Table 1.

Overview of landmark clinical trials that investigated disease-modifying drugs in autosomal dominant polycystic kidney disease (ADPKD)

Agent	Trial design	Main inclusion criteria	No. of patients	Follow-up duration	Status	Main potential adverse events	Main results
Vaptans
Tolvaptan	TEMPO 3:4 [25] Phase 3, double-blind placebo-controlled	Age 18–50 years, CrCL ≥ 60 mL/min and TKV ≥ 750 mL	1445	36 months	Published	Aquaresis and hepatotoxicity	Reduction of TKV growth (2.8% per year for tolvaptan vs 5.5 for placebo) and eGFR decline (−2.72 mL/min/1.73m2 per year for tolvaptan vs −3.70 for placebo) over the 3 year study period
	REPRISE [26] Phase 3, double-blind placebo-controlled	Age 18 - 65 years, eGFR 25 - 65 mL/min/1.73m2 (eGFR 25–44 mL/min/1.73m2 and progressive disease for patients aged 56–65 years)	1370	12 months	Published		Reduction of eGFR decline (−2.34 mL/min/1.73m2 per year for tolvaptan vs -3.61 for placebo), but no effect on eGFR decline in patients aged > 55 years
Somatostatin analogues
Octreotide LAR	ALADIN 1 [30] Phase 3, single-blind placebo-controlled	Age > 18 years, eGFR ≥ 40 mL/min/1.73m2	79	36 months	Published	Cholelithiasis, acute cholecystitis and gastrointestinal side effects	Significant reduction of TKV growth after 1 year, but not after 3 years. Slower GFR decline from year 1 to 3 in the octreotide group vs placebo (-2.28 mL/min/1.73m2 per year vs -4.32, respectively). No significant differences in GFR decline over the 3 year study period
	ALADIN 2 [31] Phase 3, double-blind placebo-controlled	Age > 18 years, eGFR 15 − 40 mL/min/1.73m2	100	36 months	Published		Reduction of TKV growth after 1 and 3 years, but no significant differences in GFR decline between groups. Less frequent progression to a composite endpoint of doubling of serum creatinine or ESKD in the octreotide LAR group vs placebo (17.6% vs 42.9, respectively)
Lanreotide	DIPAK 1 [22] Phase 3, open label	Age 18 - 60 years, eGFR 30–60 mL/min/1.73m2	309	30 months	Published	Hepatic cyst infection, cholelithiasis and related problems, and gastrointestinal side effects	Reduction of TKV growth (4.15% per year for lanreotide vs 5.56 for placebo), but no significant effect on eGFR decline (−3.53 ml/min/1.73m2 per year vs −3.46 for lanreotide and placebo, respectively)
mTOR inhibitors
Everolimus	Phase 3, double-blind, placebo-controlled [29]	eGFR > 30 mL/min/1.73m2 and TKV > 1000 mL	433	24 months	Published	Mucositis, diarrhea, acne, increased proteinuria and reduced hematopoiesis. Angioedema when combined with ACE-inhibitors	Reduction of TKV growth after 1 year (102 mL vs 157 for everolimus and placebo, respectively). Trend towards reduction of TKV growth after 2 years (230 mL for everolimus vs 301 for placebo, p=0.06). No significant differences in eGFR decline between groups
Sirolimus	Phase 3, open label [28]	Age 18–40 years, eGFR ≥ 70 mL/min/1.73m2	100	18 months	Published	Mucositis, diarrhea, acne and peripheral edema	No significant effects on TKV growth (7.8% per year for sirolimus vs 6.8 for placebo). No differences in eGFR decline between groups. Higher urinary excretion rates in the sirolimus group compared to placebo

CrCL creatinine clearance, eGFR estimated glomerular filtration rate, LAR long-acting repeatable, mTOR mammalian target of rapamycin, TKV total kidney volume