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

NCT01210560 | Completed Phase 2 Results

• 1 other identifier: 156-09-285
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 6

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. 1.To directly compare the immediate release (IR) and MR formulations
2. 2.To determine the dose range and dose regimen for MR (dose finding)

Conditions

Autosomal Dominant Polycystic Kidney Disease

Keywords

Kidney Disease; Polycystic Kidney Disease

Outcome Measures

Primary Outcomes (3)

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

  Blood samples (6 mL) for determination of tolvaptan PK parameters were collected on Day 1 predose, and on Days 7, 14 and 21 at predose, and 1, 2, 4, 6, 8, 9, 10, 12, 16, and 24 hours postdose. If a sample was not drawn at the designated time, a window of ± 3 minutes for each blood draw was acceptable. Maximum and minimum plasma concentration of the drug was calculated.

  Day 7

• Time to Maximum (Peak) Plasma Concentration (Tmax) After Tolvaptan Treatment on Day 7.

  Blood samples (6 mL) for determination of tolvaptan PK parameters were collected on Day 1 predose, and on Days 7, 14 and 21 at predose, and 1, 2, 4, 6, 8, 9, 10, 12, 16, and 24 hours postdose. If a sample was not drawn at the designated time, a window of ± 3 minutes for each blood draw was acceptable. Time to maximum plasma concentration was calculated.

  Day 7

• 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.

  Blood samples (6 mL) for determination of tolvaptan PK parameters were collected on Day 1 predose, and on Days 7, 14 and 21 at predose, and 1, 2, 4, 6, 8, 9, 10, 12, 16, and 24 hours postdose. If a sample was not drawn at the designated time, a window of ± 3 minutes for each blood draw was acceptable. Hence, both AUCT and AUC0-24h values were calculated.

  Day 7

Secondary Outcomes (14)

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

  23.5 hours post-dose

• Change From Baseline in Urine Osmolality Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) at Day 7.

  Day 7

• Change From Baseline in Urine Osmolality at Day 7.

  0-4, 4-8, 8-12, 12-16, 16-24 Hours at Day 7

• Change From Baseline in Urine Volume at 24 Hours at Day 7.

  Day 7

• Change From Baseline in Urine Volume by Interval at Day 7.

  0-4, 4-8, 8-12, 12-16, 16-24 Hours at Day 7

Study Arms (5)

20 mg MR

EXPERIMENTAL

Drug: Tolvaptan MR

40 mg MR

EXPERIMENTAL

Drug: Tolvaptan MR

60 mg MR

EXPERIMENTAL

Drug: Tolvaptan MR

120 mg MR

EXPERIMENTAL

Drug: Tolvaptan MR

120 mg IR

EXPERIMENTAL

Drug: Tolvaptan IR

Interventions

Tolvaptan MR DRUG

20 mg Tolvaptan MR capsule(morning); Placebo capsules/tablets (morning and afternoon) for 7 days

Also known as: OPC-41061

20 mg MR

Tolvaptan IR DRUG

90 mg Tolvaptan IR tablet(morning); 30 mg Tolvaptan IR tablet (afternoon); Placebo capsules (morning and afternoon) for 7 days

Also known as: OPC-41061

120 mg IR

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (6)

Tufts-New England Medical Center

Boston, Massachusetts, 02111, United States

Location

Davita Clinical Research

Minneapolis, Minnesota, 55404, United States

Location

Mayo Medical Center

Rochester, Minnesota, 55905, United States

Location

University Hospitals of Cleveland/Case

Cleveland, Ohio, 44106, United States

Location

Northwest Renal Clinic Inc.

Portland, Oregon, 97210, United States

Location

University of Pennsylvania Medical Center

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (2)

• St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.

  PMID: 39356039 DERIVED

• Gobburu J, Ivaturi V, Wang X, Shoaf SE, Jadhav P, Perrone RD. Comparing Effects of Tolvaptan and Instruction to Increase Water Consumption in ADPKD: Post Hoc Analysis of TEMPO 3:4. Kidney360. 2023 Dec 1;4(12):1702-1707. doi: 10.34067/KID.0000000000000302. Epub 2023 Nov 21.

  PMID: 37986188 DERIVED

MeSH Terms

Conditions

Polycystic Kidney, Autosomal Dominant; Kidney Diseases; Polycystic Kidney Diseases

Interventions

Tolvaptan

Condition Hierarchy (Ancestors)

Kidney Diseases, Cystic; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Ciliopathies; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Global Medical Affairs
• Organization: Otsuka Pharmaceutical Development & Commercialization, Inc

800 562-3974

Study Officials

• Frank Czerwiec, M.D., Ph.D.

  Otsuka Pharmaceutical Development & Commercialization, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 21, 2010
• First Posted: September 28, 2010
• Study Start: October 1, 2010
• Primary Completion: June 1, 2011
• Study Completion: June 1, 2011
• Last Updated: June 14, 2018
• Results First Posted: June 14, 2018

Record last verified: 2018-05

Locations

US (6)