Clinical trial NCT06582875: Glucagon-Like Peptide-1 Receptor Agonist in ADPKD
Official title: Advancing ADPKD Treatment With GLP-1RA: A Study of Glucagon-Like Peptide-1 Receptor Agonists' Efficacy, Safety, and Mechanism
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Autosomal Dominant Polycystic Kidney
Obesity
Keywords: GLP1RA
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: Washington University School of Medicine
name: Mayo Clinic
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2024-09-03
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in height-Adjusted Total kidney volume
timeFrame: Baseline, 12-months
Secondary outcomes:
measure: Change in body weight
timeFrame: Baseline, 12-months
measure: Change in abdominal adiposity
timeFrame: Baseline, 12-months
measure: Change in adiponectin (circulating)
timeFrame: Baseline, 6-months, 12-months
measure: Change in leptin (circulating)
timeFrame: Baseline, 6-months, 12-months
measure: Change in interleukin-6 (circulating)
timeFrame: Baseline, 6-months, 12-months
measure: Change in tumor necrosis-factor-alpha (circulating)
timeFrame: Baseline, 6-months, 12-months
measure: Change in high-sensitivity C-reactive protein (circulating)
timeFrame: Baseline, 6-months, 12-months
measure: Change in 8-isoprostane (circulating)
timeFrame: Baseline, 6-months, 12-months
measure: Change in copeptin (circulating)
timeFrame: Baseline, 6-months, 12-months
measure: Change in HOMA-IR
timeFrame: Baseline, 6-months, 12-months
measure: Change in HOMA-β
timeFrame: Baseline, 6-months, 12-months
measure: Change in 8-isoprostane (urinary)
timeFrame: Baseline, 6-months, 12-months
measure: Change in copeptin (urinary)
timeFrame: Baseline, 6-months, 12-months
measure: Change in renal oxygen consumption
timeFrame: Baseline, 12-months
measure: Change in gut microbiota
timeFrame: Baseline, 12-months
Other outcomes:
measure: Change in renal blood flow
timeFrame: Baseline, 12-months
measure: Safety (adverse events)
timeFrame: 12 months
measure: Adherence
timeFrame: 12 months
measure: Tolerability (dropout due to adverse events)
timeFrame: 12 months
measure: Kidney Function Decline
timeFrame: Baseline, 1 month, 3 months, 6-months, 12-months
measure: Change in dietary energy Intake
timeFrame: Baseline, 1 month, 6-months, 12-months
measure: Change in free-living physical activity
timeFrame: Baseline, 12-months
measure: Change in resting energy experniture
timeFrame: Baseline, 12 months
measure: Change in percent body fat
timeFrame: Baseline, 12 months
Locations:
city: Aurora
country: United States
facility: University of Colorado - Anschutz Medical Campus
state: Colorado
Study officials:
References: