Tirzepatide Titration to Reduce Side Effects in Individuals With Obesity

Official title

Tirzepatide Titration to Reduce Side Effects (TiTRE) in Individuals With Obesity

Overview

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

• Drug Tirzepatide (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
• Drug Tirzepatide (Flexible titration)
  Tirzepatide is administered by subcutaneous injection once weekly. Dose escalation follows a flexible titration schedule as defined in the study protocol.

Primary outcome measures

• Vomiting episodes per patient assessed using the Modified Index of Nausea, Vomiting, and Retching (M-INVR) [Time frame: From enrollment (at baseline) to the end of treatment at 76 weeks.]

Secondary outcome measures (12)

• Incidence, frequency, and duration of vomiting assessed using the MASCC Antiemesis Tool - Modified Index of Nausea and Vomiting (M-INVR) [Time frame: Baseline to Week 76]
• Change in body weight [Time frame: Baseline to Week 76]
• Proportion of participants remaining on active study medication [Time frame: Week 76]
• Change in glycated hemoglobin (HbA1c) [Time frame: Baseline to Week 76]
• Change in lean body mass assessed by dual-energy X-ray absorptiometry (DEXA) [Time frame: Baseline to Week 76]
• Change in visceral adiposity assessed by dual-energy X-ray absorptiometry (DEXA) [Time frame: Baseline to Week 76]
• Change in fat body mass assessed by dual-energy X-ray absorptiometry (DEXA) [Time frame: Baseline to Week 76]
• Change in Alanine Aminotransferase (ALT) [Time frame: Baseline to Week 76]
• Change in Aspartate Aminotransferase (AST) [Time frame: Baseline to Week 76]
• Change in Gamma-Glutamyl Transferase (GGT) [Time frame: Baseline to Week 76]
• Change in Alkaline Phosphatase (ALP) [Time frame: Baseline to Week 76]
• Change in Fibrosis-4 (FIB-4) index [Time frame: Baseline to Week 76]

Eligibility criteria

Inclusion criteria

• Adults aged 18 years and older
• A diagnosis of obesity (BMI ≥ 27 kg/m2) at screening with self-reported unsuccessful dietary efforts to lose weight.
• No diagnosis of diabetes mellites.
• Able to understand and sign the consent form
• 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 exclusion criteria, which in the investigator's opinion, might jeopardize the subject's safety or compliance with the protocol.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Kuwait · 1 center

• Dasman Diabetes Institute — Kuwait City

Identifiers

NCT: NCT07574723 · RA HM-2026-06

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗