Glucagon-Like Peptide-1 Receptor Agonist in ADPKD

NCT ID: NCT06582875

Last Updated: 2025-05-06

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 126 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-03-06
• Study Completion Date: 2029-06-30

Brief Summary

The proposed clinical trial aims to assess if a year of treatment with a glucagon-like peptide 1 receptor agonist, a medication approved for weight management that also improves the body's response to glucose and insulin, can slow kidney growth in adults with autosomal dominant polycystic kidney disease who are overweight or obese. The study will also evaluate changes in abdominal fat and kidney metabolism using cutting-edge images techniques. Blood and urine samples will provide further insight into biological changes that may be linked to the benefits of the intervention, while ensuring careful monitoring of safety and tolerability.

Detailed Description

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to kidney failure. The only approved treatment to decelerate kidney disease progression in patients with ADPKD is tolvaptan, but its usage is limited due to frequent side effects affecting adherence. Thus, alternative interventions that may slow ADPKD progression hold considerable clinical importance. In line with the general population, body-mass index and insulin resistance have been increasing in patients with ADPKD. The investigators have shown that visceral adiposity associates strongly with accelerated progression of early-stage ADPKD. Pilot study suggested that diet-induced weight loss may slow kidney growth (% in height-adjusted total kidney volume [htTKV] by magnetic resonance imaging), and the study team is currently evaluating the efficacy of daily caloric restriction-induced weight loss for slowing ADPKD progression in a phase IIa clinical trial. However, the long-term adherence to lifestyle interventions is challenging, making pharmacological interventions a compelling adjunct or alternative. Moreover, the study team recently demonstrated that adults with ADPKD and preserved kidney function exhibited insulin resistance (via the gold-standard hyperinsulinemic-euglycemic clamps) and impaired kidney oxidative metabolism (via 11C-acetate PET), which were strongly associated with htTKV. These novel data suggest that targeting improvements in insulin sensitivity and kidney oxidative metabolism, in addition to weight loss, may slow ADPKD progression. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) were recently FDA-approved for the treatment of obesity and show promise in substantially reducing adiposity and improving insulin sensitivity. Additionally, evidence indicates that GLP-1RAs may transform CKD management by reducing kidney events in patients with and without diabetes, via effects extending beyond glycemic modulation, and in part via attenuated kidney inflammation and oxidative stress. However, GLP-1RAs have not yet been evaluated as a novel therapy for slowing ADPKD progression in patients with overweight/obesity. Thus, the current study is a 12-month, phase II, randomized, placebo-controlled, double-blind clinical trial using a GLP-1RA in 126 adults with ADPKD and overweight or obesity to slow kidney growth (primary outcome). The trial will also evaluate changes in total body weight, adipose volume and function, insulin resistance, kidney oxidative metabolism, and inflammation, and carefully monitor safety and tolerability. As a novel therapeutic in ADPKD, GLP-1RAs could transform the treatment landscape for patients.

Conditions

Autosomal Dominant Polycystic Kidney; Obesity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Tirzepatide

To minimize the risk of gastrointestinal adverse events, we will use a standard dose-escalation regimen for tirzepatide (placebo-matched), starting at 2.5 mg once weekly (OW) at randomization. After 4 weeks of treatment at 2.5 mg, the dose will be escalated to 5 mg OW, which will be maintained for another 4 weeks and then continued as the target dose for 10 months until the end of treatment. As with other nutrient stimulating hormone (NuSH) therapies, dose reductions and extensions of dose-escalation intervals will be permitted if participants experience unacceptable adverse events. The minimum tolerated dose required for continued study participation is 2.5 mg/week. All dose changes will be documented in the study records.

Group Type: EXPERIMENTAL

Tirzepatide

Intervention Type: DRUG

Titrated to dose of 5 mg once weekly subcutaneous

Placebo

To minimize the risk of gastrointestinal adverse events, we will use a standard dose-escalation regimen for tirzepatide (placebo-matched), starting at 2.5 mg once weekly (OW) at randomization. After 4 weeks of treatment at 2.5 mg, the dose will be escalated to 5 mg OW, which will be maintained for another 4 weeks and then continued as the target dose for 10 months until the end of treatment. As with other nutrient stimulating hormone (NuSH) therapies, dose reductions and extensions of dose-escalation intervals will be permitted if participants experience unacceptable adverse events. The minimum tolerated dose required for continued study participation is 2.5 mg/week. All dose changes will be documented in the study records.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Titrated to dose of 5 mg once weekly subcutaneous

Interventions

Tirzepatide

Titrated to dose of 5 mg once weekly subcutaneous

Intervention Type: DRUG

Placebo

Titrated to dose of 5 mg once weekly subcutaneous

Intervention Type: OTHER

Other Intervention Names

Zepbound

Eligibility Criteria

Inclusion Criteria

• 18-65 years of age
• ADPKD diagnosis based on the modified Pei-Ravine criteria
• Body-mass index of ≥27 kg/m^2
• Estimated glomerular filtration rate ≥ 30 mL/min/1.73m^2
• Mayo Classification of C, D, or E, calculated from a previous kidney ultrasound or MRI performed within the last 12 months
• Not currently participating in or planning to participate in any formal weight loss or physical activity program, or another interventional study
• Ability to provide informed consent

Exclusion Criteria

• Diabetes mellitus
• Tolvaptan usage or plans to initiate tolvaptan
• History of hospitalization or major surgery within the last 3 months
• Uncontrolled hypertension (systolic blood pressure > 160 or diastolic blood pressure >100 mm Hg)
• Pregnancy, lactation, or unwillingness to use adequate birth control
• Regular use of prescription or over-the-counter medications that may affect weight, appetite, food intake, or energy metabolism
• History of clinically diagnosed eating disorder including: anorexia nervosa, bulimia, binge eating disorder
• Weight change of >5% in the past 3 months for any reason except post-partum weight loss
• Inability to cooperate with or clinical contraindication for MRI including: severe claustrophobia, implants, devices, or non-removable body piercings
• Presence or personal history of malignant neoplasm within 5 years prior to the day of screening
• Personal or family history of medullary thyroid carcinoma, thyroid nodule, or multiple endocrine neoplasia type 2
• Prior history of pancreatitis
• Weight ≥450 lb

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Washington University School of Medicine

OTHER

Sponsor Role: collaborator

Mayo Clinic

OTHER

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of Colorado - Anschutz Medical Campus

Aurora, Colorado, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Kristen Nowak, PhD, MPH

Role: CONTACT

Kristen.Nowak@cuanschutz.edu

3037244842

Diana George

Role: CONTACT

Diana.George@cuanschutz.edu

303-724-1684

Facility Contacts

Kristen Nowak, PhD, MPH

Role: primary

Kristen.Nowak@cuanschutz.edu

303-724-4842

Other Identifiers

R01DK138915-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

24-0594

Identifier Type: -

Identifier Source: org_study_id