Renoprotection by Pentoxifylline and Angiotensin Receptor Blocker in Chronic Kidney Disease (CKD) (CKD)

October 13, 2016 updated by: National Taiwan University Hospital

Renoprotection by Combining Pentoxifylline and Angiotensin Blockade in Chronic Kidney Disease

This is a multicenter, randomized, double-blind, placebo-controlled clinical trial to investigate the renoprotective efficacy of combined pentoxifylline (PTX) and angiotensin receptor blockers (valsartan), compared with placebo and valsartan in 700 patients with Chronic Kidney Disease (CKD) stages 3 and 4. The effect on cardiovascular comorbidity will also be observed. The observation period will be 3 years. The primary endpoints consists of doubling of serum creatinine, end stage renal disease (ESRD), and death from any cause. The secondary endpoints include changes of microalbuminuria or proteinuria, serum and urinary levels of TNF-a(tumor necrosis factor-alpha ), MCP-1(monocyte chemotactic protein), TGF-beta1(transforming growth factor ), collagens III (amino terminal peptide of procollagen III) and IV, and fibronectin, urinary N-acetyl-beta-glucosaminidase, as well as serum fibrinogen and high-sensitive CRP(C reactive protein), and development of heart failure, nonfatal myocardial infarction, and stroke or transient ischemic attack.

Study Overview

Detailed Description

This study is a multicenter placebo-controlled double-blind randomized clinical trial. The design scheme is depicted in Figure 1. (see below). At the time of screening, all pentoxifylline-naïve participants must have been receiving angiotensin receptor blockers(ARB) per day for no less than 8 weeks and have stable renal function with serum creatinine elevation < 25% in the preceding 8 weeks. For patients taking maximal dose of angiotensin receptor blockers(ARB) for more than 8 weeks, randomization will be started after recruitment. For patients taking submaximal, fixed dose of angiotensin receptor blockers(ARB)for ≥ 8 weeks, with good BP(blood pressure), i.e., ≤ 130/80 mmHg, randomization can also be started after recruitment. However, for patients taking submaximal dose of angiotensin receptor blockers(ARB) with suboptimal BP, i.e., >130/80 mmHg, patients can be recruited but will not be randomized until the dose of angiotensin receptor blockers(ARB) has been fixed for ≥ 8 weeks, or a maximal dose of angiotensin receptor blockers(ARB) has been administered for ≥ 8 weeks.The recruited CKD(Chronic kidney disease) patients will be randomized to receive pentoxifylline (400 mg once or twice a day) or placebo (one tablet once or twice a day). Patients with stage 3 CKD(estimated GFR,eGFR30-59.9ml/min/1.73 m2) will receive either pentoxifylline one tablet (400 mg) twice a day, or placebo one tablet twice a day.If the patients are still intolerant of the potential side effects, they may withdraw from the study voluntarily. Patients with stage 4 CKD(estimated Glomerular filtration rate,eGFR15-29ml/min/1.73 m2) will receive either pentoxifylline one tablet (400 mg) once per day, or placebo one tablet once per day. In patients who develop potential side effects (anorexia, epigastric distention, dizziness, and headache) to the test drug, they may withdraw from the study voluntarily. If patients have SBP(systolic blood pressure ) > 130 mmHg and/or DBP (diastolic blood pressure )> 80 mmHg, it is necessary to adjust the other antihypertensive drugs. However, the following medications are not allowed during the study: ACE(angiotensin-converting-enzyme) inhibitor; phosphodiesterase inhibitor (other than pentoxifylline); direct vasodilators (e.g., hydralazine and minoxidil), as they can blunt the decrease in proteinuria, and chronic immunosuppressive or non-steroidal anti-inflammatory drug (NSAID) therapy.

The randomization is done with the stratifications of CKD(Chronic kidney disease) stages and diabetic/non-diabetic status. CKD includes stage 3(estimated GFR,eGFR30-59.9ml/min/1.73 m2) and 4(estimated Glomerular filtration rate,eGFR15-29ml/min/1.73 m2). CKD stage 3 is further divided to 3A(estimated Glomerular filtration rate,eGFR45-59ml/min/1.73 m2) and 3B(estimated Glomerular filtration rate,eGFR30-44ml/min/1.73 m2) according to most recent guideline (NICE clinical guideline 73, Chronic kidney disease, September 2008) Two-arm random permuted block randomization with mixed block sizes 6, 8 and 10 will be implemented within each stratum. Double-blind measures will be enforced in each participating hospital. And, extra efforts will be made to avoid noncompliance, missing data, and loss to follow-up during the trial. Patient's renal function will be calculated by the Cockcroft-Gault and simplified MDRD(Modification of Diet in Renal Disease) formula. All blood and urine analyses will be performed by the Department of Laboratory Medicine, NTUH(National Taiwan University Hospital). Serum and urine samples are collected before and annually after randomization, and the specimens are allocated and stored at -70°C. Profibrotic or inflammatory markers such as serum and urinary levels of TNF-alpha, MCP-1, TGF-beta1, collagens III(amino-terminal propeptide of type III procollagen) and IV, and fibronectin, urinary NAG, as well as serum fibrinogen and high-sensitive CRP will be measured by using commercially available kits. Genetic polymorphism of MCP-1 and fractalkine receptor will also be analyzed to evaluate their association with renal outcomes.

Study Type

Interventional

Enrollment (Anticipated)

350

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Yung-Ming Chen, Professor
  • Phone Number: 66046 00886-2-23123456
  • Email: chenym@ntuh.gov.tw

Study Contact Backup

Study Locations

      • Taipei, Taiwan, 100
        • Recruiting
        • National Taiwan University Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Tun-Jun Tsai, M.D.; PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Diabetic and non-diabetic men and women between 20 and 80 years of age who have been diagnosed as CKD stage 3 to 4. The diabetic patients must be type II diabetes mellitus (DM) having overt proteinuria or microalbuminuria twice within the preceding 6 months with a clinical exclusion of non-diabetic kidney diseases. Non-diabetic patients may or may not have overt proteinuria; for proteinuric non-diabetic patients, the proteinuria must be present on two occasions within the preceding 6 months.
  • Renal replacement therapy is not expected within the forthcoming 12 months.
  • Currently under angiotensin receptor blockers(ARB) therapy for at least 8 weeks, with systolic blood pressure<150 mmHg, diastolic blood pressure <90 mmHg
  • Renal function has been stable for at least 8 weeks (fluctuation<25% of baseline) at the time of screening

Exclusion Criteria:

  • Type I DM patients
  • Patients with history of allergy to pentoxifylline or methylxanthine derivatives (such as caffeine, theophylline)or those who have been taking pentoxifylline or dipyridamole as a treatment for chronic disease in the preceding 3 months at screening.
  • Patients have been taking ACE inhibitors, renin inhibitors (eg. Rasilez); and direct vasodilators (e.g., hydralazine and minoxidil) at the time of screening
  • Females in nursing or pregnancy, or preparing for pregnancy within the next three years.
  • Obstructive uropathy.
  • Active gastrointestinal bleeding Active peptic ulcer, patients with active bleeding or bleeding tendency and patients under antiplatelet or anticoagulant therapy,except for aspirin 100 mg, clopidogrel 75 mg.
  • Unable to stop chronic immunosuppressive therapy or NSAID; or current use of phosphodiesterase inhibitors other than pentoxifylline (eg., dipyridamole)
  • Congestive heart failure of functional class III or IV.
  • Unstable angina, myocardial infarction, coronary artery bypass graft surgery, or percutaneous coronary intervention, within the past 3 months prior to signing for informed consent.
  • Cerebral vascular diseases within the past 3 months prior to signing for informed consent.
  • Retinal hemorrhage within the past 3 months prior to signing for informed consent.
  • Known or suspected secondary hypertension (e.g., primary aldosteronism, renovascular hypertension, and pheochromocytoma).
  • Poor glycemic control (HbA1c>8.5%)
  • Liver cirrhosis or hepatic dysfunction as defined by abnormal liver function test
  • Biliary obstructive disorders (e.g., cholestasis).
  • Active malignancy or infectious diseases.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: ARB & Pentoxifylline
angiotensin receptor blockers(ARB)and Pentoxifylline 400mg tablet (If CKD3 1# BID(Bi in die=two times a day); CKD4 1# QD(quaque die=one time a day); CKD5(estimated Glomerular filtration rate,eGFR<15ml/min/1.73 m2) 1# QOD(Every other day).
Angiotensin II receptor antagonists ,these medicines have names that end in "sartan".For examples:losartan,candesartan,irbesartan,olmesartan,telmisartan,valsartan
Other Names:
  • angiotensin receptor blockers(ARB)
Sugar pill manufactured to mimic Pentoxifylline 400mg tablet
Other Names:
  • Placebo(non treatment)
Active Comparator: ARB & Placebo
angiotensin receptor blockers(ARB) and Placebo tablet(If CKD3 1# BIDBi in die=two times a day); CKD4 1# QD(quaque die=one time a day); CKD5(estimated Glomerular filtration rate,eGFR<15ml/min/1.73 m2) 1# QOD(Every other day).
Sugar pill manufactured to mimic Pentoxifylline 400mg tablet
Other Names:
  • Placebo(non treatment)
This medication is used to improve the symptoms of a certain blood flow problem in the legs/arms (intermittent claudication due to occlusive artery disease)
Other Names:
  • Trental

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
doubling of serum creatinine, ESRD, and death from any cause
Time Frame: 3 years
3 years

Secondary Outcome Measures

Outcome Measure
Time Frame
changes of microalbuminuria or proteinuria, and development of heart failure, nonfatal myocardial infarction, and stroke or transient ischemic attack.
Time Frame: 3 years
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Yung-Ming Chen, M.D.; PhD, National Taiwan University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2010

Primary Completion (Anticipated)

December 1, 2018

Study Completion (Anticipated)

December 1, 2018

Study Registration Dates

First Submitted

June 8, 2010

First Submitted That Met QC Criteria

June 20, 2011

First Posted (Estimate)

June 21, 2011

Study Record Updates

Last Update Posted (Estimate)

October 14, 2016

Last Update Submitted That Met QC Criteria

October 13, 2016

Last Verified

October 1, 2016

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

if the subject have serious adverse event and Data Monitoring Committee decide need to make individual participant data,study team will provide data.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Chronic Renal Failure

Clinical Trials on ARB

3
Subscribe