Clinical trial NCT02729662: Efficacy of Tolvaptan on ADPKD Patients
Official title: Longitudinal Efficacy and Safety Study of Tolvaptan on Autosomal Dominant Polycystic Kidney Disease Patients (LET-PKD Study)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Autosomal Dominant Polycystic Kidney Disease
Lead sponsor: Kyorin University
Sponsor class: OTHER
First posted: 2016-04-06
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Investigation of the therapeutic effects of tolvaptan in patients with autosomal dominant polycystic kidney disease This is a prospective 5-year study to compare the change in total kidney volume (TKV) before and after tolvaptan therapy, as the primary endpoint, in patients with ADPKD. Study results will be summarized, analyzed, and compiled into a research paper at 5 years (data cut-off, Aug 31, 2020).

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).

Eligibility criteria: Inclusion Criteria:

1. Patients who have started or will start receiving tolvaptan at Kyorin University Hospital.
2. 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.
3. 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)
4. Patients for whom the baseline TKV and eGFR percent change is available.
5. Patients from whom freely given, written informed consent to participate in the study has been obtained.

Exclusion Criteria:

1. Patients who do not consent to participation in the study, or those who later withdraw their consent.
2. Patients who have been taking tolvaptan since the TEMPO study.
3. 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.

Primary outcomes:
measure: The percent change in TKV volumetrically
timeFrame: once a year, up to study completion, an expected average of up to 5 years
Secondary outcomes:
measure: The percent change in epidermal growth factor receptor (eGER)
timeFrame: once a month, up to study completion, an expected average of up to 5 years
measure: A number of adverse events during the study
timeFrame: through study completion, an expected average of up to 5 years
measure: The efficacy of or response to tolvaptan will be evaluated.
timeFrame: twice a year, up to study completion, an expected average of up to5 years
measure: The impact of tolvaptan on the correlation between inulin clearance and eGFR values
timeFrame: once a month, up to study completion, an expected average of up to 5 months
measure: The association between the result of DNA analysis and the effect of tolvaptan
timeFrame: through study completion, an expected average of up to 5 years
Other outcomes:
Locations:
city: Mitaka
country: Japan
facility: Kyorin University Hospital
state: Tokyo
Study officials:
affiliation: Kyorin University School of Medicine
name: Eiji Higashihara, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
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citation: 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.
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citation: 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.
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citation: 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.
citation: 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.
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