Dose-finding Study of New Tolvaptan Formulation in Subjects With ADPKD
Condition: Autosomal Dominant Polycystic Kidney Disease
MeSH terms: Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant
Intervention: Tolvaptan MR; Tolvaptan MR; Tolvaptan MR; Tolvaptan IR; Tolvaptan MR
Intervention description: 20 mg Tolvaptan MR capsule(morning); Placebo capsules/tablets (morning and afternoon) for 7 days; 20 mg Tolvaptan MR capsule(morning and afternoon); Placebo capsules/tablets (morning and afternoon) for 7 days; 60 mg Tolvaptan MR capsule(morning); Placebo capsules/tablets (morning and afternoon) for 7 days; 90 mg Tolvaptan IR tablet(morning); 30 mg Tolvaptan IR tablet (afternoon); Placebo capsules (morning and afternoon) for 7 days; 120 mg Tolvaptan MR capsule(morning); Placebo capsules/tablets (morning and afternoon) for 7 days
Intervention MeSH terms: Tolvaptan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: No
Keywords: Kidney Disease; Polycystic Kidney Disease

Summary:

      To establish pharmacokinetics (PK), pharmacodynamics (PD), and adverse event (AE) profile of
      tolvaptan administered as the modified-release (MR) formulation in ADPKD subjects. The goals
      of this trial are two-fold:

        1. To directly compare the immediate release (IR) and MR formulations

        2. To determine the dose range and dose regimen for MR (dose finding)
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects (male or female) who are surgically sterile (ie, have undergone hysterectomy)
             or using contraception or agree to remain abstinent

          -  Subjects between the ages of 18 and 50, inclusive

          -  Subjects with a body mass index between 19 to 35 kg/m2 (inclusive)

          -  Subjects with a diagnosis of ADPKD by modified Ravine criteria

          -  Subjects must be in good health as determined by medical history, physical
             examination, ECG, serum/urine biochemistry, hematology, and serology tests

          -  Subjects with the ability to provide written, informed consent prior to initiation of
             any trial-related procedures, and ability, in the opinion of the principle
             investigator, to comply with all requirements of the trial

          -  Subjects who expect to be able to complete all dosing periods and assessments within
             42 (+2) days after dosing on Day 1

        Exclusion Criteria:

          -  Subjects using diuretics within 14 days prior to check in on Day -1

          -  Subjects with incontinence, overactive bladder, or urinary retention (eg, benign
             prostatic hyperplasia)

          -  Subjects (male or female) with nocturia/urgency (outside of the 2 to 4 times awakening
             per night expected for ADPKD patients) at screening

          -  Subjects with liver disease, liver function abnormalities or serology other than that
             expected for ADPKD with cystic liver disease at baseline

          -  Subjects with clinically significant abnormality in past medical history, or at the
             Screening physical examination, that in the investigator's or sponsor's opinion may
             place the volunteer at risk or interfere with outcome variables including absorption,
             distribution, metabolism, and excretion of drug. This includes, but is not limited to,
             history of or concurrent cardiac, hepatic, renal, neurologic, endocrine,
             gastrointestinal, respiratory, hematologic, and immunologic disease

          -  Subjects with a history of drug and/or alcohol abuse within 2 years prior to screening

          -  Subjects who have a history of or test positive at screening for hepatitis B surface
             antigen (HBsAg), hepatitis C antibodies (anti-HCV), and/or human immunodeficiency
             virus (HIV)

          -  Subjects who have clinically significant allergic reactions to tolvaptan or chemically
             related structures such as benzazepines (eg, benzazepril, conivaptan, fenoldopam
             mesylate or mirtazapine)

          -  Subjects who have taken an investigational drug within 30 days preceding trial entry

          -  Subjects with any history of significant bleeding or hemorrhagic tendencies

          -  Subjects with a history of difficulty in donating blood

          -  Subjects who have donated blood or plasma within 30 days prior to dosing

          -  Subjects who have consumed alcohol and/or food or beverages containing
             methylxanthines, grapefruit, grapefruit juice, Seville oranges, or Seville orange
             juice within 72 hours prior to Day 1 dosing

          -  Subjects taking CYP3A4 inhibitors, with the exception of amiodarone, taken within 30
             days of dosing (eg, amprenavir, atorvastatin, aprepitant, chloramphenicol [not eye
             drops], cimetidine, clarithromycin, clotrimazole [if used orally], danazol,
             delavirdine, diltiazem, erythromycin, fluconazole, fluvoxamine, indinavir, isoniazid,
             itraconazole, josamycin, ketoconazole, nelfinavir, nefazadone,
             quinupristin/dalfopristin, ritonavir, saquinavir, troleandomycin, verapamil)

          -  Subjects taking CYP3A4 inducers taken within 7 days of dosing (eg, rifampin, St. Johns
             Wort)

          -  Subjects with a history of serious mental disorders

          -  Subjects with previous exposure to tolvaptan