Polycystic Kidney, Autosomal Dominant
Conditions
Keywords
STOP-PKD, ADPKD, Dapagliflozin, SGLT2, PKD, polycystic kidney disease, SGLT2i, sodium-glucose, sodium glucose, Phase 3
Brief summary
Autosomal dominant polycystic kidney disease is the most common genetic cause of kidney failure. The only approved treatment for ADPKD - tolvaptan - is limited in its use by massive therapy-associated polyuria. This trial tests if the SGLT2-inhibitor dapagliflozin slows down the loss of kidney function in ADPKD.
Detailed description
ADPKD is a genetic disease characterized by the growth of fluid-filled renal cysts, leading to progressive loss of kidney function. SGLT2- inhibitors have recently become available for the treatment of chronic kidney disease (CKD). The landmark trials, which proved the positive effect of SGLT2-inhibitors in CKD, excluded patients with ADPKD. Accordingly, current ADPKD-guidelines do not recommend the use of SGLT2-inhibitors in ADPKD. This investigator-driven, randomized, placebo-controlled, multi-center, double-blind trial will assess the effect of daily dapagliflozin (10mg) intake on the chronic eGFR-slope in 420 patients with ADPKD. As a secondary endpoint the study will assess a composite endpoint triggered by reaching either 40%-eGFR loss, kidney failure or renal death. Safety aspects will additionally be addressed by an interim safety analysis considering total kidney volume, eGFR and copeptin-levels.
Interventions
DRUGDapagliflozin 10 mg
Participants receive 10 mg of Dapagliflozin orally once daily for 36 months.
DRUGMatching Placebo
Participants receive a matching placebo orally once daily for 36 months.
Sponsors
University of Cologne
German Research Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Phase III, investigator-driven, multi-center, randomized, placebo-controlled, double-blind
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients with ADPKD (modified Ravine criteria) ≥ 18 and ≤ 60 years * Patients 18 - 39 years: eGFR ≥25 ml/min; patients 40 - 60 years: eGFR ≥25 and \<90 ml/min/1.73 m2 * Indicators of rapid progression, either of the following: * Mayo class 1D-E * Mayo class 1C AND EITHER 1. Truncating PKD1 mutation OR 2. eGFR loss \> 3ml/min/year (determined by ≥ 4 creatinine values within 4 years, ≥ 6 months measurement intervals) OR 3. PROPKD score \> 6 (patient history) * IF patient is on ACE-I /ARBs: stable dose for 4 weeks before screening
Exclusion criteria
* Treatment with tolvaptan, somatostatin analogue, lithium or SGLT2i within the last 3 months before screening * Medical history of diabetic ketoacidosis, necrotizing fasciitis or organ transplantation * Diabetes mellitus type 1 or any type of diabetes mellitus due to insulin deficiency * Uncontrolled ongoing urinary tract or genital infections * Known intolerance of the study medication ingredients * Uncontrolled grade 2 hypertension (\>160/100 mmHg) * Symptomatic hypotension, or systolic blood pressure \<90 mmHg * Primary renal disease other than ADPKD * Hepatic impairment (aspartate transaminase \[AST\] or alanine transaminase \[ALT\]\>3x the up-per limit of normal \[ULN\]; or total bilirubin \>2x ULN at time of enrolment) * Pregnancy, breastfeeding or women of child-bearing potential not using effective contraception method * Not able to comply with the study protocol, in the investigator's judgement * Not able to provide informed consent * Participation in any other interventional clinical trial in the last 2 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Chronic eGFR slope | week 6 up to week 156 (end of treatment) | The annual chronic eGFR slope will be calculated using all available serum creatinine values from week 6 to week 156 (end of treatment), using linear mixed models. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in eGFR from pre-treatment to post-treatment (off-treatment values) | Week -4 to Week 168 | Change in kidney function will be assessed by comparing the mean eGFR values before treatment (calculated as the average of serum creatinine measurements at week -4 and week 0) with the mean eGFR values after treatment (calculated as the average of measurements at week 162 and week 168). The difference between these two timepoints represents the off-treatment change in kidney function. |
| Time to first occurrence of a composite renal endpoint | From randomization (week 0) until end of follow-up (up to week 168) | Time from randomization to the first occurrence of any of the following events: 1. A sustained ≥40% decrease in eGFR from randomization, confirmed by a second measurement at the next scheduled visit or measured at the last scheduled visit before death or study end. 2. End-stage kidney disease (ESKD), defined as initiation of chronic dialysis, kidney transplantation, or a sustained eGFR \<15 mL/min/1.73 m². 3. Renal death. |
| Incidence of serious adverse events (SAEs) | From randomization (week 0) until end of follow-up (week 168) | All serious adverse events (SAEs) will be collected. |
| Incidence of adverse events of special interest (AESIs) | From randomization (week 0) until end of follow-up (week 168) | All adverse events of special interest (AESIs) will be collected. |
| Change in total kidney volume (TKV) after 1 year | Baseline (week -4 until week 0) to week 48 (first 150 patients) | In the first 150 enrolled participants, total kidney volume (TKV) will be measured at baseline and at week 48 using standardized MRI protocols. The change in TKV over 48 weeks will be used to assess potential effects of dapagliflozin on kidney size. |
Countries
Austria, Germany, Netherlands, Spain
Contacts
CONTACTRoman-Ulrich Müller, Prof.
CONTACTPhilipp Scherrer, MD
Outcome results
None listed