Dose-finding Study of New Tolvaptan Formulation in Subjects With ADPKD

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Brief Title

Dose-finding Study of New Tolvaptan Formulation in Subjects With ADPKD

Official Title

A Multi-center, Parallel-group, Randomized, Double-blind, Placebo-masked, Multiple Dose Trial of Modified-release (MR) and Immediate-release (IR) Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Brief 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)
    

Detailed Description

      Group 1 will have 12 subjects enrolled in a 3-period, randomized, crossover to compare
      multiple doses of a 90-30 mg split-dose of the tolvaptan IR formulation, a 120 mg once daily
      (QD) dose of the tolvaptan MR formulation, and, in an incomplete block randomization,
      multiple doses of either 20 mg QD, 60 mg QD, or 20 mg twice daily (BID) tolvaptan MR
      formulation. All dose regimens will be administered for 7 days. Placebo doses will be
      administered in order to mask QD vs BID treatments.

      Group 2 will have 12 subjects enrolled in a 3-period, randomized, crossover to compare
      multiple oral doses of the tolvaptan MR formulation administered for 7 days as 20 mg QD, 60
      mg QD, and 20 mg BID. Placebo capsules will be administered in order to mask QD vs BID
      treatments.

      Subjects will have in-clinic assessments on 12 days to obtain 24-hour PK and PD data.
      Subjects will visit the clinic from the afternoon of Day -1 through the morning of Day 1.
      They will return at the end of each dosing period for a similar inpatient period (ie, from
      the afternoon of Day 6 through the morning of Day 8, from the afternoon of Day 13 through the
      morning of Day 15, from the afternoon of Day 20 through the morning of Day 22). Except for
      the first dose of each period and the doses taken in the clinic on the last day of each
      regimen and the afternoon of Days 6, 13 and 20, all other doses will be taken by the subject
      as an outpatient.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7.

Secondary Outcome

 Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose.

Condition

Autosomal Dominant Polycystic Kidney Disease

Intervention

Tolvaptan MR

Study Arms / Comparison Groups

 20 mg MR
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

25

Start Date

October 2010

Completion Date

June 2011

Primary Completion Date

June 2011

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
      

Gender

All

Ages

18 Years - 50 Years

Accepts Healthy Volunteers

No

Contacts

Frank Czerwiec, M.D., Ph.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01210560

Organization ID

156-09-285


Responsible Party

Sponsor

Study Sponsor

Otsuka Pharmaceutical Development & Commercialization, Inc.


Study Sponsor

Frank Czerwiec, M.D., Ph.D., Study Director, Otsuka Pharmaceutical Development & Commercialization, Inc.


Verification Date

May 2018