Feasibility of Study of Empagliflozin in Patients With Autosomal Dominant Polycystic Kidney Disease
Study Details
Study Description
Brief Summary
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to end-stage kidney disease. Despite decades of research, tolvaptan is the only approved intervention in ADPKD. However, tolvaptan does not target cardiovascular complications of ADPKD and is constrained by high cost and side effects that limit adherence. Therefore, there is an urgent need for a well-tolerated alternative intervention to slow ADPKD progression and improve vascular health. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) have a track record of tolerability and safety in patients with proteinuric diabetic and non-diabetic kidney disease. Trials of SGLT2i in these conditions have been extremely encouraging, and these treatments are highly likely to become the standard of care for diabetic and non-diabetic kidney disease; however, the mechanisms of action are not fully elucidated, and may be non-specific to disease etiology. The potential benefit of SGLT2i has not been examined in patients with ADPKD, as major trials have excluded such patients. There are also potential benefits of SGLT2i to ADPKD patients beyond slowing loss of kidney function, as this class of drugs provide a cardiovascular mortality benefit for patients across the CKD spectrum. Studies testing the effects of SGLT2i in animal models of PKD have yield conflicting results. Five weeks of treatment with an SGLT1 and SLGT2 inhibitor phlorizon was shown to inhibit cystogenesis in the Han:SPRD rat model of PKD. The mechanisms by which SGLT2i slows cystic renal disease progression may be related to inhibition of cyst epithelial cell proliferation. SGLT2i have also antioxidant and anti-inflammatory actions, which are important for reducing fibrosis and improving vascular health, both of which occur in early stages of ADPKD. While many changes likely contribute to the development of arterial dysfunction in patients with ADPKD, among those of greatest concern is the development of stiffening of large elastic arteries, typically assessed by aortic pulse wave velocity (aPWV). The investigator proposes a pilot randomized clinical trial to determine the safety and tolerability of empagliflozin in ADPKD patients. To achieve this, the investigator will conduct a 12-month parallel-group, randomized, double-blind, placebo-controlled trial in 50 ADPKD patients with an eGFR 30-90 mL/min/1.73m2. Secondary, exploratory endpoints will determine the effect of empagliflozin on kidney volume, kidney function, aPWV, plasma copeptin levels, urinary kidney injury molecule-1 (KIM-1) and quality of life.
Specific Aim 1: To determine the feasibility, in terms of safety and tolerability, of prescribing empagliflozin 25 mg once a day in ADPKD patients at risk for progression with an eGFR of 30-90 mL/min/1.73m2.
Specific Aim 2: To derive preliminary estimates of the effect of empagliflozin compared to placebo on 12-month change in a) total kidney volume by magnetic resonance imaging, b) eGFR,
- plasma copeptin levels (a marker of vasopressin secretion), d) urinary KIM-1 (a marker of tubular injury), e) aPWV; and f) ADPKD-specific health-related quality of life (HRQoL) as quantified by the ADPKD-Impact Scale.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by development and continued growth of numerous fluid-filled kidney cysts that result in ultimate loss of kidney function in the majority of individuals. ADPKD manifestations are not limited to the kidney. It is well established that arterial stiffness, an important predictor of future cardiovascular events and mortality, is present early in the course of ADPKD. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) have a track record of tolerability and safety in patients with diabetic and non-diabetic kidney disease. Studies of SGLT2i have been extremely encouraging and the expectation is that these treatments will become standard of care for diabetic and non-diabetic kidney disease; however, the mechanism of action is not fully understood and seems non-specific with regards to disease etiology. The potential benefit of SGLT2i has not been examined in ADPKD, as major trials of SGLT2i in non-diabetic chronic kidney disease (CKD) have excluded patients with ADPKD. It is also important to note the potential benefits of SGLT2i outside of delaying loss of kidney function, as these class of drugs have been shown to provide a mortality benefit for patients across the CKD spectrum. Thus, novel interventions to slow kidney disease progression and reduce vascular morbidity within ADPKD population are of clinical importance.
Limited data suggests SGLT2i may stimulate vasopressin and vasopressin receptor expression by causing glucosuria, natriuresis, and glucose osmotic diuresis, at least in patients and animal models without ADPKD. Vasopressin is known to stimulate cyst growth in ADPKD and promote disease progression. SGLT2i have been studied in animal models of ADPKD, with conflicting data. Some studies in rodent ADPKD models treated with SGLT2i failed to show a significant reduction in cyst growth. However, because of SGLT2i's beneficial effects on kidney function, vascular function, and mortality in non-ADPKD patients with CKD, further investigations of SGLT2i in patients with ADPKD are needed.
Primary Outcome Measure (Aim1): Safety will be assessed by laboratory testing and recording of adverse events. Tolerability will be assessed by subject drop-out rate due to adverse events and the proportion tolerating the maximal dose of study drug. Adherence to the intervention will be assessed by counting the returned number of tablets during check-in visits. Subjects will have check-in visits every 2 weeks the 1st month, monthly on month 2 and 3 and then every 3 months until the end of the study. Subjects will discuss issues with tolerability or treatment-emergent adverse events with a member of the clinical staff who is blinded to treatment status.
Secondary (Exploratory) Outcome Measures (Aim 2): (a) Height-adjusted total kidney volume will be examined by magnetic resonance imaging, at baseline, 3 months and 12 months after treatment with empagliflozin or placebo; (b) Aortic stiffness will be evaluated as aortic pulse wave velocity, at baseline, 3 months and 12 months after treatment with empagliflozin or placebo; (c) Plasma copeptin levels and urinary kidney injury molecule-1 will be measured at baseline, 3 months and 12 months after treatment with empagliflozin or placebo; and (d) Patient related outcomes will be measured using the ADPKD Impact Scale (ADPKD-IS) at baseline, 3 months and 12 months after treatment with empagliflozin or placebo.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Experimental Empagliflozin |
Drug: Empagliflozin
Empagliflozin: The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3furanyl]oxy]phenyl]methyl]phenyl]-, (1S). Empagliflozin is a white to yellowish, non-hygroscopic powder. It is very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol and acetonitrile; soluble in 50% acetonitrile/water; and practically insoluble in toluene. Empagliflozin power will be added in white and bovine origin gelatin capsules. Each capsule of empagliflozin will contain 10 mg or 25 mg of empagliflozin (free base) and the following inactive ingredients: microcrystalline cellulose magnesium, stearate, dicalcium phosphate, and silicone dioxide.
|
| Placebo Comparator: Placebo comparator Placebo |
Drug: Placebo
Placebo capsules will be matched in size and color to empagliflozin capsules. Each placebo capsule will contain the following inactive ingredients: microcrystalline cellulose magnesium, stearate, dicalcium phosphate, and silicone dioxide.
|
Outcome Measures
Primary Outcome Measures
- Safety [12 months]
Safety will be assessed by recording of adverse events.
- Tolerability [12 months]
Tolerability will be assessed by subject drop-out rate due to adverse events.
- Adherence [12 months]
Adherence to the intervention will be assessed by counting the returned number of tablets during check-in visits.
Secondary Outcome Measures
- Height-Adjusted Total kidney volume [Baseline, check-in visit (3 months), post-testing (12-months)]
To assess kidney growth, we will measure change in height-adjusted total kidney volume by magnetic resonance imaging at baseline, 3 months and 12 months.
- Aortic Pulse Wave Velocity (aPWV) [Baseline, check-in visit (3 months), post-testing (12 months)]
A transcutaneous custom tonometer (SphygmoCor XCEL PWA and PWV System; Atcor Medical Inc, Naperville IL) will be positioned at the carotid and femoral arteries and aPWV will be calculated as the distance between recording sites/time between the foot of the carotid and femoral arterial waveforms. Data will be expressed as cm/s.
- Mechanistic Biomarkers [Baseline, check-in visit (3 months), post-testing (12 months)]
Venous blood samples will be analyzed for the following circulating mechanistic biomarker: Plasma copeptin. Urine samples will be analyzed for the following mechanistic biomarker: Kidney Injury Molecule -1 (KIM-1).
- Patient Related Outcomes [12 months]
The ADPKD Impact Scale (ADPKD-IS) includes 18 items representing 3 distinct domains (physical function, fatigue, and emotional function
Eligibility Criteria
Criteria
Inclusion Criteria:
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Autosomal Dominant Polycystic Kidney Disease (ADPKD) as defined by modified Pei-Ravine Criteria;
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Age 18-50 yrs;
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Estimated Glomerular Filtration Rate (eGFR) 30-90 ml/min/1.73m2;
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Mayo imaging-based risk classification 1C, 1D, or 1E;
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Stable renal function over prior 3 months.
Exclusion Criteria:
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Known diabetes mellitus;
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Fasting Glucose >120 mg/dL;
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HbA1C≥6.5%;
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Seated systolic blood pressure <100 mm Hg;
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Seated systolic blood pressure >160 mm Hg;
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Known heart failure with reduced ejection fraction (HFrEF);
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Current use of loop diuretic;
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Current use of tolvaptan or other V2 receptor antagonist;
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Current urinary tract or urogenital infection;
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Pregnant or lactating;
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Vascular claudication, lower extremity skin infection or ulcers;
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Contraindication to magnetic resonance imaging (e.g., severe claustrophobia, implanted ferromagnetic device).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Coloardo Anschutz Medical Campus | Aurora | Colorado | United States | 80045 |
Sponsors and Collaborators
- University of Colorado, Denver
- University of Maryland
Investigators
- Principal Investigator: Michel B Chonchol, MD, University of Colorado, Denver
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- COMIRB 22-0616
- 1 R01 DK131755-01A1