Efficacy of Tolvaptan on ADPKD Patients

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).

• Tolvaptan (Drug), also known as Samsca: * 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

Primary outcomes

• The percent change in TKV volumetrically [once a year, up to study completion, an expected average of up to 5 years]: 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).

Secondary outcomes

• The percent change in epidermal growth factor receptor (eGER) [once a month, up to study completion, an expected average of up to 5 years]: 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.
• A number of adverse events during the study [through study completion, an expected average of up to 5 years]: 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. 1. Serious adverse event 2. Non-serious adverse event 3. Pregnancy 4. Other safety information
• The efficacy of or response to tolvaptan will be evaluated. [twice a year, up to study completion, an expected average of up to5 years]: 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.
• The impact of tolvaptan on the correlation between inulin clearance and eGFR values [once a month, up to study completion, an expected average of up to 5 months]: 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.
• The association between the result of DNA analysis and the effect of tolvaptan [through study completion, an expected average of up to 5 years]: The association between the result of DNA analysis and the effect of tolvaptan will be analyzed.

Sex: All, ages: 18 Years to any

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.

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• Eiji Higashihara, MD, Principal investigator, Kyorin University School of Medicine