Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD) (TEMPO3:4)

Study Description

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Brief Summary:

This study's purpose is to evaluate the long-term safety and efficacy of tolvaptan versus placebo in patients with ADPKD.

Condition or disease	Intervention/treatment	Phase
Polycystic Kidney Disease, Autosomal Dominant	Drug: Tolvaptan; Drug: Placebo	Phase 3

Detailed Description:

This study evaluated whether or not tolvaptan is potentially beneficial, while maintaining an adequate safety profile, by reducing the rate of total kidney volume increase, while impacting the onset, severity, and progression of other important consequences of ADPKD.

During the 3-week titration phase, tolvaptan or placebo was titrated in weekly intervals from lowest to highest tolerated levels given in split-dose regimens of 45/15 mg, 60/30 mg and 90/30 mg orally upon awakening and approximately 9 hours later. As soon as a subject could not tolerate a given dose, the titration phase was over and the maintenance phase began at the dose level tolerated. The maintenance phase lasted to Month 36. Subjects were able to titrate down at any point during the study. Subjects were able to titrate up during the maintenance phase with Medical Monitor approval.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	1445 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official 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
Study Start Date :	January 2007
Actual Primary Completion Date :	January 2012
Actual Study Completion Date :	January 2012

Arms and Interventions

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Arm	Intervention/treatment
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.	Drug: Tolvaptan; Tolvaptan was supplied as tablets.; Other Names: OPC-41061; OPC-156
Placebo Comparator: Placebo; Participants received placebo (upon awakening and 9 hours later) orally for 36 months.	Drug: Placebo; Placebo was supplied as tablets.

Outcome Measures

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Primary Outcome Measures :

1. Percentage Change Per Year in Total Kidney Volume From Baseline to Month 36 [ Time Frame: 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.

Secondary Outcome Measures :

1. Number of ADPKD Clinical Progression Events Per 100 Follow-up Years From Baseline to Month 36 [ Time Frame: 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.
2. Change in Renal Function Per Year From Week 3 to Month 36 [ Time Frame: 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.
3. Change in Mean Arterial Blood Pressure Per Year in Non-hypertensive Participants From Baseline to Month 36 [ Time Frame: 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.
4. Area Under the Concentration-time Curve of Change in Renal Pain From Baseline to Month 36 [ Time Frame: At screening, Baseline, Day 1, every 4 months up to month 36/early tremination (ET), follow-up visit 1 and 2 ]
   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.
5. Number of Hypertensive Events Per 100 Follow-up Years in Non-hypertensive Participants From Baseline to Month 36 [ Time Frame: 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.
6. Percentage of Participants With a Clinically Sustained Decrease of Blood Pressure Leading to a Sustained Reduction in Antihypertensive Therapy From Baseline to Month 36 [ Time Frame: Baseline to Month 36 ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 50 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

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.

Contacts and Locations

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  Show 133 Study Locations

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 Czerwiec, MD, PhD	Otsuka Pharmaceutical Development and Commercialization, Inc.
Study Director:	Osamu Sato	Otsuka Pharmaceutical Corporation, Ltd. Japan

More Information

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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#SA2.

Spital A. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013 Mar 28;368(13):1257. doi: 10.1056/NEJMc1300762#SA1.

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#SA4.

Sexton DJ. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013 Mar 28;368(13):1258. doi: 10.1056/NEJMc1300762#SA3.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

McEwan P, Bennett Wilton H, Ong ACM, Ørskov B, Sandford R, Scolari F, Cabrera MV, Walz G, O'Reilly K, Robinson P. A model to predict disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD): the ADPKD Outcomes Model. BMC Nephrol. 2018 Feb 13;19(1):37. doi: 10.1186/s12882-017-0804-2.

Muto S, Kawano H, Higashihara E, Narita I, Ubara Y, Matsuzaki T, Ouyang J, Torres VE, Horie S. The effect of tolvaptan on autosomal dominant polycystic kidney disease patients: a subgroup analysis of the Japanese patient subset from TEMPO 3:4 trial. Clin Exp Nephrol. 2015 Oct;19(5):867-77. doi: 10.1007/s10157-015-1086-2. Epub 2015 Feb 7.

Responsible Party:	Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier:	NCT00428948 History of Changes
Other Study ID Numbers:	156-04-251; 2006-002768-24 ( EudraCT Number )
First Posted:	January 30, 2007
Results First Posted:	July 2, 2017
Last Update Posted:	July 2, 2017
Last Verified:	May 2017

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

ADPKD; Polycystic; kidney; ADPKD (Autosomal Dominant Polycystic Kidney Disease)

Additional relevant MeSH terms:

Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Urologic Diseases; Kidney Diseases, Cystic; Genetic Diseases, Inborn; Abnormalities, Multiple	Congenital Abnormalities; Tolvaptan; Antidiuretic Hormone Receptor Antagonists; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Physiological Effects of Drugs