Efficacy and Safety of Tolvaptan in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease

Study Overview
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Brief Summary
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The purpose of the study is to determine whether tolvaptan is effective and safe for the treatment of late-stage chronic kidney disease due to autosomal dominant polycystic kidney disease (ADPKD)

Detailed Description
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The protocol will extend the understanding of the efficacy and safety of tolvaptan treatment in ADPKD patients with late stage 2 to early stage 4 CKD (chronic kidney disease). This trial will compare the efficacy of tolvaptan treatment in reducing the annualized change in estimated glomerular filtration rate (eGFR) from pre-treatment baseline to post-treatment follow-up, as compared with placebo, in subjects who tolerate tolvaptan during an initial run-in period. The change in eGFR, calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) formula, will provide kidney function data that are complementary to the data demonstrating the benefits previously observed primarily in ADPKD subjects with earlier stages of disease. Also, it will compare the efficacy of tolvaptan treatment in reducing the decline of annualized eGFR slope, as compared with placebo, in this type of subjects. Finally, it will compare the overall and hepatic safety profile of tolvaptan with placebo and to compare incidence of ADPKD complications (outcomes) during the trial

Official Title
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A Phase 3b, Multi-center, Randomized-withdrawal, Placebo-controlled, Double-blind, Parallel-group Trial to Compare the Efficacy and Safety of Tolvaptan (45 to 120 mg/Day, Split-dose) in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease

Conditions
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Chronic Kidney Disease, Autosomal Dominant Polycystic Kidney Disease

Intervention / Treatment
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* Drug: Tolvaptan (OPC-41061)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects with eGFR between 25-65 mL/min/1.73m2 (if aged 18 to55) or eGFR between 25-44 mL/min/1.73m2 (if aged 56 to <66) Tolvaptan naïve Diagnosis of ADPKD by modified pei-Ravine criteria 1) 3 cysts per kidney by sonography or 5 cysts by CT or MRI with family history of ADPKD or 2) 10 cysts per kidney by any radiologic method and exclusion of other cystic kidney diseases if without family history Exclusion Criteria: Women of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of Investigational medicinal product (IMP) Women who are breast-feeding and/or who have a positive pregnancy test prior to receiving IMP Need for chronic diuretic use Hepatic impairment or liver function abnormalities other than that expected for ADPKD with typical cystic liver disease Advanced diabetes, evidence of additional significant renal disease, renal cancer, single kidney, recent renal surgery or acute kidney injury Contraindications to required trial assessments Medical history or medical findings inconsistent with safety or compliance with trial assessments

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tolvaptan<br>Tolvaptan (OPC-41061) | Drug: Tolvaptan (OPC-41061)<br>* Tolvaptan tablets (15 or 30 mg) will be self-administered orally as split-dose regimens, once upon awakening and another approximately 8 to 9 hours later.<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Matching placebo tablets will be self-administered orally as split-dose regimens, once upon awakening and another approximately 8 to 9 hours later<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up. | The mean annualized change in eGFR was calculated using the Chronic Kidney Disease-Epidemiology (CKD-EPI) formula from pretreatment baseline to post-treatment follow-up, annualized (divided) by each subject's trial duration. The baseline for the primary endpoint was defined as the average of up to 3 eGFR values observed during the screening and placebo run-in periods. | Pretreatment baseline to post-treatment follow-up (up to 61 weeks). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Annualized Slope of eGFR Change | To compare the efficacy of tolvaptan treatment in reducing the decline of annualized eGFR slope, as compared with placebo, in subjects with late-stage CKD due to ADPKD who tolerated tolvaptan during an initial run-in period, the annualized rate of eGFR change was derived from each individual subject's eGFR slope using the CKD-EPI formula. The annualized eGFR change slope was derived from all eGFR observations from placebo-run-in, tolvaptan run-in, double-blind treatment and post-treatment follow-up periods using the linear mixed model of analysis. The mean annualized slope of eGFR change is presented. | Pretreatment baseline to post-treatment follow-up (up to 61 weeks). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Kidney Disease, Autosomal Dominant Polycystic Kidney Disease