Subacute Effect of Tolvaptan on Total Kidney Volume in Adult Patients With Autosomal Dominant Polycystic Kidney Disease

Study Overview
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Brief Summary
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Investigator initiated controlled multi-centre trial in a Prospective, Randomised, Open, Blinded Endpoint (PROBE) design. Patients will be randomised in a 1:1 ratio either to treatment with tolvaptan for six weeks followed by six weeks observation without trial medication or no tolvaptan treatment, but following the same visit and investigation plan as the subjects taking tolvaptan.

Detailed Description
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Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic kidney disease and the fourth leading cause of end-stage renal disease in adults Worldwide. The tolvaptan tablet has been approved by EMA (European Medicines Agency) with the indication of slowing the progression of cysts development and renal insufficiency in adults with ADPKD. It is the newest and only possible treatment for this patient group and could be initiated in patients with evidence for rapidly progressive disease Development. There is however in Denmark and other countries both scientific and financial reluctance to initiate this expensive treatment for several reasons e.g. selection of patients who might benefit, effect on progression of kidney disease, side effects and tolerability. Before deciding on implementation in Denmark, more knowledge is needed. The results of the PoCKET trial will contribute with guidance on this decision. Foremost the trial is designed to address not only the change in kidney volume, but the change in kidney function, which is what matters to the patients and their prognosis in terms of postponing time to end stage renal disease. Furthermore, important data on side effects and tolerability will be generated.

Official Title
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Subacute Effect of Tolvaptan on Total Kidney Volume in Adult Patients With Autosomal Dominant Polycystic Kidney Disease

Conditions
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Autosomal Dominant Polycystic Kidney

Intervention / Treatment
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* Drug: Tolvaptan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients between 18 and 65 years Diagnosis of typical ADPKD tKV above or equal to 750 ml by MRI scanning Estimated GFR (e-GFR) by CKD-EPI formula of above or equal to 45 mL/min/1.73 m2 Exclusion Criteria: Kidney transplant recipient Known liver disease except for liver cysts relating to ADPKD ASAT and ALAT above upper normal level Current treatment with thiazide and thiazide-line diuretics, mineral corticoid receptor antagonists, amiloride or loop diuretics Evidence of urinary tract obstruction Current treatment with CYP3A4 inhibitors Active malignant disease Current or previous treatment with tolvaptan

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
Interventional Model Description: Patients will be randomised in a 1:1 ration either to treatment with tolvaptan for six weeks followed by six weeks observation without trial medicaion or to the Control group receiving no tolvaptan treatment for 12 weeks
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tolvaptan group<br>Treatment with tolvaptan for six weeks followed by six weeks observation without trial medication | Drug: Tolvaptan<br>* At baseline the tolvaptan dosing will start with daily morning and afternoon doses of 45 mg and 15 mg respectively, with weekly increases to 60 mg and 30 mg and then to 90 mg and 30 mg according to subject tolerability<br>* Other names: Jinarc;|
| No Intervention: Control group<br>No tolvaptan treatment but following the same visit and investigation plan as the subjects in the tolvaptan group | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in total Kidney Volume (tKV) measured by MRI scanning | The change in the total Kidney Volume after six and 12 weeks participation in the trial | Between baseline and six weeks and between six and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in GFR | The changes in GFR measured by Cr-EDTA clearance | Between baseline and six weeks and between baseline and 12 weeks | 
| Changes in relevant genetic and non-genetic biomarkers associated with CKD and ESRD | Prediction of change in progression of the disease over time in the genes PKD1, PKD2, PKHD1 and HNF1B. The following biomarkers will be determined: NGAL, UMOD, MCP-1, KIM-1, cystatin-C and copeptin | Between baseline and six weeks and between baseline and 12 weeks | 
| Changes in Quality of Life | Questionnaire SF36 Health Survey - with 36 questions to subject's health and wellbeing | Between baseline and six weeks and between baseline and 12 weeks | 
| Subject estimation of own health | Estimated by a Visual Analogue Scale from 0 (worth wellbeing) to 100 (best wellbeing | Between baseline and six weeks and between baseline and 12 weeks | 
| Changes in ASAT and ALAT | Changes estimated from laboratory results | Between baseline and six weeks and between baseline and 12 weeks | 
| Incidence of Adverse Events | Evaluation of Adverse Events including severity, causality, outcome and seriousness assessments | Between baseline and six weeks and between baseline and 12 weeks |