Clinical trial NCT00413777: Tolvaptan Open-label Pilot Efficacy, Tolerability, and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Official title: A Phase 2, Multi-center, Open-label Study to Determine Long-term Safety, Tolerability and Efficacy of Split-dose Oral Regimens of Tolvaptan Tablets in a Range of 30 to 120 mg/d in Patients With Autosomal Dominant Polycystic Kidney Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Polycystic Kidney, Autosomal Dominant
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Otsuka Pharmaceutical Co., Ltd.
First posted: 2006-12-20
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study's purpose is to evaluate the long-term safety of open-label tolvaptan regimens to determine the maximally-tolerated dose and acquire pilot efficacy data in patients with autosomal dominant polycystic kidney disease (ADPKD).

Detailed description: Autosomal Dominant Polycystic Kidney Disease is a genetic disease classified by the formation of fluid-filled cysts in the kidneys. The accumulation of these cysts causes the kidneys to enlarge several times the normal size and leads to the eventual loss of renal function and ultimately results in renal failure in end-stage patients. This is a disease with life-threatening implications to those who have it, and their family members who may also be affected. Aside from early anti-hypertensive control and dietary protein restriction, which are presumed to offer a modest degree of protection, most surviving patients require renal replacement therapy (dialysis and transplant) and suffer from high morbidity and mortality.

A rationale for use of tolvaptan in these genetic disorders has been proven, in principle, through use of a variety of animal models. In these models, tolvaptan is effective in halting or reversing the progression of this renal disease.

The current study is being undertaken in order to evaluate whether tolvaptan, an oral vasopressin V2 receptor inhibitor, will maintain an adequate safety profile and show a potential clinical benefit by reducing total renal volume in the hopes of making an impact upon disease progression.

Eligibility criteria: Inclusion Criteria:

* Prior participation in designated tolvaptan ADPKD studies (156-04-248, 156-04-249).
* Able to give Informed Consent.

Exclusion Criteria:

* Women who are breast feeding and females of childbearing potential who are not using acceptable contraceptive methods.
* In the opinion of the study investigator or sponsor may present a safety risk.
* Patients who are unlikely to adequately comply with study procedures.
* Patients who at Day 1 have an estimated glomerular filtration rate (GFR) below 30 mL/min or who anticipate renal-replacement therapy within one year of study entry.
* Patients having contraindications to magnetic resonance imaging (MRI) or gadolinium contrast will be eligible but will not be able to participate in MRI.
* Patients taking a diuretic within 1 week of enrollment or likely to need diuretic therapy prior to Month 2.

Primary outcomes:
measure: Safety Assessments Based on Vital Signs, Electrocardiogram (ECG's), Clinical Laboratory Tests, Physical Examinations Are Reported as Adverse Events (AEs) Upon Study Physician Discretion.
timeFrame: AEs were recorded from screening (ICF was signed) until 7-Day follow-up
Secondary outcomes:
measure: Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose.
timeFrame: Baseline to Month 36
measure: Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose.
timeFrame: Baseline to Month 24
measure: Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime.
timeFrame: Baseline to Month 24
measure: Percent Change From Baseline in Renal Volume.
timeFrame: Baseline to Month 36
measure: Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR).
timeFrame: Baseline to Month 36
measure: Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose- Extension.
timeFrame: Baseline to Months 2, 6, 12, 24, 36, Extension Day 1, Extension Month 12
measure: Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose- Extension.
timeFrame: Baseline to Month 24
measure: Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime- Extension.
timeFrame: Baseline to Month 24
measure: Percent Change From Baseline in Renal Volume-Extension.
timeFrame: Baseline to Months 2, 12, 24, 36, Extension Day 1, Extension Month 12
measure: Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension.
timeFrame: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 12
measure: Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment.
timeFrame: Baseline to Month 36
measure: Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment.
timeFrame: Baseline to Month 36
measure: Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment.
timeFrame: Baseline to Month 36
measure: Mean Change From Baseline in sBP for Hypertension Assessment- Extension.
timeFrame: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 4, Extension Month 8, Extension Month 12
measure: Mean Change From Baseline in dBP for Hypertension Assessment- Extension.
timeFrame: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 4, Extension Month 8, Extension Month 12
measure: Mean Change From Baseline in MAP for Hypertension Assessment- Extension.
timeFrame: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 4, Extension Month 8, Extension Month 12
measure: Mean Change From Baseline in Patient-assessed Renal Pain Scale.
timeFrame: Baseline to Month 36
measure: Mean Change From Baseline in Patient-assessed Renal Pain Scale- Extension.
timeFrame: Baseline to Months 2, 6, 12, 24, 36, Extension Day 1, Extension Month 12
measure: Mean Change From Baseline in Abdominal Girth Measurement.
timeFrame: Baseline to Month 36
measure: Mean Change From Baseline in Abdominal Girth Measurement- Extension.
timeFrame: Baseline to Extension Day 1, Extension Month 12
Other outcomes:
Locations:
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Jacksonville
country: United States
facility: Jacksonville Center for Clinical Research
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Kansas City
country: United States
facility: Univerisity of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins School of Medicine
state: Maryland
city: Minneapolis
country: United States
facility: Davita Clinical Research
state: Minnesota
city: Rochester
country: United States
facility: Mayo Medical Center
state: Minnesota
city: New York
country: United States
facility: Rogosin Institute
state: New York
city: Portland
country: United States
facility: Northwest Renal Clinic
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Charlottesville
country: United States
facility: Nephrology Clinical Research Center at the University of Virginia
state: Virginia
Study officials:
affiliation: Mayo Medical Center
name: Vicente Torres, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc.
name: Frank Czerweic, MD
role: STUDY_DIRECTOR
References:
citation: Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med. 2003 Oct;9(10):1323-6. doi: 10.1038/nm935. Epub 2003 Sep 21.
citation: Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH 2nd. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med. 2004 Apr;10(4):363-4. doi: 10.1038/nm1004. Epub 2004 Feb 29.
citation: Higashihara E, Torres VE, Chapman AB, Grantham JJ, Bae K, Watnick TJ, Horie S, Nutahara K, Ouyang J, Krasa HB, Czerwiec FS; TEMPOFormula and 156-05-002 Study Investigators. Tolvaptan in autosomal dominant polycystic kidney disease: three years' experience. Clin J Am Soc Nephrol. 2011 Oct;6(10):2499-507. doi: 10.2215/CJN.03530411. Epub 2011 Sep 8.