Obesity
Conditions
Brief summary
The goal of this clinical trial is to determine whether a flexible, symptom-guided titration strategy for tirzepatide can reduce gastrointestinal side effects while maintaining weight-loss effectiveness in adults with obesity without diabetes. The main questions it aims to answer are: 1. Does flexible, symptom-guided titration reduce nausea and vomiting compared with standard per-label titration? 2. Does flexible titration achieve weight loss comparable to standard titration? Researchers will compare standard per-label titration with a click-based, symptom-guided titration approach to assess differences in tolerability and treatment effectiveness. Participants will: * Be randomly assigned to standard or flexible tirzepatide titration * Use a click-based dosing method that allows small dose increases based on tolerability (flexible group) * Attend study visits over 76 weeks for safety and outcome assessments This study addresses the lack of evidence for individualized titration strategies in obesity treatment and aims to improve tolerability, adherence, and long-term treatment outcomes.
Detailed description
Tirzepatide is an effective treatment for obesity, but gastrointestinal adverse events during dose escalation may limit tolerability and adherence. Current labeling recommends a fixed titration schedule that does not account for individual differences in symptom tolerance. Evidence supporting individualized titration strategies in obesity treatment remains limited. This randomized clinical trial aims to evaluate whether a flexible, symptom-guided titration strategy for tirzepatide can reduce gastrointestinal side effects while maintaining weight-loss effectiveness in adults with obesity without diabetes. Participants will be randomly assigned to either standard per-label titration or a flexible, click-based titration approach that allows smaller dose increments based on individual tolerability. Participants in the standard group will follow the approved fixed dose-escalation schedule, while participants in the flexible group will advance doses according to gastrointestinal symptom severity, with the goal of minimizing nausea and vomiting. All participants will attend study visits over 76 weeks for assessment of weight change, tolerability, safety, and treatment adherence. This study will compare gastrointestinal tolerability and weight-loss outcomes between titration strategies and aims to inform individualized dosing approaches that may improve adherence and long-term obesity treatment outcomes.
Interventions
DRUGTirzepatide (Per-label titration)
Tirzepatide is administered by subcutaneous injection once weekly. Dose escalation follows the manufacturer's prescribing information, with advancement through labeled dose levels at prespecified intervals to the assigned maintenance dose
Tirzepatide is administered by subcutaneous injection once weekly. Dose escalation follows a flexible titration schedule as defined in the study protocol.
Sponsors
Dasman Diabetes Institute
University of Ulster
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Blinding will be maintained for outcome assessors and data analysts to minimize bias. While participants cannot be blinded to treatment allocation due to the nature of the intervention, all personnel involved in outcome measurement and statistical analysis will remain unaware of group assignments. Procedures for maintaining blinding will include secure allocation concealment and restricted access to randomization codes.
Intervention model description
The is an open-label, two-arm, parallel, randomized controlled trial over 76 weeks, enrolling individuals with obesity (BMI ≥ 27 kg/m2) and without diabetes, with participants randomized to either a per-label arm or a flexible titration arm
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
1. Adults aged 18 years and older 2. A diagnosis of obesity (BMI ≥ 27 kg/m2) at screening with self-reported unsuccessful dietary efforts to lose weight. 3. No diagnosis of diabetes mellites. 4. Able to understand and sign the consent form 5. Able to undergo DEXA scan.
Exclusion criteria
* 1\. History of type 1 or type 2 diabetes mellites. 2. Obesity-related: * A self-reported change in body weight \>5 kg (11 lbs) within 90 days before screening irrespective of medical records. * Treatment with any medication for the indication of obesity within the past 90 days before screening. * Previous or planned (during the trial period) obesity treatment with surgery or a weight-loss device. However, the following are allowed: (1) liposuction and/or abdominoplasty, if performed \>1 year before screening; (2) lap banding, if the band has been removed \>1 year before screening; (3) intragastric balloon, if the balloon has been removed \>1 year before screening; or (4) duodenal-jejunal bypass sleeve, if the sleeve has been removed \>1 year before screening. * Uncontrolled thyroid disease, defined as thyroid stimulating hormone \>6.0 mIU/L or \<0.4 mIU/L as measured by the central laboratory at screening. 3\. Mental health: * History of major depressive disorder within 2 years before screening. * Diagnosis of other severe psychiatric disorder (e.g. schizophrenia, bipolar disorder). * A Patient Health Questionnaire-9 score of ≥15 at screening. * A lifetime history of a suicidal attempt. * Suicidal behavior within 30 days before screening. 4. General safety: * Use of non-herbal Chinese medicine or other non-herbal local medicine with unknown/unspecified content within 90 days before screening. * Presence of acute pancreatitis within the past 180 days prior to the day of screening. * History or presence of chronic pancreatitis. * Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma. * Renal impairment measured as estimated glomerular filtration rate value of \<15 mL/min/1.73 m2 as defined by KDIGO 2012 by the central laboratory at screening. * History of malignant neoplasms within the past 5 years prior to screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed. * Any of the following: myocardial infarction, stroke, hospitalization for unstable angina, or transient ischemic attack within the past 60 days prior to screening. * Subject presently classified as being in New York Heart Association Class IV. * Surgery scheduled for the duration of the trial, except for minor surgical procedures, in the opinion of the investigator. * Known or suspected abuse of alcohol or recreational drugs. * Known or suspected hypersensitivity to trial product(s) or related products. * Previous participation in this trial. Participation is defined as signed informed consent. * Participation in another clinical trial within 90 days before screening. * Female who is pregnant, breast-feeding, or intends to become pregnant, or is of child-bearing potential and not using a highly effective contraceptive method. * Any disorder, unwillingness, or inability, not covered by any of the other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Vomiting episodes per patient assessed using the Modified Index of Nausea, Vomiting, and Retching (M-INVR) | From enrollment (at baseline) to the end of treatment at 76 weeks. | Vomiting episodes per patient will be assessed using the validated Modified Index of Nausea, Vomiting, and Retching (M-INVR). The vomiting component is administered weekly, with scores ranging from 0 (no vomiting) to 4 (severe or frequent vomiting), where higher scores indicate worse outcomes. Vomiting burden will be summarized as: * Weekly vomiting severity scores based on M-INVR, and * An exposure-adjusted rate of vomiting episodes (episodes per patient-week), calculated by dividing the total number of reported vomiting episodes by the total duration of follow-up for each participant. This approach accounts for differences in treatment duration and follow-up time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence, frequency, and duration of vomiting assessed using the MASCC Antiemesis Tool - Modified Index of Nausea and Vomiting (M-INVR) | Baseline to Week 76 | Vomiting is assessed weekly using the MASCC Antiemesis Tool - Modified Index of Nausea and Vomiting (M-INVR), a validated patient-reported outcome measure. The vomiting subscale score is calculated as the sum of relevant vomiting items, with scores ranging from 0 to 16, where higher scores indicate greater incidence, frequency, and duration of vomiting (worse outcome). |
| Change in body weight | Baseline to Week 76 | Absolute and percentage change in body weight from baseline. |
| Proportion of participants remaining on active study medication | Week 76 | Number of participants continuing to receive active study medication at the end of the trial. |
| Change in glycated hemoglobin (HbA1c) | Baseline to Week 76 | Change in HbA1c from baseline. |
| Change in lean body mass assessed by dual-energy X-ray absorptiometry (DEXA) | Baseline to Week 76 | Change in total lean body mass measured by dual-energy X-ray absorptiometry (DEXA). |
| Change in visceral adiposity assessed by dual-energy X-ray absorptiometry (DEXA) | Baseline to Week 76 | Change in visceral adipose tissue measured by dual-energy X-ray absorptiometry (DEXA). |
| Change in fat body mass assessed by dual-energy X-ray absorptiometry (DEXA) | Baseline to Week 76 | Change in total fat body mass measured by dual-energy X-ray absorptiometry (DEXA). |
| Change in Alanine Aminotransferase (ALT) | Baseline to Week 76 | Change from baseline in serum alanine aminotransferase (ALT) levels in U/L, measured using standard laboratory methods. |
| Change in Aspartate Aminotransferase (AST) | Baseline to Week 76 | Change from baseline in serum aspartate aminotransferase (AST) levels in U/L, measured using standard laboratory methods. |
| Change in Gamma-Glutamyl Transferase (GGT) | Baseline to Week 76 | Change from baseline in serum gamma-glutamyl transferase (GGT) levels in U/L, measured using standard laboratory methods. |
| Change in Alkaline Phosphatase (ALP) | Baseline to Week 76 | Change from baseline in serum alkaline phosphatase (ALP) levels in U/L, measured using standard laboratory methods. |
| Change in Fibrosis-4 (FIB-4) index | Baseline to Week 76 | Change from baseline in the Fibrosis-4 (FIB-4) index, a composite score calculated as: FIB-4 = (Age × AST) / (Platelet count × √ALT), where age is measured in years, AST and ALT in U/L, and platelet count in 10⁹/L. The FIB-4 index is reported as a unitless value, with higher values indicating greater liver fibrosis. Values typically range from approximately 0 to 10. |
| Change in Total Cholesterol | Baseline to Week 76 | Change from baseline in fasting total cholesterol levels measured using standard laboratory methods. |
| Change in Low-Density Lipoprotein Cholesterol (LDL-C) | Baseline to Week 76 | Change from baseline in fasting low-density lipoprotein cholesterol (LDL-C) levels measured using standard laboratory methods. |
| Change in High-Density Lipoprotein Cholesterol (HDL-C) | Baseline to Week 76 | Change from baseline in fasting high-density lipoprotein cholesterol (HDL-C) levels measured using standard laboratory methods. |
| Change in Triglycerides | Baseline to Week 76 | Change from baseline in fasting triglyceride levels measured using standard laboratory methods. |
| Change in estimated glomerular filtration rate (eGFR) | Baseline to Week 76 | Change from baseline in estimated glomerular filtration rate (eGFR) calculated using a standard equation. |
| Change in serum creatinine | Baseline to Week 76 | Change from baseline in serum creatinine measured using standard laboratory methods. |
| Change in urinary microalbumin | Baseline to Week 76 | Change from baseline in urinary microalbumin concentration measured using standard laboratory methods. |
| Change in urine albumin-to-creatinine ratio (ACR) | Baseline to Week 76 | Change from baseline in urine albumin-to-creatinine ratio (ACR) measured using standard laboratory methods. |
| Change in thyroid-stimulating hormone (TSH) | Baseline to Week 76 | Change from baseline in serum thyroid-stimulating hormone (TSH) measured using standard laboratory methods. |
| Change in free thyroxine (free T4) | Baseline to Week 76 | Change from baseline in serum free thyroxine (free T4) measured using standard laboratory methods. |
| Change in interleukin-6 (IL-6) | Baseline to Week 76 | Change from baseline in circulating interleukin-6 (IL-6) concentration measured using standard laboratory methods. |
| Change in interleukin-10 (IL-10) | Baseline to Week 76 | Change from baseline in circulating interleukin-10 (IL-10) concentration measured using standard laboratory methods. |
| Change in interleukin-1 receptor antagonist (IL-1Ra) | Baseline to Week 76 | Change from baseline in circulating interleukin-1 receptor antagonist (IL-1Ra) concentration measured using standard laboratory methods. |
| Change in tumor necrosis factor-alpha (TNF-α) | Baseline to Week 76 | Change from baseline in circulating tumor necrosis factor-alpha (TNF-α) concentration measured using standard laboratory methods. |
| Change in health-related quality of life assessed using the 36-Item Short Form Health Survey (SF-36) | Baseline to Week 76 | Health-related quality of life is assessed using the 36-Item Short Form Health Survey (SF-36), a validated patient-reported outcome measure. The SF-36 yields an overall score ranging from 0 to 100, with higher scores indicating better health-related quality of life. |
| Change in dietary intake patterns | Baseline to Week 76 | Changes in macronutrient composition and total caloric intake assessed using multiple-pass 24-hour dietary recalls. |
| Incidence of adverse events and laboratory abnormalities | Baseline to Week 76 | Incidence of treatment-emergent adverse events and clinically significant laboratory abnormalities. |
| Change in retinal nerve fiber layer thickness assessed by optical coherence tomography (OCT) | Baseline to Week 76 | Change from baseline in retinal nerve fiber layer thickness measured by optical coherence tomography |
| Change in arterial stiffness measured by pulse wave velocity (PWV) | Baseline to Week 76 | Change from baseline in arterial stiffness assessed by carotid-femoral pulse wave velocity. |
| Change in sudomotor function assessed by Sudoscan | Baseline to Week 76 | Change from baseline in sudomotor function measured by electrochemical skin conductance using Sudoscan. |
| Treatment Persistence and Discontinuation | Up to 76 weeks | Treatment persistence will be assessed by the proportion of participants remaining on active study medication at week 76. Treatment discontinuation and reasons for discontinuation will be recorded throughout the study and categorized as gastrointestinal adverse events (including nausea and vomiting), other adverse events, lack of efficacy, participant preference, protocol non-adherence, loss to follow-up, pregnancy, investigator decision, or other specified reasons. |
Countries
Kuwait
Outcome results
None listed