Advancing ADPKD Treatment With GLP-1RA: A Study of Glucagon-Like Peptide-1 Receptor Agonists' Efficacy, Safety, and Mechanism
Trial Snapshot
- Phase
- Phase 2
- Status
- Recruiting
- Enrollment
- 126
- Locations
- 1
- Primary Endpoint
- Change in height-Adjusted Total kidney volume
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
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.
Intervention: Tirzepatide (Drug)
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.
Intervention: Placebo (Other)
Outcomes
Primary Outcomes
Change in height-Adjusted Total kidney volume
Time Frame: Baseline, 12-months
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.
Secondary Outcomes
- Change in body weight(Baseline, 12-months)
- Change in abdominal adiposity(Baseline, 12-months)
- Change in adiponectin (circulating)(Baseline, 6-months, 12-months)
- Change in leptin (circulating)(Baseline, 6-months, 12-months)
- Change in interleukin-6 (circulating)(Baseline, 6-months, 12-months)
- Change in tumor necrosis-factor-alpha (circulating)(Baseline, 6-months, 12-months)
- Change in high-sensitivity C-reactive protein (circulating)(Baseline, 6-months, 12-months)
- Change in 8-isoprostane (circulating)(Baseline, 6-months, 12-months)
- Change in copeptin (circulating)(Baseline, 6-months, 12-months)
- Change in HOMA-IR(Baseline, 6-months, 12-months)
- Change in HOMA-β(Baseline, 6-months, 12-months)
- Change in 8-isoprostane (urinary)(Baseline, 6-months, 12-months)
- Change in copeptin (urinary)(Baseline, 6-months, 12-months)
- Change in renal oxygen consumption(Baseline, 12-months)
- Change in gut microbiota(Baseline, 12-months)