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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00428948




Registration number
NCT00428948
Ethics application status
Date submitted
26/01/2007
Date registered
30/01/2007
Date last updated
2/07/2017

Titles & IDs
Public title
Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Scientific title
A Phase 3, Multi-center, Double-blind, Placebo-controlled, Parallel-arm Trial to Determine Long-term Safety and Efficacy of Oral Tolvaptan Tablets Regimens in Adult Subjects With Autosomal Dominant Polycystic Kidney Disease
Secondary ID [1] 0 0
2006-002768-24
Secondary ID [2] 0 0
156-04-251
Universal Trial Number (UTN)
Trial acronym
TEMPO3:4
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Polycystic Kidney Disease, Autosomal Dominant 0 0
Condition category
Condition code
Renal and Urogenital 0 0 0 0
Kidney disease
Renal and Urogenital 0 0 0 0
Other renal and urogenital disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tolvaptan
Treatment: Drugs - Placebo

Experimental: Tolvaptan - Participants received the highest tolerated split-dose regimen (upon awakening and 9 hours later) of tolvaptan 45/15 mg, 60/30 mg, or 90/30 mg orally for 36 months.

Placebo Comparator: Placebo - Participants received placebo (upon awakening and 9 hours later) orally for 36 months.


Treatment: Drugs: Tolvaptan
Tolvaptan was supplied as tablets.

Treatment: Drugs: Placebo
Placebo was supplied as tablets.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage Change Per Year in Total Kidney Volume From Baseline to Month 36 - Kidney volume was assessed in T1-weighted magnetic resonance images collected at each study site and sent to a central reviewing facility. At the central reviewing facility, blinded radiologists used proprietary software to measure the volume of both kidneys.
Timepoint [1] 0 0
Baseline to Month 36
Secondary outcome [1] 0 0
Number of ADPKD Clinical Progression Events Per 100 Follow-up Years From Baseline to Month 36 - These ADPKD events in the key secondary Outcome Measure were selected on the basis of their potential relationship to progressing cystogenesis. Reducing the rate of cyst development and expansion would likely slow the progression of ADPKD. The 4 events were: (1) Onset or progression of hypertension (someone is hypertensive if they have > 139 mmHg systolic blood pressure [BP], > 89 mmHg diastolic BP, or if they are taking antihypertensive medication at any BP level); (2) severe renal pain requiring medical intervention; (3) worsening albuminuria (by category, see below); and (4) worsening renal function, defined as a 25% decrease in 1/serum creatinine from Baseline. Albuminuria was assessed using spot urine albumin/creatinine ratio measurements (all measurements in mg/mmol). Categories included normal (< 2.8 female or < 2.0 male), microalbuminuria (2.8-28 female or 2.0-20 male), and overt proteinuria (> 28 female or > 20 male.
Timepoint [1] 0 0
Baseline to Month 36
Secondary outcome [2] 0 0
Change in Renal Function Per Year From Week 3 to Month 36 - Renal function was assessed using serum creatinine measurements and was estimated using 1/serum creatinine. The formula for 1/serum creatinine is: 1/Pcr, where Pcr = serum creatinine concentration (mg/dL). The change in renal function per year was based on the slope of change, obtained by regressing renal function data against time by subject.
Timepoint [2] 0 0
Week 3 to Month 36
Secondary outcome [3] 0 0
Change in Mean Arterial Blood Pressure Per Year in Non-hypertensive Participants From Baseline to Month 36 - For participants who were non-hypertensive (systolic BP = 139 mmHg and diastolic BP = 89 mmHg without taking antihypertensive medications) at baseline, mean arterial blood pressure was measured at scheduled clinic visits up to the point of exposure to antihypertensive therapy for any reason. The change in mean arterial blood pressure per year was based on the slope of blood pressure, obtained by regressing blood pressure against time by subject.
Timepoint [3] 0 0
Baseline to Month 36
Secondary outcome [4] 0 0
Area Under the Concentration-time Curve of Change in Renal Pain From Baseline to Month 36 - Change from baseline in renal pain was assessed by a 0 to 10 pain scale as average area under the concentration-time curve (AUC) between baseline and the last trial visit or the last visit prior to initiating medical (eg, narcotic or anti-nociceptives [eg, tricyclic antidepressants]) or surgical therapy for pain. In the pain scale, score 0 represented no pain at all and score 10 represented the worst pain. A negative change score indicates less pain. AUC of renal pain was derived from renal pain scores within treatment period and was calculated using the trapezoidal rule, by dividing the number of days between the first and last assessment.
Timepoint [4] 0 0
At screening, Baseline, Day 1, every 4 months up to month 36/early tremination (ET), follow-up visit 1 and 2
Secondary outcome [5] 0 0
Number of Hypertensive Events Per 100 Follow-up Years in Non-hypertensive Participants From Baseline to Month 36 - A hypertensive event was defined as a change from non-hypertensive (systolic BP = 139 mmHg and diastolic BP = 89 mmHg without taking antihypertensive medications) status to 1 of 3 conditions: (1) High pre-hypertensive (systolic BP [sBP] > 129 mmHg and/or diastolic BP [dBP] > 84 mmHg), (2) hypertensive (sBP > 139 mmHg and/or dBP > 89 mmHg), or (3) requiring antihypertensive therapy.
Timepoint [5] 0 0
Baseline to Month 36
Secondary outcome [6] 0 0
Percentage of Participants With a Clinically Sustained Decrease of Blood Pressure Leading to a Sustained Reduction in Antihypertensive Therapy From Baseline to Month 36
Timepoint [6] 0 0
Baseline to Month 36

Eligibility
Key inclusion criteria
- Legal adult age and able to give Informed Consent.

- Adult subjects with a diagnosis of ADPKD. A diagnosis of ADPKD (age 18 or 20-50)
required several cysts in each kidney (3 if by sonography, 5 if by CT or MRI) in those
with a family history of ADPKD and 10 cysts (by any radiologic method) in each kidney
and exclusion of other cystic kidney diseases if there was no family history.

- Willingness to comply with reproductive precautions, if female.

- Estimated creatinine clearance = 60 mL/min. Estimated from serum creatinine during
screening using Cockcroft-Gault with correction for gender and race, where possible.

- Rapidly progressive kidney growth (total volume = 750 cc) by magnetic resonance
imaging (MRI) at randomization.
Minimum age
18 Years
Maximum age
50 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Prior exposure to tolvaptan or other experimental PKD therapies.

- Currently taking medication for purpose of affecting PKD cysts.

- 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 or
confound study objectives.

- Patients who are unlikely to adequately comply with study procedures.

- Patients having contraindications to MRI.

- Patients taking medications or having any illnesses likely to affect ADPKD outcomes.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
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Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 0 0
Queen Elizebeth Hospital - Adelaide
Recruitment hospital [3] 0 0
Princess Alexandra Hospital - Brisbane
Recruitment hospital [4] 0 0
Royal Melbourne Hospital - Melbourne
Recruitment hospital [5] 0 0
Melbourne Renal Research Group - Melbourne
Recruitment hospital [6] 0 0
Royal Perth Hospital - Perth
Recruitment hospital [7] 0 0
Royal North Shore Hospital - Sydney
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Westmead Hospital - Sydney
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5000 - Adelaide
Recruitment postcode(s) [2] 0 0
5011 - Adelaide
Recruitment postcode(s) [3] 0 0
4102 - Brisbane
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3050 - Melbourne
Recruitment postcode(s) [5] 0 0
3121 - Melbourne
Recruitment postcode(s) [6] 0 0
6054 - Perth
Recruitment postcode(s) [7] 0 0
2065 - Sydney
Recruitment postcode(s) [8] 0 0
2145 - Sydney
Recruitment outside Australia
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Otsuka Pharmaceutical Development & Commercialization, Inc.
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Otsuka Pharmaceutical Co., Ltd.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This study's purpose is to evaluate the long-term safety and efficacy of tolvaptan versus
placebo in patients with ADPKD.
Trial website
https://clinicaltrials.gov/show/NCT00428948
Trial related presentations / 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. Epub 2003 Sep 21.
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. Epub 2004 Feb 29.
Torres VE, Meijer E, Bae KT, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang JJ, Czerwiec FS. Rationale and design of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3-4 Study. Am J Kidney Dis. 2011 May;57(5):692-9. doi: 10.1053/j.ajkd.2010.11.029. Epub 2011 Feb 17.
Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012 Dec 20;367(25):2407-18. doi: 10.1056/NEJMoa1205511. Epub 2012 Nov 3.
Watkins PB, Lewis JH, Kaplowitz N, Alpers DH, Blais JD, Smotzer DM, Krasa H, Ouyang J, Torres VE, Czerwiec FS, Zimmer CA. Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database. Drug Saf. 2015 Nov;38(11):1103-13. doi: 10.1007/s40264-015-0327-3.
Kher A. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013 Mar 28;368(13):1257-8. doi: 10.1056/NEJMc1300762.
Spital A. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013 Mar 28;368(13):1257. doi: 10.1056/NEJMc1300762.
Torres VE, Gansevoort RT, Czerwiec FS. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013 Mar 28;368(13):1259. doi: 10.1056/NEJMc1300762.
Jouret F, Krzesinski JM. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013 Mar 28;368(13):1258-9. doi: 10.1056/NEJMc1300762.
Sexton DJ. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013 Mar 28;368(13):1258. doi: 10.1056/NEJMc1300762.
Public notes

Contacts
Principal investigator
Name 0 0
Vicente Torres, MD, PhD
Address 0 0
Mayo Medical Center
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications