Table 1 Eligibility criteria for subjects in Study 204 and Study 307

Inclusion criteria

 Clinical diagnosis of ARPKD

Age range: from 28 days to < 12 weeks

Age range: from 28 days to < 18 years

Subjects must have all the following:

• Nephromegaly, and

• Detection of multiple kidney cysts or increased kidney echogenicity suggesting microcysts, and

• History of oligohydramnios or anhydramnios

 Ability of parent/legal guardian to provide written, informed consent prior to initiation of any trial-related procedures, and ability, in the opinion of the principal investigator, to comply with all the requirements of the trial

Ability to provide written informed assent from all subjects old enough per local laws to provide assent

Exclusion criteria

 Premature birth (≤ 32 weeks gestational age) for infants 28 days to < 12 weeks of age

Females who are breast-feeding or who have a positive pregnancy test result prior to receiving tolvaptan

 Anuria or KRT defined as intermittent or continuous hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration or history of kidney transplantation

Subjects with a history of substance abuse within the last 6 months (depending on age)

 Evidence of syndromic conditions associated with kidney cysts (other than ARPKD)

Subjects with a history of persistent noncompliance with antihypertensive or other important medical therapy

 Abnormal liver function tests including ALT and AST, > 1.2 × ULN

Subjects who do not agree to remain abstinent or assent to use a combination of 2 of the following highly effective birth control methods for at least 28 days before the first dose of tolvaptan, during the trial (including during tolvaptan dose interruptions), and for at least 30 days after the last dose of tolvaptan:

• Barrier method of contraception: condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide

• Intrauterine device

• Hormone-based contraceptives which are associated with inhibition of ovulation

 Has splenomegaly or portal hypertension

 Parents with kidney cystic disease

 Receiving chronic diuretic that could not be adjusted after tolvaptan initiation

 Cannot be monitored for fluid balance

 Has or at risk of having sodium and potassium electrolyte imbalances, as determined by the investigator

 Has or at risk of having significant hypovolemia (e,g., subjects that lack free access to water, without adequate fluid monitoring and management) as determined by investigator

 Clinically significant anemia, as determined by investigator

 Platelets < 50,000 µL

 Severe systolic dysfunction defined as ejection fraction < 14%

 Serum sodium levels < 130 mmol/L or > 145 mmol/L (or the ULN of the local laboratory, whichever is lower)

 Taking any other experimental medications

 Require ventilator support

 Taking medications known to induce CYP3A4

 Having an active infection including viral that would require therapy disruptive to tolvaptan dosing

 Subjects who have bladder dysfunction and/or difficulty voiding

 Subjects taking a vasopressin agonist (e.g., desmopressin)

 Subjects having concomitant illnesses or taking medications likely to confound endpoint assessments, including taking approved (i.e., marketed) therapies for the purpose of affecting PKD cysts such as tolvaptan, vasopressin antagonists, anti-sense RNA therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs (i.e., octreotide, sandostatin)

 Received or are scheduled to receive a liver transplant

 History of cholangitis

 Has findings consistent with clinically significant portal hypertension (e.g., varices, variceal bleeding, hypersplenism indicated by thrombocytopenia)