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Effect of the Aquaretic Tolvaptan on Nitric Oxide System (TOPO)

Primary Purpose

Autosomal Dominant Polycystic Kidney Disease

Status
Completed
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
Tolvaptan
Placebo
Sponsored by
Regional Hospital Holstebro
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Autosomal Dominant Polycystic Kidney Disease focused on measuring Tolvaptan, L-NMMA, ADPKD

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Caucasian men and women
  2. Age between 18-65 years

  3. ADPKD, diagnosed by genetic testing of PKD1 (>85%) or PKD2 mutations, or by ultrasonography:

    1. patients with negative family history for ADKPD and more than 10 cysts in each kidney and no extrarenal or renal findings that suggest causes to cyst formation.

    2. patients with positive family history for ADPKD:

      • 15-39 yr of age and at least 3 or more unilateral or bilateral.
      • 40-59 yr of age and 2 or more cysts in each kidney.
      • 60 yr of age and at least 4 cysts in each kidney.
  4. Kidney function corresponding to CKD stages 1-3(eGFR> 30 mL/min/1,73 m2),
  5. BMI between 18.5 and 35.5 kg/m2.

Exclusion Criteria:

  1. Clinical signs of diseases in the heart, lungs, endocrine organs, brain or neoplastic disease,
  2. clinically significant abnormalities in blood or urine sample at the inclusion
  3. previous cerebrovascular insults,
  4. previous clinical evidence for aneurysm
  5. Alcohol or drug abuse,
  6. smoking,
  7. pregnancy or breastfeeding,
  8. clinically significant changes in the electrocardiogram,
  9. medication except antihypertensive agents and oral contraceptives,
  10. blood pressure>170/105 mmHg despite treatment with metoprolol and/or amlodipine.

Sites / Locations

  • Department of Medical Research and Medicine, Holstebro Regional Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

60 mg Tolvaptan

Placebo

Arm Description

Oral administration of 60 mg tolvaptan on each examination day.

Oral administration of a Unikalk tablet.

Outcomes

Primary Outcome Measures

CH2O (Measurement of H2O clearance)
Measurement of H2O clearance at baseline, during and after L-NMMA infusion

Secondary Outcome Measures

Urine biomarkers(Aquaporins and Epithelial Sodium Channels γ)
Central and brachial blood pressure
Augmentation Index
Vasoactive Hormones( Angiotensin II, Aldosterone, Endothelin, Atrial Natriuretic Peptide, Brain Natriuretic Peptide, Arginin Vasopressin)
Fractional sodium excretion
Measurement of Sodium excretion at baseline, during and after L-NMMA infusion.

Full Information

First Posted
February 18, 2015
Last Updated
February 28, 2017
Sponsor
Regional Hospital Holstebro
Collaborators
Aarhus University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02527863
Brief Title
Effect of the Aquaretic Tolvaptan on Nitric Oxide System
Acronym
TOPO
Official Title
The Effects of Tolvaptan on Renal Handling of Water and Sodium, Vasoactive Hormones and Central Hemodynamics During Baseline Conditions and After Inhibition of the Nitric Oxide System in Patients With Autosomal Dominant Polycystic Kidney Disease
Study Type
Interventional

2. Study Status

Record Verification Date
February 2017
Overall Recruitment Status
Completed
Study Start Date
February 2015 (Actual)
Primary Completion Date
August 2016 (Actual)
Study Completion Date
August 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Regional Hospital Holstebro
Collaborators
Aarhus University Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Tolvaptan is a selective vasopressin receptor antagonist (V2R) that increases free water and sodium excretion. Inhibition of V2R increases vasopressin concentration in plasma, which stimulates V1-receptors in the vascular bed and may change both central and brachial hemodynamics and plasma concentration of vasoactive hormones. The purpose of the study is to measure the effects of tolvaptan on renal handling of water and sodium, systemic hemodynamics and vasoactive hormones at baseline and during nitric oxide (NO)-inhibition with L-NG-monomethyl-arginine (L-NMMA) in patients with autosomal dominant polycystic kidney disease.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autosomal Dominant Polycystic Kidney Disease
Keywords
Tolvaptan, L-NMMA, ADPKD

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
60 mg Tolvaptan
Arm Type
Active Comparator
Arm Description
Oral administration of 60 mg tolvaptan on each examination day.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Oral administration of a Unikalk tablet.
Intervention Type
Drug
Intervention Name(s)
Tolvaptan
Other Intervention Name(s)
Samsca
Intervention Description
60 mg Tolvaptan pr day for 1 day
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Unikalk
Intervention Description
1 tablet Unikalk pr day for 1 day
Primary Outcome Measure Information:
Title
CH2O (Measurement of H2O clearance)
Description
Measurement of H2O clearance at baseline, during and after L-NMMA infusion
Time Frame
5-6 Hours
Secondary Outcome Measure Information:
Title
Urine biomarkers(Aquaporins and Epithelial Sodium Channels γ)
Time Frame
5-6 Hours
Title
Central and brachial blood pressure
Time Frame
5-6 Hours
Title
Augmentation Index
Time Frame
5-6 Hours
Title
Vasoactive Hormones( Angiotensin II, Aldosterone, Endothelin, Atrial Natriuretic Peptide, Brain Natriuretic Peptide, Arginin Vasopressin)
Time Frame
5-6 Hours
Title
Fractional sodium excretion
Description
Measurement of Sodium excretion at baseline, during and after L-NMMA infusion.
Time Frame
5-6 Hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Caucasian men and women Age between 18-65 years ADPKD, diagnosed by genetic testing of PKD1 (>85%) or PKD2 mutations, or by ultrasonography: patients with negative family history for ADKPD and more than 10 cysts in each kidney and no extrarenal or renal findings that suggest causes to cyst formation. patients with positive family history for ADPKD: 15-39 yr of age and at least 3 or more unilateral or bilateral. 40-59 yr of age and 2 or more cysts in each kidney. 60 yr of age and at least 4 cysts in each kidney. Kidney function corresponding to CKD stages 1-3(eGFR> 30 mL/min/1,73 m2), BMI between 18.5 and 35.5 kg/m2. Exclusion Criteria: Clinical signs of diseases in the heart, lungs, endocrine organs, brain or neoplastic disease, clinically significant abnormalities in blood or urine sample at the inclusion previous cerebrovascular insults, previous clinical evidence for aneurysm Alcohol or drug abuse, smoking, pregnancy or breastfeeding, clinically significant changes in the electrocardiogram, medication except antihypertensive agents and oral contraceptives, blood pressure>170/105 mmHg despite treatment with metoprolol and/or amlodipine.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Erling B Pedersen
Organizational Affiliation
Department of Medical Research and Medicine, Holstebro Regional Hospital Holstebro, Holstebro, Denmark, 7500
Official's Role
Study Chair
Facility Information:
Facility Name
Department of Medical Research and Medicine, Holstebro Regional Hospital
City
Holstebro
ZIP/Postal Code
7500
Country
Denmark

12. IPD Sharing Statement

Citations:
PubMed Identifier
28810844
Citation
Al Therwani S, Malmberg MES, Rosenbaek JB, Bech JN, Pedersen EB. Effect of tolvaptan on renal handling of water and sodium, GFR and central hemodynamics in autosomal dominant polycystic kidney disease during inhibition of the nitric oxide system: a randomized, placebo-controlled, double blind, crossover study. BMC Nephrol. 2017 Aug 15;18(1):268. doi: 10.1186/s12882-017-0686-3.
Results Reference
derived

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Effect of the Aquaretic Tolvaptan on Nitric Oxide System

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