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Abstract
Introduction Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary condition that causes the formation of cysts primarily in the kidneys. The continuous growth of multiple cysts leads to the destruction of functional parenchyma, which may progress to end-stage kidney disease. Tolvaptan is the only drug specifically approved for slowing down the progression of ADPKD. Sodium-glucose transporter 2 inhibitors might provide additional benefits but there is currently no information on safety and outcome effects of SGLT2i in patients with ADPKD, as these patients were excluded in SGLT2i trials. In particular, there has been speculation that SGLT2i might increase cyst growth and accelerate the loss of kidney function in ADPKD. The EMPA-PKD trial is assessing the safety of empagliflozin in patients with rapid progressive ADPKD with and without concomitant tolvaptan use by monitoring the total kidney volume and the loss of kidney function.
Methods and analysis This is an investigator-initiated, double-blind, single-centre, placebo-controlled, randomised clinical trial including patients with rapidly progressive ADPKD (n=44). Participants will be randomly allocated (1:1) to receive a daily dose of either empagliflozin (10 mg/day) or placebo for 18 months. Patients will be stratified according to concomitant tolvaptan use. The primary endpoint is the progression of cystic kidney growth by monitoring MRI-based changes in total kidney volume and the secondary endpoint is the change in glomerular filtration rate. Additional endpoints include changes in copeptin levels, albuminuria and blood pressure.
Ethics and dissemination The protocol has been approved by the German Federal Institute for Drugs and Medical Devices (BfArM) after review by the independent ethics committee Landesarztekammer Rheinland-Pfalz. Participation in this study will be voluntary and informed consent will be obtained. Regardless of the outcome, the results will be disseminated through a peer-reviewed international medical journal.
Trial registration numbers EU-CT number 2023-505890-34-00, NCT06391450.
- NEPHROLOGY
- Nephrology
- Adult nephrology
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This randomised controlled trial will evaluate the safety of empagliflozin in patients with rapid progressive autosomal dominant polycystic kidney disease.
This study will include patients with and without concomitant tolvaptan use.
The primary endpoint will be the change in total kidney volume as measured by MRI.
The limited number of patients will be insufficient to ultimately address questions of therapeutic efficacy.
Introduction
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder, which results in the formation of fluid-filled cysts primarily in the kidneys, leading to progressive organ enlargement, distortion of renal architecture, vascular rarefaction and progressive loss of kidney function. ADPKD is the most common inherited kidney disease affecting >10 million people worldwide.1 ADPKD often results in end-stage kidney disease with approximately 8%–10% of all dialysis or transplant patients in the USA and Europe being ADPKD patients. The disease is most commonly caused by mutations in the PKD1 and PKD2 genes, which encode the proteins polycystin-1 and polycystin-2, respectively.1 2 So far, the only approved drug for rapid-progressive ADPKD is the vasopressin receptor 2 antagonist tolvaptan, which diminishes the activation of adenylate cyclase. In the case of ADPKD patients, this does not only inhibit the vasopressin effect on water reabsorption through aquaporin-2, but also on cystic cell proliferation and fluid secretion into cysts. The loss of estimated glomerular filtration rate (eGFR) is significantly slower in ADPKD patients with rapid progressive disease treated with tolvaptan.3 4 However, disease progression is not stopped and the need for renal replacement therapy can only be postponed.
Sodium-glucose transporter 2 inhibitors, originally developed as antidiabetic drugs, represent an important new class of drugs in renal and cardiovascular medicine. They work as antidiabetic drugs because they reduce the reabsorption of glucose in the proximal tubule, which leads to glucosuria and lowers blood sugar levels. SGLT2is also cause increased sodium and chloride delivery to the macula densa, thereby inducing afferent arteriolar constriction and a subsequent reduction in intraglomerular capillary pressure. SGLT2i was shown to improve cardiovascular, metabolic and renal outcomes in patients with diabetes.5–7 Significant improvements in the progression of chronic kidney disease (CKD) were subsequently also found in non-diabetic patients in the landmark DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) and EMPA-KIDNEY (Study of Heart and Kidney Protection with Empagliflozin) trials including a great variety of renal diseases, such as IgA nephropathy, ischaemic and hypertensive kidney disease.8 9 Both trials were terminated early due to supreme efficacy of the study drugs dapagliflozin and empagliflozin in slowing down CKD progression.
Importantly, ADPKD was an exclusion criterion for DAPA-CKD and EMPA-KIDNEY, and it is still unclear, whether the documented clinical benefits are also applicable to patients with ADPKD. In fact, there is only controversial experimental data from rodent models10–12 and a limited number of retrospective case reports on the potential impact of SGLT2i in ADPKD patients.13–15 In two comprehensive overviews, Patel and Dahl and Afsar et al summarised the current knowledge.16 17 The authors raised two major concerns: (1) By causing glycosuria, natriuresis and glucose-driven osmotic diuresis, SGLT2i might stimulate vasopressin release,18 which is known to stimulate cyst growth. (2) Similarly, concomitant treatment of SGLT2i with tolvaptan might result in volume depletion with subsequent stimulation of vasopressin release and deterioration of ADPKD. Two independent single-centre reports from Japan suggested accelerated kidney growth after starting dapagliflozin in ADPKD patients.14 15 The effect was similar between patients with or without concomitant tolvaptan use. On the other hand, SGLT2i might have beneficial effects and alleviate adverse mechanisms in ADPKD. In particular, glomerular hyperfiltration is thought to play a negative role in ADPKD progression19 and could be targetable by SGLT2i through activation of the tubuloglomerular feedback. Furthermore, it seems possible that SGLT2i-dependent changes in tubular glucose uptake might positively affect the metabolism of cyst lining epithelial cells and their dependence on aerobic glycolysis.20 SGLT2i treatment is associated with a modest but consistent increase in circulating levels of ketones, which could conceivably mediate renoprotective effects in ADPKD.21
The few existing animal experiments in PKD models are difficult to interpret and cannot be easily extrapolated to the clinical situation, as they showed conflicting results either protecting or aggravating cyst growth depending on the model. While Rodriguez et al found that dapagliflozin treatment in Han:SPRD rats with polycystic kidney disease was associated with improved renal function and decreased albuminuria, they observed no effect on cyst growth in Cy/+ rats.11 Subsequently, the same group reported that dapagliflozin caused osmotic diuresis, hyperfiltration, albuminuria and an increase in cyst volume in PCK rats.10
Drug approval of SGLT2i for the treatment of CKD differs between the USA and the European Union. In contrast to the European approval, the US Food and Drug Administration does not recommend the use of dapagliflozin or empagliflozin in ADPKD patients stating that potential benefits and risks are unknown.22 23 In contrast, the European Commission approval contains no such ADPKD-related restrictions but authorises dapagliflozin and empagliflozin for all patients with CKD. This discrepancy adds to the uncertainty as to whether SGLT2i should be prescribed to ADPKD patients or not.
SGLT2is are currently authorised for the treatment of diabetes mellitus type 2, CKD and treatment of heart failure (HF). Seminal trials have demonstrated that the use of SGLT2i reduces the risk of HF hospitalisation and cardiovascular death in patients with reduced or preserved ejection fraction.7 24–26 Consequently, SGLT2is have become a class I recommendation in current HF guidelines. Given the strongly increased incidence of cardiovascular disease in ADPKD patients,27 SGTL2i could play a critical role in this patient group. Extrarenal metabolic and cardiovascular benefits of SGLT2i have thus to be weighed against potential renal effects in ADPKD patients.
In accordance with recommendations of the KDIGO (Kidney Disease: Improving Global Outcomes) 2024 clinical practice guideline for the evaluation and management of CKD,28 there is a clear need to find out whether SGLT2i improve or worsen CKD progression in ADPKD patients. The EMPA-PKD trial is the first step to fill this knowledge gap. The EMPA-PKD study will assess the safety of SGLT2i treatment in ADPKD patients. According to the above experimental data, there is concern that SGLT2i could lead to increased cyst growth. Therefore, the study will focus on the question, whether there is a faster growth of ADPKD kidneys under SGLT2i treatment and will compare total kidney volume (TKV) before and after an 18-month study period. The results of the trial will serve as a basis for larger-scale efficacy trials.
Methods and analysis
Trial design
The EMPA-PKD study is an investigator-initiated, double-blind, single-centre placebo-controlled, randomised clinical trial comparing 18 months of treatment with empagliflozin versus placebo in patients with rapid progressive ADPKD. Patients will be randomised 1:1 to either 10 mg empagliflozin or placebo taken once daily per os. Randomisation will be stratified by concomitant tolvaptan use. The primary endpoint is the relative change of TKV and the secondary endpoint is the change of eGFR during the 18 months study period. Additional exploratory endpoints include any adverse events, changes in plasma concentration of copeptin, albuminuria and blood pressure.
Patient characteristics
The study population will consist of ADPKD patients recruited at the specialised outpatient clinic of Hannover Medical School with signs of rapid progression as judged by Mayo classification (Mayo class 1 C, D, E) and kidney function (age-related eGFR as evaluated according to table 1). About 120 potential participants fulfilling these criteria were identified in the Hannover Medical School outpatient cohort. This number of eligible patients allows for successful recruitment despite the single-centre setting. Adequate participant enrolment to reach the target sample size is ensured through direct recruitment of patients with regular outpatient visits in the ADPKD clinic.
Inclusion and exclusion criteria of the trial
Inclusion and exclusion criteria
A total of 44 patients aged over 18 years who fulfil the inclusion criteria (table 1) will be included. ADPKD has to be diagnosed by unified criteria (combination of family history, ultrasound, MRI/CT) and screening eGFR needs to be ≥25 and ≤90 mL/min/1.73m2 or ≤65 mL/min/1.73m2 if >50 years of age. Mayo class 1 C, D, E will be used as a likely indicator of rapid progression that needs to be fulfilled. Patients with tolvaptan will be eligible for inclusion if tolvaptan has been taken for ≥3 months at study entry. The exclusion criteria include a history of kidney or any other solid organ transplants; patients currently receiving empagliflozin or other SGLT2i; concomitant treatment with systemic steroids or any other systemic immunosuppressive agent; hypersensitivity to the active principle (empagliflozin) or any of the excipients (eg, lactose); ketoacidosis (laboratory based) in the past 5 years; type 1 diabetes mellitus; ongoing urinary tract or genital infection (table 1).
Study blinding and randomisation
All patients, investigators, site personnel and other involved entities with direct involvement in the study will be blinded to the treatment arm throughout the trial. Tablets and packages containing active IMP (investigational medicinal product) or matching placebo will be indistinguishable from each other in terms of taste, appearance, durability, packaging, labelling and instructions for use. A blind review meeting will take place before unblinding the data. Patients will be randomised 1:1 to empagliflozin or placebo. Randomisation will be stratified by concomitant tolvaptan use (yes or no). An equal number of patients (n=22) for each stratum is intended to be randomised. Within each strata, a block randomisation with variable block length is implemented. A fixed seed in combination with a random number generator is applied to generate the randomisation list that is used for blinded allocation of the patients (ie, only medication numbers that do not include the allocated treatment will be provided).
Study intervention and study assessments
Participants will be randomised 1:1 to either empagliflozin 10 mg or placebo taken once daily per os. The dose rationale follows the approved dose for the treatment of patients with CKD. Following randomisation on day 1, participants will be contacted at week 2 via telephone to capture any adverse events and will then follow scheduled visits at weeks 4, 12, 26, 38, 52, 64 and 78. At visits, physical exams will be performed and demographic information, anthropomorphic measurements, adverse events and pathology tests (blood and urine) will be recorded. A last additional visit will take place at week 80, which is 14 days after stopping the study medication, to assess kidney function (blood and urine). Evidence from several large trials has shown that TKV may be used as an appropriate surrogate marker for ADPKD disease progression.29 The EMPA-PKD trial investigated longitudinal changes in TKV as the primary endpoint. Changes in eGFR will be recorded as a secondary endpoint. The study is neither powered, nor designed to provide pivotal evidence about potential treatment benefits. Safety signals concerning changes in TKV growth provided in this trial will be important as a basis for future larger multicentre trials to study the definitive efficacy of SGLT2i in slowing disease progression in ADPKD.
TKV will be measured based on MRI at baseline and week 78 (end of treatment) using an ellipsoid equation (π/6×L×W×D).30 MRI will be performed in headfirst supine position at a 1.5T machine (Magnetom Avanto, Siemens Healthcare, Erlangen, Germany). Coronal T2-weighted fat-saturated images will be acquired using a turbo spin echo sequence after intravenous administration of 20–40 mg scopolamine butylbromide to reduce bowel movement.
Biochemical analysis
Blood collections will be performed at baseline and every study visits to measure serum creatinine, urea, potassium, sodium, chloride, phosphorous, uric acid, lactate dehydrogenase (LDH), alanin aminotransferase (ALAT), aspartat-aminotransferase (ASAT), glycosylated hemoglobin (HbA1c), copeptin, haematocrit, haemoglobin, red blood cells, MCV, MCH, MCHC, white blood cells and platelets. eGFR will be calculated based on the CKD-EPI formula.31 Spot urine samples will be collected to measure urine albumin-to-creatinine ratio (UACR), urine protein-to-creatinine ratio, U-osmolality and to perform urine pregnancy test for female participants with childbearing potential.
Primary endpoint
The primary endpoint is the log-transformed annualised relative change of TKV (%/year) from baseline to week 78 of treatment.
Secondary and exploratory endpoints
The secondary endpoint is the change in the eGFR from baseline eGFR to week 78 of treatment. eGFR will be assessed based on CKD-EPI formula.31 Further, exploratory endpoints include the change of the vasopressin-surrogate copeptin plasma concentration (change from baseline to weeks 26, 52 and 78 of treatment), change in albuminuria (baseline UACR to week 78 of treatment), change in blood pressure (baseline systolic and diastolic to week 78). eGFR and UACR will also be assessed at week 80 (off-treatment) to account for anticipated GFR-lowering effects during SGLT2i treatment.
Patient and public involvement
None.
Statistical analysis
The study will use the concept to demonstrate the non-inferiority of empagliflozin compared with placebo regarding an increase in TKV with the assumption of superiority of empagliflozin over placebo, which is in line with the approach outlined by Freidlin et al.32 The idea of Freidlin et al originates in rare disease oncology where formal superiority of an experimental product cannot be demonstrated due to the limited number of patients. Under the assumption that the experimental product is efficacious, the concept aims to show that a certain detriment or safety concern of the experimental product can be excluded, that is, is able to meet a suggested non-inferiority margin. Notably, with the corresponding sample size non-inferiority can only be demonstrated, if the positive effect of the experimental product is truly present as assumed. If non-inferiority can be shown and adverse effects can be excluded, then subsequently superiority of the experimental product can be tested at the same significance level 0.025 (the one-sided type I error will be controlled at the intended level). Since the primary aim of this approach is to exclude the detriment of an experimental product, this study is powered to show that kidney growth under empagliflozin is not substantially larger compared with tolvaptan. While then superiority over placebo most likely cannot be demonstrated, the advantage of this approach is that less patients are needed to demonstrate non-inferiority of empagliflozin. However, the study is not powered to demonstrate that empagliflozin is as efficacious as tolvaptan (or even better) and, thus, a larger trial is probably needed in case no safety concerns arise based on the results of this study.
The treatment effect of empagliflozin is assumed to be similar to tolvaptan. Thus, a non-inferiority margin of 2.79%/year, which is equal to the mean TKV slope difference between tolvaptan and placebo observed by Irazabal et al (assuming a true TKV improvement of −2.79%/year), will be used for the comparison between empagliflozin and placebo.30 If the upper boundary of the corresponding 95% CI is below the non-inferiority margin, non-inferiority of empagliflozin can be demonstrated. In the primary analysis, an ANCOVA (analysis of covariance) model will be used to compare the mean log-transformed annualised relative TKV change from baseline (TKV slope) at 18 months. The baseline TKV value as a covariate and tolvaptan use as stratification factor will be included as independent variables. Significance tests will be based on least-square means using a two-sided α=0.05 (two-sided 95% CI). The primary treatment comparison will be the contrast between empagliflozin and placebo in the annualised relative TKV change at 18 months. The primary analysis will be performed in the full analysis set population that includes all enrolled and randomised subjects. Sensitivity analysis will be performed in the per-protocol population. Missing values will be imputed by the mean of individual patient TKV slopes for the respective treatment group at 18 months. No interim analysis is planned and there will be no adjustment for multiplicity issues. The secondary endpoint change in eGFR from baseline to 18 months will be analysed using a linear mixed model for repeated measures.
Sample size calculation
Sample size calculation is based on the study of Irazabal et al where a difference in TKV slopes between placebo and tolvaptan (−2.79 (−2.20; −3.38)) was shown for Mayo class 1C, D, E patients.30 The same TKV slope difference is assumed for empagliflozin. When the sample size in each group is n=22 patients (n=44 overall), a two-group one-sided 0.025 significance level t-test will have 80% power to reject the null hypothesis that empagliflozin is inferior to placebo by more than 2.79%/year (the difference in TKV mean slopes, μempagliflozin−μplacebo, is 2.79 or farther from zero in the same direction) in favour of the alternative hypothesis that the decline in TKV mean slope with empagliflozin is non-inferior to placebo or even better. The assumed pooled SD is 6.32%/year and is derived from the upper limit of the treatment effect. The ANCOVA used in the primary analysis is assumed to increase power over a t-test.
Ethics and dissemination
Ethical considerations
The clinical trial has received approval from the Federal Institute for Drugs and Medical Devices (BfArM) based on an independent ethics committee Landesarztekammer Rheinland-Pfalz review (processing number B_01224; EU-CT-Number EMPA-PKD_2023-505890-34-00 protocol version number 3.0, dated 14 February 2024, approval on 5 March 2024). The study protocol follows the recommendations determined by the Declaration of Helsinki. For this study, all subjects will provide a signed informed consent form. Participation is on a voluntary basis and participants are allowed to withdraw at any time. Empagliflozin is approved in Germany for the treatment of patients with CKD, including ADPKD patients. The EMPA-PKD trial is thus an ‘in-label study’, for which we rate risks beyond the study objectives as minimal.
Dissemination
Regardless of the outcome, the results of the trial will be disseminated through presentations at scientific meetings and in suitable peer-reviewed medical journals. After completion of the study, participants will receive information on their personal and overall study results on request.
Ethics statements
Patient consent for publication
Acknowledgments
We thank our clinical research team at Hannover Medical School and the Boehringer-Ingelheim team for organisational support in the regulatory and logistic study setup.
References
Footnotes
EB-K and SH are joint first authors.
Contributors EB-K, JG, DH, JK, BMWS, KS-O and RS conceptualised the trial, designed the clinical study plan, wrote the trial protocol. SH and AK designed the statistical protocol. SK and VCW performed the planning for patient enrolment. All authors substantially contributed to critically reviewing and revising the manuscript. RS is responsible for the overall content as guarantor.
Funding This study is subsidised by an external collaborative research grant by Boehringer Ingelheim, Grant Number: Germany ECR_2022_00003209.
Disclaimer The funder provided input during the review process of the protocol but had no role in the overall study design and will have no role in collection, management, analysis, interpretation of data and writing of the report.
Competing interests RS has received honoraria from Fresenius Medical Care, AstraZeneca, Otsuka, Novartis, Baxter, Bayer. There are no competing interests for all other authors.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.