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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier:
NCT01210560
First received: September 21, 2010
Last updated: February 20, 2012
Last verified: February 2012
  Purpose

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)

Condition Intervention Phase
Autosomal Dominant Polycystic Kidney Disease
Drug: Tolvaptan MR
Drug: Tolvaptan IR
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Primary Outcome Measures:
  • Pharmacokinetics [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Peak maximal concentration of drug, minimum concentration, concentration at 24 hours postdose, time to maximum (peak) plasma concentration, area under the concentration-time curve from time 0 to 24 hours postdose for tolvaptan. Depending on the data, some parameters may not be able to be determined.


Secondary Outcome Measures:
  • Urine Osmolality [ Time Frame: 23.5 hours post-dose ] [ Designated as safety issue: No ]
    Number of Sujects with urine osmolality < 300 mOsm/kg

  • Urine Osmolality AUC [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
  • Urine Volume [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
  • Urine Osmolality By Interval [ Time Frame: 0-4, 4-8, 8-12, 12-16, 16-24 hours ] [ Designated as safety issue: No ]
  • Urine volume by interval [ Time Frame: 0-4, 4-8, 8-12, 12-16, 16-24 hours ] [ Designated as safety issue: No ]
  • Urine Osmolality Suppression [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
    Duration Urine Osmolality remains below 300 mOsm/kg

  • Urine voids during awake periods [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Average number of daily urine voids during awake periods for each dose group

  • Urine voids during sleep periods [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Average number of daily urine voids during sleep periods for each dose group

  • Symptom burden by ADPKD Nocturia Quality of Life Questionnaire [ Time Frame: 6 days ] [ Designated as safety issue: No ]
  • Symptom burden by ADPKD Urgency Questionnaire [ Time Frame: 6 days ] [ Designated as safety issue: No ]
  • Symptom burden by ADPKD Frequency Questionnaire [ Time Frame: 6 days ] [ Designated as safety issue: No ]
  • Treatment ranking [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    Patient reported treatment ranking for tolerability


Enrollment: 25
Study Start Date: October 2010
Study Completion Date: June 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 20 mg MR Drug: Tolvaptan MR
20 mg Tolvaptan MR capsule(morning); Placebo capsules/tablets (morning and afternoon) for 7 days
Other Name: OPC-41061
Experimental: 40 mg MR Drug: Tolvaptan MR
20 mg Tolvaptan MR capsule(morning and afternoon); Placebo capsules/tablets (morning and afternoon) for 7 days
Other Name: OPC-41061
Experimental: 60 mg MR Drug: Tolvaptan MR
60 mg Tolvaptan MR capsule(morning); Placebo capsules/tablets (morning and afternoon) for 7 days
Other Name: OPC-41061
Experimental: 120 mg MR Drug: Tolvaptan MR
120 mg Tolvaptan MR capsule(morning); Placebo capsules/tablets (morning and afternoon) for 7 days
Other Name: OPC-41061
Experimental: 120 mg IR Drug: Tolvaptan IR
90 mg Tolvaptan IR tablet(morning); 30 mg Tolvaptan IR tablet (afternoon); Placebo capsules (morning and afternoon) for 7 days
Other Name: OPC-41061

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.

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01210560

Locations
United States, Massachusetts
Tufts-New England Medical Center
Boston, Massachusetts, United States, 02111
United States, Minnesota
Davita Clinical Research
Minneapolis, Minnesota, United States, 55404
Mayo Medical Center
Rochester, Minnesota, United States, 55905
United States, Ohio
University Hospitals of Cleveland/Case
Cleveland, Ohio, United States, 44106
United States, Oregon
Northwest Renal Clinic Inc.
Portland, Oregon, United States, 97210
United States, Pennsylvania
University of Pennsylvania Medical Center
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigators
Study Director: Frank Czerwiec, M.D., Ph.D. Otsuka Pharmaceutical Development & Commercialization, Inc.
  More Information

No publications provided

Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT01210560     History of Changes
Other Study ID Numbers: 156-09-285
Study First Received: September 21, 2010
Last Updated: February 20, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
Kidney Disease
Polycystic Kidney Disease

Additional relevant MeSH terms:
Kidney Diseases
Multicystic Dysplastic Kidney
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant
Congenital Abnormalities
Kidney Diseases, Cystic
Urogenital Abnormalities
Urologic Diseases

ClinicalTrials.gov processed this record on October 22, 2014