Efficacy of Tolvaptan on ADPKD Patients

Autosomal Dominant Polycystic Kidney Disease Clinical Trial

Official title:

Longitudinal Efficacy and Safety Study of Tolvaptan on Autosomal Dominant Polycystic Kidney Disease Patients (LET-PKD Study)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02729662
• Other study ID #: LET-PKD-1
• Status: Active, not recruiting
• Phase: N/A
• Start date: October 1, 2016
• Est. completion date: September 30, 2021

Study information

• Verified date: June 2020
• Source: Kyorin University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 118
• Est. completion date: September 30, 2021
• Est. primary completion date: August 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Autosomal Dominant Polycystic Kidney Disease
• Kidney Diseases
• Polycystic Kidney Diseases
• Polycystic Kidney, Autosomal Dominant

Intervention

Drug:
• Tolvaptan
Before administration of tolvaptan TKV·Liver capacity: Once/year (an additional measurement within 3 months before start of administration) 24-hour urine collection·Hematology/urinalysis: Once/year Physical findings: Blood pressure and medical interview at ambulatory visit Hospitalization for education and examination at the start of tolvaptan administration 24-hour urine collection·Hematology/urinalysis·Inulin clearance Physical findings: Body weight, blood pressure Adverse Events After administration of tolvaptan TKV·Liver capacity·inulin clearance: Once/year 24-hour urine collection: Once/6 months Hematology/urinalysis: Once/month in principle Physical findings: Blood pressure and medical interview at ambulatory visit Adverse Events

Locations

Country	Name	City	State
Japan	Kyorin University Hospital	Mitaka	Tokyo

Sponsors (1)

Lead Sponsor	Collaborator
Kyorin University

Country where clinical trial is conducted

Japan, 

References & Publications (11)

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. — View 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. — View Citation

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. — View Citation

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. — View 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. — View Citation

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. — View 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. — View Citation

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. — View 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. — View 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. — View 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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The percent change in TKV volumetrically	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, a (% 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
Secondary	The percent change in epidermal growth factor receptor (eGER)	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.	once a month, up to study completion, an expected average of up to 5 years
Secondary	A number of adverse events during the study	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.; Serious adverse event; Non-serious adverse event; Pregnancy; Other safety information	through study completion, an expected average of up to 5 years
Secondary	The efficacy of or response to tolvaptan will be evaluated.	Based on the data obtained from 24-hour urine collection (Urine volume, urinary protein, Na, K, Cl, UN, creatinine, NAG, ß2-MG, albumin, urinary osmolality), blood tests (Na, K, Cl, Ca, IP, BUN, creatinine, eGFR, uric acid, total protein, albumin, globulin, total bilirubin, ?-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.	twice a year, up to study completion, an expected average of up to5 years
Secondary	The impact of tolvaptan on the correlation between inulin clearance and eGFR values	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.	once a month, up to study completion, an expected average of up to 5 months
Secondary	The association between the result of DNA analysis and the effect of tolvaptan	The association between the result of DNA analysis and the effect of tolvaptan will be analyzed.	through study completion, an expected average of up to 5 years