- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02729662
Efficacy of Tolvaptan on ADPKD Patients
Longitudinal Efficacy and Safety Study of Tolvaptan on Autosomal Dominant Polycystic Kidney Disease Patients (LET-PKD Study)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Based on the results of a study entitled "The Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO 3:4) 1)," tolvaptan was approved in March 2014 for the treatment of autosomal dominant polycystic Kidney Disease (ADPKD) in Japan, followed by in other regions such as Europe and Canada.
In May 2014, Kyorin University Hospital started administration of tolvaptan to patients with ADPKD. In the clinical setting in which the dosing conditions differ from those in the TEMPO study, aspects that were not addressed in the TEMPO study may be investigated. The present study is a longitudinal clinical study to investigate the changes before and after administration of tolvaptan by employing a method different from that used in the TEMPO study in patients in whom the clinical course of the disease has been monitored since prior to the approval of tolvaptan.
The observation period (for a maximum duration of 3 years) of the study was originally planned to be completed on March 31, 2018 and the analyses of study results and the preparation of a research paper until September 2019. However, the study will be extended for another 2 years, because the long-term effects of the drug should be further investigated.
The indication approved in Japan defines the target population as those with an eGFR ≥15 mL/min/1.73 m2, but not specifies the upper limit of age. Therefore, the present study will permit the assessment of therapeutic effects of the drug in patients who are older or have more severe renal impairment as compared with in those participating in the TEMPO3:4 and 4.4 studies. Since such patients generally have a greater TKV, the study may also provide information to decide whether the efficacy of tolvaptan differs according to TKV. The present study is a single-arm longitudinal study, unlike the preceding studies that were placebo-controlled studies 1,2); therefore, tolvaptan may be evaluated from different perspectives.
Rationale of DNA analysis The association between pathogenic genotype and the effects of tolvaptan has been reported, but the impact of mutation site has not been cleared 2). Genetic analysis for polycystic kidney will be included in the study to decide whether the effects of tolvaptan is associated with mutation site as well as pathogenic genotype (PKD1, PKD2).
Validation of alpha as a HtTKV slope Assuming that TKV corrected for the height at the age at measurement (t years old), HtTKVt (mL/m), increases at a constant annual rate (α, %/ per year) and the HtTKV0 is 150 mL/m, the following equation will be satisfied: HtTKVt = 150 (1+α)t. The α value calculated from the equation will be used as an indicator for supplementarily assessing the effect of tolvaptan on HtTKV slope 5,6).
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Tokyo
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Mitaka, Tokyo, Japan, 181-8611
- Kyorin University Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients who have started or will start receiving tolvaptan at Kyorin University Hospital.
Patients whose use of Samsca complies with the criteria specified by the Ministry of Health, Labour and Welfare.
- TKV ≥ 750 mL.
- The increase in total renal capacity ≥ approximately 5%/year.
- Patients who have given signed consent to the examination protocol, which includes hospitalization at the initiation of tolvaptan treatment (i.e. examination/educational hospitalization for the first 3 days. Monthly blood tests at the time of ambulatory visits, 24-hour urine collection every 6 months, annual TKV measurement by MRI and inulin clearance measurement)
- Patients for whom the baseline TKV and eGFR percent change is available.
- Patients from whom freely given, written informed consent to participate in the study has been obtained.
Exclusion Criteria:
- Patients who do not consent to participation in the study, or those who later withdraw their consent.
- Patients who have been taking tolvaptan since the TEMPO study.
Patients who are not eligible at our hospital to take tolvaptan for the stated indication based on the criteria for careful administration of Samsca as specified by the Ministry of Health, Labour and Welfare.
- Patients with a history of hypersensitivity to tolvaptan or similar chemical compounds.
- Patients who do not feel thirsty or have difficulty swallowing water.
- Patients with hypernatremia.
- Patients with eGFR < 15 mL/min/1.73 m2.
- Patients with chronic hepatitis, drug-induced hepatic dysfunction and other hepatic dysfunctions.
- Pregnant women or women suspected of being pregnant. Female patients who wish to become pregnant.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Other: Patients with ADPKD
This analysis set consists of patients whose at least 2 TKV data are available both before and after taking tolvaptan.
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Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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The percent change in TKV volumetrically
Time Frame: once a year, up to study completion, an expected average of up to 5 years
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To evaluate the efficacy, the percent change in TKV volumetrically measured by MRI (% per year) is to be compared before and after administering tolvaptan to the same patients. The evaluation will include stratified analyses by patient background variables and examination data obtained during treatment. [Supplementary assessment of the primary outcome variable] Using HtTKV slope, α (% per year), calculated from the HtTKVt at t years old as an indicator, the effect of tolvaptan on HtTKV slope will be supplementarily assessed 5,6). |
once a year, up to study completion, an expected average of up to 5 years
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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The percent change in epidermal growth factor receptor (eGER)
Time Frame: once a month, up to study completion, an expected average of up to 5 years
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The percent change in eGFR (mL/min/1.73
m2 per year) will be compared before and after administration for evaluation.
The evaluation will include stratified analyses by patient background variables and examination data obtained during treatment.
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once a month, up to study completion, an expected average of up to 5 years
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A number of adverse events during the study
Time Frame: through study completion, an expected average of up to 5 years
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The following events that occurred in subjects who received a medicinal product of Otsuka Pharmaceutical from the time of informed consent and in the time of the study completion will be recorded.
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through study completion, an expected average of up to 5 years
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The efficacy of or response to tolvaptan will be evaluated.
Time Frame: twice a year, up to study completion, an expected average of up to5 years
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Based on the data obtained from 24-hour urine collection (Urine volume, urinary protein, Na, K, Cl, UN, creatinine, NAG, β2-MG, albumin, urinary osmolality), blood tests (Na, K, Cl, Ca, IP, BUN, creatinine, eGFR, uric acid, total protein, albumin, globulin, total bilirubin, γ-GTP, AST, ALT, HDL-cholesterol, LDL-cholesterol, triglyceride, cystatin-C, serum osmolality, WBC, RBC, Hb, Ht, Plt, MCV, MCH, MCHC, Retic), inulin clearance, and TKV, the efficacy of or response to tolvaptan will be evaluated.
The evaluation will include stratified analyses by patient background variables, and examination data obtained during treatment.
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twice a year, up to study completion, an expected average of up to5 years
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The impact of tolvaptan on the correlation between inulin clearance and eGFR values
Time Frame: once a month, up to study completion, an expected average of up to 5 months
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The correlation between inulin clearance and eGFR values obtained from the formulae to estimate eGFR will be investigated to elucidate the impact of tolvaptan on the correlation.
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once a month, up to study completion, an expected average of up to 5 months
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The association between the result of DNA analysis and the effect of tolvaptan
Time Frame: through study completion, an expected average of up to 5 years
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The association between the result of DNA analysis and the effect of tolvaptan will be analyzed.
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through study completion, an expected average of up to 5 years
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Eiji Higashihara, MD, Kyorin University School of Medicine
Publications and helpful links
General Publications
- 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.
- Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Dandurand A, Ouyang J, Czerwiec FS, Blais JD; TEMPO 4:4 Trial Investigators. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial. Nephrol Dial Transplant. 2017 Jul 1;32(7):1262. doi: 10.1093/ndt/gfx079. No abstract available.
- Higashihara E, Nutahara K, Okegawa T, Shishido T, Tanbo M, Kobayasi K, Nitadori T. Kidney volume and function in autosomal dominant polycystic kidney disease. Clin Exp Nephrol. 2014 Feb;18(1):157-65. doi: 10.1007/s10157-013-0834-4. Epub 2013 Jul 18.
- Higashihara E, Nutahara K, Okegawa T, Tanbo M, Hara H, Miyazaki I, Kobayasi K, Nitatori T. Kidney volume estimations with ellipsoid equations by magnetic resonance imaging in autosomal dominant polycystic kidney disease. Nephron. 2015;129(4):253-62. doi: 10.1159/000381476. Epub 2015 Apr 16.
- Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, Bae KT, Chapman AB, Grantham JJ, Mrug M, Hogan MC, El-Zoghby ZM, Harris PC, Erickson BJ, King BF, Torres VE; CRISP Investigators. Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol. 2015 Jan;26(1):160-72. doi: 10.1681/ASN.2013101138. Epub 2014 Jun 5.
- Girardat-Rotar L, Braun J, Puhan MA, Abraham AG, Serra AL. Temporal and geographical external validation study and extension of the Mayo Clinic prediction model to predict eGFR in the younger population of Swiss ADPKD patients. BMC Nephrol. 2017 Jul 17;18(1):241. doi: 10.1186/s12882-017-0654-y.
- Kinoshita M, Higashihara E, Kawano H, Higashiyama R, Koga D, Fukui T, Gondo N, Oka T, Kawahara K, Rigo K, Hague T, Katsuragi K, Sudo K, Takeshi M, Horie S, Nutahara K. Technical Evaluation: Identification of Pathogenic Mutations in PKD1 and PKD2 in Patients with Autosomal Dominant Polycystic Kidney Disease by Next-Generation Sequencing and Use of a Comprehensive New Classification System. PLoS One. 2016 Nov 11;11(11):e0166288. doi: 10.1371/journal.pone.0166288. eCollection 2016.
- Higashihara E, Horie S, Kinoshita M, Harris PC, Okegawa T, Tanbo M, Hara H, Yamaguchi T, Shigemori K, Kawano H, Miyazaki I, Kaname S, Nutahara K. A potentially crucial role of the PKD1 C-terminal tail in renal prognosis. Clin Exp Nephrol. 2018 Apr;22(2):395-404. doi: 10.1007/s10157-017-1477-7. Epub 2017 Oct 5.
- Tan AY, Michaeel A, Liu G, Elemento O, Blumenfeld J, Donahue S, Parker T, Levine D, Rennert H. Molecular diagnosis of autosomal dominant polycystic kidney disease using next-generation sequencing. J Mol Diagn. 2014 Mar;16(2):216-28. doi: 10.1016/j.jmoldx.2013.10.005. Epub 2013 Dec 27.
- Irazabal MV, Torres VE, Hogan MC, Glockner J, King BF, Ofstie TG, Krasa HB, Ouyang J, Czerwiec FS. Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease. Kidney Int. 2011 Aug;80(3):295-301. doi: 10.1038/ki.2011.119. Epub 2011 May 4.
- Boertien WE, Meijer E, de Jong PE, Bakker SJ, Czerwiec FS, Struck J, Oberdhan D, Shoaf SE, Krasa HB, Gansevoort RT. Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease. Kidney Int. 2013 Dec;84(6):1278-86. doi: 10.1038/ki.2013.285. Epub 2013 Jul 31.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Urologic Diseases
- Congenital Abnormalities
- Genetic Diseases, Inborn
- Abnormalities, Multiple
- Kidney Diseases, Cystic
- Ciliopathies
- Kidney Diseases
- Polycystic Kidney Diseases
- Polycystic Kidney, Autosomal Dominant
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Natriuretic Agents
- Antidiuretic Hormone Receptor Antagonists
- Tolvaptan
Other Study ID Numbers
- LET-PKD-1
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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