Glucagon-Like Peptide-1 Receptor Agonist in ADPKD

Advancing ADPKD Treatment With GLP-1RA: A Study of Glucagon-Like Peptide-1 Receptor Agonists' Efficacy, Safety, and Mechanism

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.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Autosomal Dominant Polycystic Kidney
• Intervention / Treatment: Drug: Tirzepatide; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 126
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Diana George; Phone Number: 303-724-1684; Email: Diana.George@cuanschutz.edu
• Study Contact Backup: Name: Kristen Nowak, PhD, MPH; Phone Number: 3037244842; Email: Kristen.Nowak@cuanschutz.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado - Anschutz Medical Campus
      • Contact: Kristen Nowak, PhD, MPH; Phone Number: 303-724-4842; Email: Kristen.Nowak@cuanschutz.edu
      • Principal Investigator: Kristen Nowak, PhD, MPH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Tirzepatide; Titrated to dose of 5 mg once weekly subcutaneous; Other Names: Zepbound
Placebo Comparator: 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.	Other: Placebo; Titrated to dose of 5 mg once weekly subcutaneous

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in height-Adjusted Total kidney volume	To assess kidney growth,height-adjusted total kidney volume will be measured by magnetic resonance imaging at baseline and 12 months to determine annual percent change.	Baseline, 12-months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in abdominal adiposity	Abdominal adiposity (subcutaneous, visceral, and total) will be assessed by magnetic resonance imaging.	Baseline, 12-months
Change in adiponectin (circulating)	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 6-months, 12-months
Change in leptin (circulating)	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 6-months, 12-months
Change in interleukin-6 (circulating)	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 6-months, 12-months
Change in tumor necrosis-factor-alpha (circulating)	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 6-months, 12-months
Change in high-sensitivity C-reactive protein (circulating)	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 6-months, 12-months
Change in 8-isoprostane (circulating)	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 6-months, 12-months
Change in copeptin (circulating)	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 6-months, 12-months
Change in HOMA-IR	The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) will use fasting glucose and insulin to calcuate insulin sensitivity	Baseline, 6-months, 12-months
Change in HOMA-β	The Homeostatic Model Assessment of β-cell function (HOMA-β) will use fasting glucose and insulin to calcuate insulin secretion.	Baseline, 6-months, 12-months
Change in 8-isoprostane (urinary)	Sport urine samples will be analyzed for this mechanistic biomarker	Baseline, 6-months, 12-months
Change in copeptin (urinary)	Sport urine samples will be analyzed for this mechanistic biomarker	Baseline, 6-months, 12-months
Change in renal oxygen consumption	Renal oxygen consumption will be assessed by a PET/CT scan using 11-C acetate in a sub-set of participants	Baseline, 12-months
Change in gut microbiota	16S rRNA gene sequencing will be used for taxonomic characterization of the gut microbiota in a subset of participants.	Baseline, 12-months
Change in body weight	Change in body weight over the 12-month period will be measured using a calibrated digital scale.	Baseline, 12-months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in renal blood flow	Phase contrast magentic resonance imaging will be used to measure change in renal blood flow	Baseline, 12-months
Safety (adverse events)	Number of participants with treatment-related adverse events in each group as evaluated by the DSMB	12 months
Adherence	Compliance will be assessed by cross-checking the following sources and comparing these to the expected use: (1) drug accountability information; (2) counting returned trial product, visual inspection of pens; and (3) discussion with participants.	12 months
Tolerability (dropout due to adverse events)	Subject dropout due to treatment-emergent adverse events	12 months
Change in dietary energy Intake	Multiple pass 24-hr dietary recalls will be analyzed to evaluate self-reported energy intake	Baseline, 1 month, 6-months, 12-months
Change in free-living physical activity	Estimated energy expenditure (METs) over a 7-day period will be quantified using the ActiGraph wGT3X-BT activity monitor	Baseline, 12-months
Change in resting energy experniture	Resting energy expenditure will be assessed using indirect calorimetry.	Baseline, 12 months
Change in percent body fat	Percent body fat will be assessed via DEXA scan in a sub-set of participants.	Baseline, 12 months
Kidney Function Decline	Estimated glomerular filtration rate trajectories will be compared between the active and placebo group as an exploratory endpoint to inform a subsequent phase III trial.	Baseline, 1 month, 3 months, 6-months, 12-months

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Mayo Clinic; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2025
• Primary Completion (Estimated): June 30, 2029
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: August 26, 2024
• First Submitted That Met QC Criteria: August 30, 2024
• First Posted (Actual): September 3, 2024

Study Record Updates

• Last Update Posted (Actual): May 6, 2025
• Last Update Submitted That Met QC Criteria: May 5, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: GLP1RA
• Additional Relevant MeSH Terms: Ciliopathies; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genetic Diseases, Inborn; Congenital Abnormalities; Abnormalities, Multiple; Kidney Diseases, Cystic; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Tirzepatide
• Other Study ID Numbers: 24-0594; R01DK138915-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data obtained through this study may be provided to qualified researchers with academic interest in ADPKD. Data shared will be coded, with no PHI included. Approval of the request and execution of all applicable agreements (i.e. data use agreement) are prerequisites to the sharing of data with the requesting party.
• IPD Sharing Time Frame: Data requests can be submitted starting 9 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.
• IPD Sharing Access Criteria: Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No