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Tolvaptan Open-label Pilot Efficacy, Tolerability, and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD) (TEMPO 2:4)

This study has been completed.
Sponsor:
Collaborator:
Otsuka Pharmaceutical Co., Ltd.
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier:
NCT00413777
First received: December 18, 2006
Last updated: May 30, 2017
Last verified: May 2017
  Purpose
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).

Condition Intervention Phase
Polycystic Kidney, Autosomal Dominant Drug: Tolvaptan Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Safety Assessments Based on Vital Signs, Electrocardiogram (ECG's), Clinical Laboratory Tests, Physical Examinations Are Reported as Adverse Events (AEs) Upon Study Physician Discretion. [ Time Frame: AEs were recorded from screening (ICF was signed) until 7-Day follow-up ]
    An AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in a study , whether or not it was considered drug-related by the study physician. A treatment-emergent AE (TEAE) was defined as an AE that started after start of study drug treatment; or if the event was continuous from Baseline and was serious, study drug related, or resulted in death, discontinuation.


Secondary Outcome Measures:
  • Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose. [ Time Frame: Baseline to Month 36 ]
    Spot urine osmolality at trough was determined for urine samples collected immediately prior to morning dosing for Day 1 (Baseline), Months 2, 6, 12, 24, 36 for all participants. Sample was taken after the first morning's void and was provided as a mid-stream, clean catch sample. During the titration period (Weeks 1, 2, 3 and 4) and at Month 6, additional samples were collected for the preceding day immediately preceding the 2nd daily dose and at bed-time. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration. At the Month 36 visit, participants were given a urine container and brought back the specimen at Extension Day 1. All participants were fasting.

  • Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose. [ Time Frame: Baseline to Month 24 ]

    Urine osmolality at steady state (after at least 4 days of dosing) including "absolute trough" prior to the second daily dose.

    Samples for this assessment were taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day immediately preceding the second daily dose. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.


  • Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime. [ Time Frame: Baseline to Month 24 ]

    Urine osmolality at steady state (after at least 4 days of dosing) including "average of troughs" (the mean urine osmolality prior to bedtime).

    Samples for this assessment were to be taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day at bedtime. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.


  • Percent Change From Baseline in Renal Volume. [ Time Frame: Baseline to Month 36 ]
    Total Kidney Volume (TKV) was assessed by the central magnetic resonance imaging (MRI) rater.

  • Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR). [ Time Frame: Baseline to Month 36 ]
    GFR was estimated using reciprocal serum creatinine formula. The formula does not adjust for body weight or height, but this may be done to normalize to body surface area. The formula for reciprocal Serum creatinine is: 1/Pcr. (Pcr = serum creatinine concentration [mg/dL]). Clinic weight scales were calibrated at least yearly.

  • Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose- Extension. [ Time Frame: Baseline to Months 2, 6, 12, 24, 36, Extension Day 1, Extension Month 12 ]
    Spot urine osmolality at trough was determined for urine samples collected immediately prior to morning dosing for Day 1 (Baseline), Months 2, 6, 12, 24, 36, Extension Day 1, and Extension Month 12 for all participants. Sample was taken after the first morning's void and was provided as a mid-stream, clean catch sample. During the titration period (Weeks 1, 2, 3 and 4) and at Month 6, additional samples were collected for the preceding day immediately preceding the 2nd daily dose and at bed-time. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration. At the Month 36 visit, participants were given a urine container and brought back the specimen at Extension Day 1. All participants were fasting.

  • Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose- Extension. [ Time Frame: Baseline to Month 24 ]

    Urine osmolality at steady state (after at least 4 days of dosing) including "absolute trough" prior to the second daily dose.

    Samples for this assessment were taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day immediately preceding the second daily dose. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.


  • Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime- Extension. [ Time Frame: Baseline to Month 24 ]

    Urine osmolality at steady state (after at least 4 days of dosing) including "average of troughs" (the mean urine osmolality prior to bedtime).

    Samples for this assessment were to be taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day at bedtime. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.


  • Percent Change From Baseline in Renal Volume-Extension. [ Time Frame: Baseline to Months 2, 12, 24, 36, Extension Day 1, Extension Month 12 ]
    TKV was assessed by the central magnetic resonance imaging (MRI) rater.

  • Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. [ Time Frame: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 12 ]
    GFR was estimated using reciprocal serum creatinine formula. The formula does not adjust for body weight or height, but this may be done to normalize to body surface area. The formula for reciprocal Serum creatinine is: 1/Pcr. (Pcr = serum creatinine concentration [mg/dL]). Clinic weight scales were calibrated at least yearly.

  • Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment. [ Time Frame: Baseline to Month 36 ]
    The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP < 100 mm Hg and off therapy), high normal (sBP > 129 and or dBP > 84 mm Hg off therapy) or hypertensive (sBP >140 and/or dBP > 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + [1/3 x pulse pressure (ie systolic - diastolic pressure)] in mm Hg).

  • Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment. [ Time Frame: Baseline to Month 36 ]
    The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP < 100 mm Hg and off therapy), high normal (sBP > 129 and or dBP > 84 mm Hg off therapy) or hypertensive (sBP >140 and/or dBP > 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + [1/3 x pulse pressure (ie systolic - diastolic pressure)] in mm Hg).

  • Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment. [ Time Frame: Baseline to Month 36 ]
    The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP < 100 mm Hg and off therapy), high normal (sBP > 129 and or dBP > 84 mm Hg off therapy) or hypertensive (sBP >140 and/or dBP > 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + [1/3 x pulse pressure (ie systolic - diastolic pressure)] in mm Hg).

  • Mean Change From Baseline in sBP for Hypertension Assessment- Extension. [ Time Frame: 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 ]
    The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP < 100 mm Hg and off therapy), high normal (sBP > 129 and or dBP > 84 mm Hg off therapy) or hypertensive (sBP >140 and/or dBP > 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + [1/3 x pulse pressure (ie systolic - diastolic pressure)] in mm Hg).

  • Mean Change From Baseline in dBP for Hypertension Assessment- Extension. [ Time Frame: 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 ]
    The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP < 100 mm Hg and off therapy), high normal (sBP > 129 and or dBP > 84 mm Hg off therapy) or hypertensive (sBP >140 and/or dBP > 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + [1/3 x pulse pressure (ie systolic - diastolic pressure)] in mm Hg).

  • Mean Change From Baseline in MAP for Hypertension Assessment- Extension. [ Time Frame: 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 ]
    The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP < 100 mm Hg and off therapy), high normal (sBP > 129 and or dBP > 84 mm Hg off therapy) or hypertensive (sBP >140 and/or dBP > 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + [1/3 x pulse pressure (ie systolic - diastolic pressure)] in mm Hg).

  • Mean Change From Baseline in Patient-assessed Renal Pain Scale. [ Time Frame: Baseline to Month 36 ]
    Participants were asked the question to assess the relative level of pain attributed to their kidneys. This question was, "On a scale of 0 to 10, with zero represented no pain at all and 10 represented the worst pain ever experienced, what was the worst kidney pain experienced in the last 4 months?" If the latest assessment was less than 4 months prior, the question was substituted "since your last visit" for "in the last 4 months". The same interrogator designated to this task was used throughout the study for each participant.

  • Mean Change From Baseline in Patient-assessed Renal Pain Scale- Extension. [ Time Frame: Baseline to Months 2, 6, 12, 24, 36, Extension Day 1, Extension Month 12 ]
    Participants were asked the question to assess the relative level of pain attributed to their kidneys. This question was, "On a scale of 0 to 10, with zero represented no pain at all and 10 represented the worst pain ever experienced, what was the worst kidney pain experienced in the last 4 months?" If the latest assessment was less than 4 months prior, the question was substituted "since your last visit" for "in the last 4 months". The same interrogator designated to this task was used throughout the study for each participant.

  • Mean Change From Baseline in Abdominal Girth Measurement. [ Time Frame: Baseline to Month 36 ]
    The participant had a measurement of their abdominal girth recorded. The measurement will be taken with a tape measure extending around the abdomen at the level of the iliac crests laterally and the umbilicus anteriorly. The examiner should also palpate for each kidney and liver edge, noting presence or enlargement. (By definition if the kidneys are palpable they are enlarged, the liver edge may be palpable but not enlarged).

  • Mean Change From Baseline in Abdominal Girth Measurement- Extension. [ Time Frame: Baseline to Extension Day 1, Extension Month 12 ]
    The participant had a measurement of their abdominal girth recorded. The measurement will be taken with a tape measure extending around the abdomen at the level of the iliac crests laterally and the umbilicus anteriorly. The examiner should also palpate for each kidney and liver edge, noting presence or enlargement. (By definition if the kidneys are palpable they are enlarged, the liver edge may be palpable but not enlarged).


Enrollment: 46
Study Start Date: December 2005
Study Completion Date: June 2010
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tolvaptan 45/15 mg/day orally for up to 4 years
Participants received tolvaptan 45 mg orally in the morning and 15 mg orally 8 hours later for up to 4 years.
Drug: Tolvaptan
Participants were titrated to either the tolvaptan 45/15 or 60/30 mg split-dose over a 2-month Titration Period. They received the titrated dose for 34 months during the Fixed-dose Period. Following a planned off-treatment period, participants had the option to enter an Extension Period for an additional 12 months. Tolvaptan was supplied as tablets.
Other Name: OPC-41061
Experimental: Tolvaptan 60/30 mg/day orally for up to 4 years
Participants received tolvaptan 60 mg orally in the morning and 30 mg orally 8 hours later for up to 4 years.
Drug: Tolvaptan
Participants were titrated to either the tolvaptan 45/15 or 60/30 mg split-dose over a 2-month Titration Period. They received the titrated dose for 34 months during the Fixed-dose Period. Following a planned off-treatment period, participants had the option to enter an Extension Period for an additional 12 months. Tolvaptan was supplied as tablets.
Other Name: OPC-41061

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

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  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: NCT00413777

Locations
United States, Colorado
University of Colorado
Denver, Colorado, United States
United States, Florida
Jacksonville Center for Clinical Research
Jacksonville, Florida, United States
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States
United States, Kansas
Univerisity of Kansas Medical Center
Kansas City, Kansas, United States
United States, Maryland
Johns Hopkins School of Medicine
Baltimore, Maryland, United States
United States, Minnesota
Davita Clinical Research
Minneapolis, Minnesota, United States
Mayo Medical Center
Rochester, Minnesota, United States
United States, New York
Rogosin Institute
New York, New York, United States
United States, Oregon
Northwest Renal Clinic
Portland, Oregon, United States
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States
United States, Virginia
Nephrology Clinical Research Center at the University of Virginia
Charlottesville, Virginia, United States
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
Otsuka Pharmaceutical Co., Ltd.
Investigators
Principal Investigator: Vicente Torres, MD, PhD Mayo Medical Center
Study Director: Frank Czerweic, MD Otsuka Pharmaceutical Development & Commercialization, Inc.
  More Information

Publications:
Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT00413777     History of Changes
Other Study ID Numbers: 156-04-250
Study First Received: December 18, 2006
Results First Received: March 29, 2017
Last Updated: May 30, 2017

Additional relevant MeSH terms:
Kidney Diseases
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant
Urologic Diseases
Kidney Diseases, Cystic
Tolvaptan
Antidiuretic Hormone Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 21, 2017