoglobin. Body Mass Index. Timepoint: Before the intervention and 6 months after initiation of the intervention. Method of measurement: Fixed stadiometer and weighing scale (Body Mass Index (BMI) equals weight in kilograms divided by height in square meters (kg/m²)). Quality of life. Timepoint: Before the intervention and 6 months after initiation of the intervention. Method of measurement: Score of Kansas City Cardiomyopathy Questionnaire. Systolic blood pressure. Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Measurement of Systolic Blood Pressure using a calibrated automatic blood pressure monitor after at least 5 minutes of rest in the seated position. Amylase. Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Venous blood sampling and measurement of serum amylase using a standard laboratory assay kit based on the enzymatic colorimetric method. Alanine Aminotransferase (ALT). Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Venous blood sampling and measurement of serum Alanine Aminotransferase (ALT) using a standard laboratory assay kit based on the enzymatic spectrophotometric method. N-terminal pro–B-type Natriuretic Peptide (NT-proBNP). Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Human N-terminal pro–B-type Natriuretic Peptide (NT-proBNP) Enzyme-Linked Immunosorbent Assay (ELISA) Kit. Total Cholesterol (TC). Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Venous blood sampling after at least 8 hours of fasting and measurement of serum Total Cholesterol (TC) using a standard laboratory assay kit based on the enzymatic colorimetric method. Ejection Fraction (EF). Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Echocardiography. Gallbladder-related complications (cholelithiasis and cholecystitis). Timepoint: At baseline (prior to initiation of the intervention), at the end of month 2, at the end of month 4, and at the end of month 6. Method of measurement: Blood tests and ultrasonography. Injection-site reaction. Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Physical Examination. Hypoglycemia. Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Standard laboratory assay kit for measurement of Blood Glucose using the enzymatic glucose oxidase method. Gastrointestinal adverse effects. Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Interview and monitoring. Pancreatitis. Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Clinical assessment, standard laboratory assay kits for serum amylase and lipase measurement, and imaging studies when indicated. Tachycardia. Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Physical examination, interview and monitoring. Diastolic blood pressure. Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Measurement of diastolic Blood Pressure using a calibrated automatic blood pressure monitor after at least 5 minutes of rest in the seated position. Lipase. Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Venous blood sampling and measurement of serum Lipase using a standard laboratory assay kit based on the enzymatic colorimetric method . Aspartate Aminotransferase (AST). Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Venous blood sampling and measurement of serum Aspartate Aminotransferase (AST) using a standard laboratory assay kit based on the enzymatic spectrophotometric method. Alkaline Phosphatase (ALP). Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Venous blood sampling and measurement of serum Alkaline Phosphatase (ALP) using a standard laboratory assay kit based on the enzymatic spectrophotometric method. Low-Density Lipoprotein (LDL). Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Venous blood sampling after at least 8 hours of fasting and measurement of serum Low-Density Lipoprotein (LDL) using a standard laboratory assay kit based on the enzymatic colorimetric method. High-Density Lipoprotein (HDL). Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Venous blood sampling after at least 8 hours of fasting and measurement of serum High-Density Lipoprotein (HDL) using a standard laboratory assay kit based on the enzymatic colorimetric method. Triglycerides (TG). Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Venous blood sampling after at least 8 hours of fasting and measurement of serum Triglycerides (TG) using a standard laboratory assay kit based on the enzymatic colorimetric method in the central laboratory of the study center. Pulmonary Artery Pressure (PAP). Timepoint: Before the intervention and at the end of the second month, the end of the fourth month, and the end of the sixth month after initiation of the intervention. Method of measurement: Echocardiography. Change in shared Molecular and Genetic Pathways Linking Obesity and Heart Failure with Reduced Ejection Fraction. Timepoint: Before the intervention and at the end of the sixth month after initiation of the intervention. Method of measurement: Venous blood sampling before the intervention and at the end of the study, extraction of ribonucleic acid from peripheral blood samples, and assessment of changes in the expression of genes involved in the shared molecular pathways of obesity and Heart Failure with Reduced Ejection Fraction using quantitative real-time polymerase chain reaction, next-generation sequencing techniques, and bioinformatics analysis. Shahid Beheshti University of Medical Sciences Approved 2026-04-29 Research Ethics Committees of National Research Institute of Tuberculosis and Lung Diseases - SBMU Masih Daneshvari Tuberculosis and Pulmonary Diseases Research, Educational, and Medical Center, Shahid Beheshti University of Medical Sciences, Darabad Avenue, Shahid Bahonar roundabout Tehran Tehran Iran (Islamic Republic of)