Clinical trial NCT01210560: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Autosomal Dominant Polycystic Kidney Disease
Keywords: Kidney Disease
Polycystic Kidney Disease
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
First posted: 2010-09-28
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7.
timeFrame: Day 7
measure: Time to Maximum (Peak) Plasma Concentration (Tmax) After Tolvaptan Treatment on Day 7.
timeFrame: Day 7
measure: Area Under the Concentration-time Curve During the Dosing Interval at Steady State and Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUCT & AUC0-24h) After Tolvaptan Treatment on Day 7.
timeFrame: Day 7
Secondary outcomes:
measure: Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose.
timeFrame: 23.5 hours post-dose
measure: Change From Baseline in Urine Osmolality Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) at Day 7.
timeFrame: Day 7
measure: Change From Baseline in Urine Osmolality at Day 7.
timeFrame: 0-4, 4-8, 8-12, 12-16, 16-24 Hours at Day 7
measure: Change From Baseline in Urine Volume at 24 Hours at Day 7.
timeFrame: Day 7
measure: Change From Baseline in Urine Volume by Interval at Day 7.
timeFrame: 0-4, 4-8, 8-12, 12-16, 16-24 Hours at Day 7
measure: Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7.
timeFrame: Baseline and Day 7
measure: Change From Baseline in Number of Urine Voids During Awake Periods.
timeFrame: Days 1, 2, 3, 4, 5, 6 and 7
measure: Change From Baseline in Number of Urine Voids During Sleep Periods.
timeFrame: Days 1, 2, 3, 4, 5, 6 and 7
measure: Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6.
timeFrame: Day 6
measure: Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6.
timeFrame: Baseline and Day 6
measure: Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6.
timeFrame: Day 6
measure: Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6.
timeFrame: Baseline and Day 6
measure: Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6.
timeFrame: Day 6
measure: Ranking of Treatment Tolerability.
timeFrame: Day 22/Early Termination
Other outcomes:
Locations:
city: Boston
country: United States
facility: Tufts-New England Medical Center
state: Massachusetts
city: Minneapolis
country: United States
facility: Davita Clinical Research
state: Minnesota
city: Rochester
country: United States
facility: Mayo Medical Center
state: Minnesota
city: Cleveland
country: United States
facility: University Hospitals of Cleveland/Case
state: Ohio
city: Portland
country: United States
facility: Northwest Renal Clinic Inc.
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Medical Center
state: Pennsylvania
Study officials:
affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc.
name: Frank Czerwiec, M.D., Ph.D.
role: STUDY_DIRECTOR
References: