Table 2.

Overview of the most important ongoing or recently completed clinical trials investigating disease-modifying drugs in ADPKD

Agent	Trial design	Main inclusion criteria	No. of patients	Follow-up duration (mo)	Status	Main potential adverse events	Primary outcome/main results
Vaptans
Lixivaptan	ALERT [63] Phase 3, open label	Age 18–65 years, eGFR ≥ 20 mL/min/1.73 m2, contra-indication to treatment with tolvaptan due to hepatocellular toxicity	50	16.8	Active, recruiting	Aquaresis	Hepatic safety (indicated by serum ALT levels)
	ACTION [62] Phase 3, double-blind placebo-controlled, followed by 1 year open label phase	Age 18–60 years, eGFR 25–90 mL/min/1.73m2, Mayo class 1C, 1D or 1E	1200	24	Active, recruiting		Annualized change in eGFR during the first study year (placebo-controlled phase)
Somatostatin analogues
Lanreotide	LIPS [33] Phase 3, double-blind, placebo-controlled	Age > 18 years, mGFR 30 − 89 mL/min/1.73m2	159	36	Completed, unpublished	Hepatic cyst infection, cholelithiasis and related problems, and gastrointestinal side effects	Changes in measured GFR
Octreotide LAR plus tolvaptan vs tolvaptan	TOOL [170] Phase 2, double-blind, placebo-controlled	Age > 18 years, mGFR > 80 mL/min/1.73m2 and stable renal function, TKV 1000–2000 mL	20	4	Active, not recruiting	Cholelithiasis, acute cholecystitis and gastrointestinal side effects	Changes in measured GFR
GCS inhibitors
Venglustat	STAGED-PKD [23] Phase 2-3, double-blind placebo-controlled	Age 18–55 years, eGFR > 30 mL/min/1.73m2 and < 90 mL/min/1.73m2, Mayo class 1C, 1D or 1E	478	26	Terminated, unpublished	Gastrointestinal side effects, possibly also ocular lens degeneration and depression	Terminated for futility based on interim analyses. Primary outcomes were changes in TKV, the results are not yet available
AL01211	Phase 1, double-blind placebo-controlled [67]	Age 18–55 years, eGFR 30–89 mL/min/1.73m2 for ADPKD patients	98 subjects (18 ADPKD patients)	3	Active, recruiting	Unknown	Safety and tolerability (based on incidence of (serious) adverse events)
Nrf2 activators
Bardoxolone	FALCON [82] Phase 3, double-blind placebo-controlled	Age 18–70 years, eGFR 30–90 or 30–44 mL/min/1.73m2 depending on age. Patients with eGFR ≥ 60 mL/min/1.73m2 or age ≥ 56 years must have progressive disease (eGFR decline of ≥ 2.0 mL/min/1.73m2 per year). No evidence of cardiac disease	550	24	Active, recruiting	Congestive heart failure and possibly tubuloglomerular damage secondary to glomerular hyperfiltration	Changes in eGFR between baseline and week 108 (off-treatment), and safety
CFTR modulators
GLPG2737	Phase 2, double-blind, placebo-controlled followed by 1 year open label phase [96]	Age 18–50 years, eGFR 30–90 or 30–60 mL/min/1.73m2 depending on age, TKV >750 mL and Mayo class 1C, 1D or 1E	66	24	Active, not recruiting	Possibly nasopharyngitis, headache, pulmonary and gastrointestinal side effects	Changes in htTKV and safety
Biguanide analogues
Metformin	Phase 2, double-blind, placebo-controlled [45]	Age 30–60 years, eGFR 50–80 mL/min/1.73m2, non-diabetic	51	12	Published	Gastrointestinal side effects, vitamin B12 deficiency and lactic acidosis	82% of patients tolerated a metformin dose of ≥ 1000 mg/day. No significant differences in changes of htTKV or eGFR between metformin and placebo groups (exploratory outcomes)
	TAME [110] Phase 2, double-blind, placebo-controlled	Age 18–60 years, eGFR > 50 mL/min/1.73m2, non-diabetic	97	26	Published		67% of metformin treated patients tolerated the target dose of 2000mg/day. No significant differences in changes of htTKV or eGFR between metformin and placebo groups (exploratory outcomes)
Metformin extended release	IMPEDE-PKD [111] Phase 3, double-blind, placebo-controlled	Age 18–70 years, eGFR 45–90 mL/min/1.73m2 and (risk of) rapidly progressive disease (based on volumetric criteria, PROPKD score or eGFR decline), non-diabetic	1164	24	Active, not yet recruiting		Changes in eGFR
miRNA inhibitors
RGLS4326	Phase 1, open label [123]	Age 18–70 years, eGFR 30–90 mL/min/1.73m2, Mayo class 1C, 1D or 1E	19	2.3	Completed, unpublished	Unknown	Changes in polycystin 1 and -2 levels in urinary exosomes
Other agents
Pravastatin	Phase 4, double-blind, placebo-controlled [148]	Age 25–60 years, eGFR ≥ 60 mL/min/1.73m2, TKV > 500 mL	200	24	Active, recruiting	Muscle pain, headache, gastrointestinal side effects	Changes in TKV
	Phase 3, double-blind, placebo-controlled [171]	Age 8–22 years, eGFR ≥ 80 mL/min/1.73m2	110	36	Completed, published		Reduced increase of several proinflammatory and oxidative stress markers in pravastatin treated patients compared to placebo
Pravastatin plus sodium citrate	ADPKD-SAT [149] Phase 2, open label	Age > 18 years, eGFR ≥ 30 mL/min/1.73m2 and evidence of metabolic acidosis	30	12	Active, recruiting		Changes in kidney function, liver function, blood pressure and incidence of muscle tenderness/rhabdomyolysis
Pioglitazone	PIOPKD [151] Phase 1b, double-blind, placebo-controlled	Age 18–55 years, eGFR ≥ 50 mL/min/1.73m2 and (risk of) rapidly progressive disease (based on volumetric criteria), non-diabetic	18	24	Completed, published	Hypoglycemia	Low-dose pioglitazone appeared safe. No effect on TKV or eGFR
Tesevatinib	Phase 1-2, open label [172]	Age 18–62 years, eGFR ≥ 35 mL/min/1.73m2, htTKV ≥ 1000 mL	74	24	Completed, unpublished	QT-prolongation, diarrhea and acne	Safety, pharmacokinetics, maximum tolerated dose and changes in eGFR
	Phase 2, double-blind, placebo-controlled [152]	Age 18–60 years, eGFR 25–90 mL/min/1.73m2, htTKV ≥ 500 mL, ≥ 750 mL or ≥ 900 mL depending on age	80	24	Active, not recruiting		Changes in htTKV
Curcumin	Phase 4, double-blind, placebo-controlled [164]	Age 6–25 years, eGFR > 80 mL/min/1.73m2	68	12	Completed, published	Nausea and diarrhea (at high doses)	No differences between surrogate markers of vascular endothelial dysfunction and arterial stiffness in curcumin treated patients vs placebo. No significant differences in htTKV or eGFR (exploratory outcomes)

ADPKD autosomal dominant polycystic kidney disease, ALT alanine aminotransferase, eGFR estimated glomerular filtration rate, mo months, mGFR measured GFR, TKV total kidney volume, htTKV height-adjusted TKV