NCT00285805

Brief Summary

Thiazolidinedione derivates (TZD's) are Peroxisome-Proliferator-Activated-Receptor-γ agonists (PPARγ-agonists) and enhance insulin sensitivity. One of the side effects, however, is the fact that subjects treated with these drugs seem to be more prone to fluid retention. The precise mechanism of rosiglitazone-related fluid retention is unknown, but it is clear that either primary or secondary renal sodium retention is part of the mechanism. Furthermore in observational studies, TZD-related oedema seems to be resistant to loop diuretic therapy. The recent finding that rosiglitazone induces upregulation of the epithelial sodium channel (ENaC) in the kidney could be the explanation for TZD-related fluid retention and the observed resistance to loop diuretics. In the present human in-vivo study the following hypothesis will be tested: Rosiglitazone treatment stimulates the activity of ENaC in the distal nephron, which enhances the natriuretic effect of amiloride and decreases the natriuretic effect of furosemide in parallel.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
13

participants targeted

Target at below P25 for not_applicable

Timeline
Completed

Started Feb 2006

Shorter than P25 for not_applicable

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

February 1, 2006

Completed
Same day until next milestone

Study Start

First participant enrolled

February 1, 2006

Completed
1 day until next milestone

First Posted

Study publicly available on registry

February 2, 2006

Completed
8 months until next milestone

Primary Completion

Last participant's last visit for primary outcome

October 1, 2006

Completed
1 month until next milestone

Study Completion

Last participant's last visit for all outcomes

November 1, 2006

Completed
Last Updated

August 24, 2010

Status Verified

October 1, 2008

Enrollment Period

8 months

First QC Date

February 1, 2006

Last Update Submit

August 23, 2010

Conditions

Insulin Resistance

Keywords

RosiglitazoneFurosemideAmilorideEpithelial sodium channelSodium excretion

Outcome Measures

Primary Outcomes (1)

  • Difference in cumulative sodium excretion over an 8-hour period following amiloride infusion after 9 weeks of treatment with either rosiglitazone or placebo.

    week: 9, 22

Secondary Outcomes (2)

  • The difference in ER50 (urine excretion rate of furosemide with the half maximal effect) after 8 weeks of treatment with either rosiglitazone or placebo.

    week: 8, 21

  • The difference in the ENac abundance in exosomes in the urine measured after 8 weeks of treatment with either rosiglitazone or placebo

    week: 8, 21

Study Arms (2)

Rosiglitazone-placebo

OTHER
Drug: Rosiglitazone versus placeboDrug: response (sodium excretion) to amiloride infusionDrug: response (sodium excretion) to furosemide infusion

placebo-rosiglitazone

OTHER
Drug: Rosiglitazone versus placeboDrug: response (sodium excretion) to amiloride infusionDrug: response (sodium excretion) to furosemide infusion

Interventions

Rosiglitazone versus placeboDRUG
Rosiglitazone-placeboplacebo-rosiglitazone
response (sodium excretion) to amiloride infusionDRUG
Rosiglitazone-placeboplacebo-rosiglitazone
response (sodium excretion) to furosemide infusionDRUG
Rosiglitazone-placeboplacebo-rosiglitazone

Eligibility Criteria

Age30 Years - 70 Years
Sexall
Healthy VolunteersYes
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Healthy but with 2 features of the metabolic syndrome (AHA/NHLBI) (16)
  • Willing and able to provide a signed and dated written informed consent.
  • Male or female subject aged between 30 and 70 years

You may not qualify if:

  • Fasting glucose \> 7,0 mmol/L or the use of hypoglycaemic agents. If fasting plasma glucose is between 6.1 and 7,0 mmol/L,an oral 75 g glucose test will be performed to exclude diabetes mellitus.
  • Exposure to a PPAR-g agonist during the last 4 months or a documented significant hypersensitivity to a PPAR-g agonist.
  • Participant in another study.
  • Angina or heart failure (NYHA I-IV).
  • Clinically significant liver disease (3 times the upper normal limit of ALAT, ASAT, AF, γGT or LDH)
  • Clinically significant anaemia (male Hb \< 6,9 mmol/L, female \< 6,25 mmol/L)
  • Creatinin clearance \< 40 mL/min
  • Pregnancy, lactation
  • Alcohol or drug abuse. Liquorice

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Radboud University Nijmegen medical centre

Nijmegen, 6500 HB, Netherlands

Location

Related Publications (7)

  • Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M, Porte D, Semenkovich CF, Smith S, Young LH, Kahn R; American Heart Association; American Diabetes Association. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. October 7, 2003. Circulation. 2003 Dec 9;108(23):2941-8. doi: 10.1161/01.CIR.0000103683.99399.7E. No abstract available.

    PMID: 14662691BACKGROUND

  • Hong G, Lockhart A, Davis B, Rahmoune H, Baker S, Ye L, Thompson P, Shou Y, O'Shaughnessy K, Ronco P, Brown J. PPARgamma activation enhances cell surface ENaCalpha via up-regulation of SGK1 in human collecting duct cells. FASEB J. 2003 Oct;17(13):1966-8. doi: 10.1096/fj.03-0181fje. Epub 2003 Aug 15.

    PMID: 12923071BACKGROUND

  • Guan Y, Hao C, Cha DR, Rao R, Lu W, Kohan DE, Magnuson MA, Redha R, Zhang Y, Breyer MD. Thiazolidinediones expand body fluid volume through PPARgamma stimulation of ENaC-mediated renal salt absorption. Nat Med. 2005 Aug;11(8):861-6. doi: 10.1038/nm1278. Epub 2005 Jul 10.

    PMID: 16007095BACKGROUND

  • Niemeyer NV, Janney LM. Thiazolidinedione-induced edema. Pharmacotherapy. 2002 Jul;22(7):924-9. doi: 10.1592/phco.22.11.924.33626.

    PMID: 12126225BACKGROUND

  • van Meyel JJ, Smits P, Russel FG, Gerlag PG, Tan Y, Gribnau FW. Diuretic efficiency of furosemide during continuous administration versus bolus injection in healthy volunteers. Clin Pharmacol Ther. 1992 Apr;51(4):440-4. doi: 10.1038/clpt.1992.44.

    PMID: 1563213BACKGROUND

  • Baba WI, Lant AF, Smith AJ, Townshend MM, Wilson GM. Pharmacological effects in animals and normal human subjects of the diuretic amiloride hydrochloride (MK-870). Clin Pharmacol Ther. 1968 May-Jun;9(3):318-27. doi: 10.1002/cpt196893318. No abstract available.

    PMID: 5649984BACKGROUND

  • Pisitkun T, Shen RF, Knepper MA. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13368-73. doi: 10.1073/pnas.0403453101. Epub 2004 Aug 23.

    PMID: 15326289BACKGROUND

MeSH Terms

Conditions

Insulin Resistance

Condition Hierarchy (Ancestors)

HyperinsulinismGlucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic Diseases

Study Officials

  • Paul Smits, MD, PhD

    Radboud University Nijmegen Medical Centre, head of department Pharmacology and Toxicology.

    PRINCIPAL INVESTIGATOR

  • Cees JJ Tack, MD, PhD

    Radboud University Nijmegen Medical Centre, chairman of the departement of diabetology

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
not applicable
Allocation
RANDOMIZED
Masking
TRIPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR
Purpose
TREATMENT
Intervention Model
CROSSOVER
Sponsor Type
OTHER

Study Record Dates

First Submitted

February 1, 2006

First Posted

February 2, 2006

Study Start

February 1, 2006

Primary Completion

October 1, 2006

Study Completion

November 1, 2006

Last Updated

August 24, 2010

Record last verified: 2008-10

Locations

NL(1)