8-Week Study of Tolvaptan Dose Forms in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

A Phase 2, Multicenter, Randomized, Placebo-controlled, Double-blind, Placebo-masked, Parallel-group Pilot Trial to Compare the Efficacy, Tolerability, and Safety of Tolvaptan Modified-release and Immediate-release Formulations in Subjects With Autosomal Dominant Polycystic Kidney Disease

The purpose of this study is to compare the short-term effects of two tolvaptan formulations in patients with ADPKD.

Inclusion Criteria:

1. Age 18 to 50

2. Subjects with:

   • BMI between 19 and 35 kg/m2

   • diagnosis of ADPKD by modified Ravine criteria:

     • family history: 3cysts/kidney if by sonography or 5 by CT or MRI
     • Without family history: 10 cysts per kidney

   • an eGFR > 45 mL/min/1.73 m2 by the CKD-EPI equation

3. Subjects not planning to become pregnant willing to comply with birth control requirements.

4. Subjects must be in good health as determined by screening tests.

5. Subjects providing informed consent and able to comply with all trial requirements.

Exclusion Criteria:

1. Subjects using diuretics within 14 days prior to randomization, or the requirement for intermittent or constant diuretic use for any reason

2. Subjects who had an eGFR < 45 mL/min/1.73 m2 calculated based on the most recent historical creatinine during the last 12 months

3. Subjects with:

   • incontinence, overactive bladder, or urinary retention (eg, BPH), meaning subjects with symptoms of frequent nocturia, as determined by medical history or urinary urgency should be carefully evaluated to exclude non-ADPKD GU issues prior to entry.
   • liver disease, liver function abnormalities, or serology other than that expected for ADPKD with cystic liver disease at baseline
   • a history of renal surgery or cyst drainage within 6 months of randomization
   • blood pressure 150/95 mmHg or < 90/40 mmHg.
   • heart rate outside the range of 40 to 90 bpm.
   • advanced diabetes with a history of poor control, evidence of significant renal disease renal cancer, single kidney, or recent renal surgery
   • other significant medical history that may interfere with the study objectives
   • significant abnormalities in serum sodium concentration (< 135 or > 145 mEq/L)
   • a history of drug and/or alcohol abuse within 2 years prior to screening
   • clinically significant allergic reactions to tolvaptan or chemically related structures such as benzazepines (eg, benzazepril, conivaptan, fenoldopam mesylate, or mirtazapine)

4. Subjects having taken an investigational drug within 30 days preceding randomization on Day 0

5. Subjects taking medications or having concomitant illnesses likely to confound endpoint assessments, including taking approved (ie, marketed) therapies for the purpose of affecting PKD cysts such as tolvaptan, somatostatin agonists (ie, octreotide, sandostatin), Rapamune (sirolimus), anti-sense RNA therapies, other vasopressin antagonists (eg, OPC-31260 [mozavaptan] and Vaprisol® [conivaptan]) or agonists (eg, desmopressin), and cyst reduction surgery

6. Subjects on antihypertensives that have not been on the same antihypertensive regimen for at least 30 days prior to the first dose of IMP

7. Subjects having contraindications to, or interference with, MRI assessments

8. Subjects with a history of serious mental disorders that, in the opinion of the investigator, would exclude the subject from participating in this trial

9. Subjects with previous exposure to tolvaptan