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Polycystic Kidney, Autosomal DominantPhase 2TEMPO 2:4NCT00413777

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

A Phase 2 study testing Tolvaptan in people with Polycystic Kidney, Autosomal Dominant, run by Otsuka Pharmaceutical Development & Commercialization, Inc. at 11 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Polycystic Kidney, Autosomal Dominant
What is being tested?
Tolvaptan
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
46 participants
Where
11 sitesUnited States
Study dates
Dec 2005to Jun 2010
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

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

Who cannot join

  • 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.

Trial locations and contacts

11 sites in 1 country.

11 sites in 1 country

United States11 sites

  • Emory University School of Medicine

    Atlanta, Georgia

  • Johns Hopkins School of Medicine

    Baltimore, Maryland

  • Nephrology Clinical Research Center at the University of Virginia

    Charlottesville, Virginia

  • University of Colorado

    Denver, Colorado

  • Jacksonville Center for Clinical Research

    Jacksonville, Florida

  • Univerisity of Kansas Medical Center

    Kansas City, Kansas

  • Davita Clinical Research

    Minneapolis, Minnesota

  • Vanderbilt University Medical Center

    Nashville, Tennessee

  • Rogosin Institute

    New York, New York

  • Northwest Renal Clinic

    Portland, Oregon

  • Mayo Medical Center

    Rochester, Minnesota

Other trials in United States

About this study

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

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).

Read the 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.

Being tested
Tolvaptan
Medical subject headings
Polycystic Kidney, Autosomal Dominant

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TolvaptanDrug

    Also called OPC-41061

    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.

Study groups in NCT00413777
Study groupRoleWhat they receive
Tolvaptan 45/15 mg/day orally for up to 4 yearsExperimentalParticipants received tolvaptan 45 mg orally in the morning and 15 mg orally 8 hours later for up to 4 years.
Receives: Drug: Tolvaptan
Tolvaptan 60/30 mg/day orally for up to 4 yearsExperimentalParticipants received tolvaptan 60 mg orally in the morning and 30 mg orally 8 hours later for up to 4 years.
Receives: Drug: Tolvaptan

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Safety Assessments Based on Vital Signs, Electrocardiogram (ECG's), Clinical Laboratory Tests, Physical Examinations Are Reported as Adverse Events (AEs) Upon Study Physician Discretion.

    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.

    Measured: AEs were recorded from screening (ICF was signed) until 7-Day follow-up

Secondary outcomes (20)

  1. Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose.

    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.

    Measured: Baseline to Month 36

  2. Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose.

    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.

    Measured: Baseline to Month 24

  3. Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime.

    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.

    Measured: Baseline to Month 24

  4. Percent Change From Baseline in Renal Volume.

    Total Kidney Volume (TKV) was assessed by the central magnetic resonance imaging (MRI) rater.

    Measured: Baseline to Month 36

  5. Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR).

    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.

    Measured: Baseline to Month 36

  6. Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose- Extension.

    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.

    Measured: Baseline to Months 2, 6, 12, 24, 36, Extension Day 1, Extension Month 12

  7. Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose- Extension.

    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.

    Measured: Baseline to Month 24

  8. Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime- Extension.

    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.

    Measured: Baseline to Month 24

  9. Percent Change From Baseline in Renal Volume-Extension.

    TKV was assessed by the central magnetic resonance imaging (MRI) rater.

    Measured: Baseline to Months 2, 12, 24, 36, Extension Day 1, Extension Month 12

  10. Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension.

    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.

    Measured: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 12

  11. Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment.

    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).

    Measured: Baseline to Month 36

  12. Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment.

    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).

    Measured: Baseline to Month 36

  13. Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment.

    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).

    Measured: Baseline to Month 36

  14. Mean Change From Baseline in sBP for Hypertension Assessment- Extension.

    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).

    Measured: 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

  15. Mean Change From Baseline in dBP for Hypertension Assessment- Extension.

    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).

    Measured: 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

  16. Mean Change From Baseline in MAP for Hypertension Assessment- Extension.

    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).

    Measured: 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

  17. Mean Change From Baseline in Patient-assessed Renal Pain Scale.

    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.

    Measured: Baseline to Month 36

  18. Mean Change From Baseline in Patient-assessed Renal Pain Scale- Extension.

    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.

    Measured: Baseline to Months 2, 6, 12, 24, 36, Extension Day 1, Extension Month 12

  19. Mean Change From Baseline in Abdominal Girth Measurement.

    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).

    Measured: Baseline to Month 36

  20. Mean Change From Baseline in Abdominal Girth Measurement- Extension.

    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).

    Measured: Baseline to Extension Day 1, Extension Month 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Dec 2006 (estimated)
  2. Study startDec 2005
  3. Primary completionJun 2010
  4. Study completionJun 2010

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
46 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00413777
Sponsor's protocol ID
156-04-250
Acronym
TEMPO 2:4
Status last verified
May 2017
First submitted
18 Dec 2006
Last updated
2 Jul 2017

Publications

  • 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.

    PubMed 14502283

  • 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.

    PubMed 14991049

  • 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.

    PubMed 21903984

  • 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.

    PubMed 39356039

  • Lioudis M, Zhou X, Davenport E, Nunna S, Krasa HB, Oberdhan D, Fernandes AW. Effects of tolvaptan discontinuation in patients with autosomal dominant polycystic kidney disease: a post hoc pooled analysis. BMC Nephrol. 2023 Jun 22;24(1):182. doi: 10.1186/s12882-023-03247-6.

    PubMed 37349694

  • Chebib FT, Zhou X, Garbinsky D, Davenport E, Nunna S, Oberdhan D, Fernandes A. Tolvaptan and Kidney Function Decline in Older Individuals With Autosomal Dominant Polycystic Kidney Disease: A Pooled Analysis of Randomized Clinical Trials and Observational Studies. Kidney Med. 2023 Apr 14;5(6):100639. doi: 10.1016/j.xkme.2023.100639. eCollection 2023 Jun.

    PubMed 37250503

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Tolvaptan in people with Polycystic Kidney, Autosomal Dominant, run by Otsuka Pharmaceutical Development & Commercialization, Inc. at 11 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 2 Jul 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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. (time frame: AEs were recorded from screening (ICF was signed) until 7-Day follow-up). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00413777, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.

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