Renoprotection by Pentoxifylline and Valsartan in Chronic Kidney Disease (CKD)

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2013 by National Taiwan University Hospital
Sponsor:
Collaborators:
Far Eastern Memorial Hospital
Mackay Memorial Hospital
Taipei Medical University Hospital
Shin Kong Wu Ho-Su Memorial Hospital
Cathay General Hospital
Information provided by (Responsible Party):
National Taiwan University Hospital
ClinicalTrials.gov Identifier:
NCT01377285
First received: June 8, 2010
Last updated: October 25, 2013
Last verified: October 2013
  Purpose

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-alpha, MCP-1, TGF-beta1, 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, and development of heart failure, nonfatal myocardial infarction, and stroke or transient ischemic attack.


Condition Intervention Phase
Chronic Renal Failure
Drug: Valsartan
Drug: Pentoxifylline
Drug: Placebo (for Pentoxifylline)
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Renoprotection by Combining Pentoxifylline and Angiotensin Blockade in Chronic Kidney Disease

Resource links provided by NLM:


Further study details as provided by National Taiwan University Hospital:

Primary Outcome Measures:
  • doubling of serum creatinine, ESRD, and death from any cause [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • changes of microalbuminuria or proteinuria, and development of heart failure, nonfatal myocardial infarction, and stroke or transient ischemic attack. [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 350
Study Start Date: June 2010
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Valsatan & Pentoxifylline
Valsatan 160mg/120mg/80mg tablet and Pentoxifylline 400mg tablet (If CKD3 1# BID; CKD4 1# QD; CKD5 1# QOD.)
Drug: Valsartan
Other Name: Diovan
Drug: Pentoxifylline
Other Name: Trental
Active Comparator: Valsatan & Placebo
Valsatan 160mg/120mg/80mg tablet and Placebo tablet(If CKD3 1# BID; CKD4 1# QD; CKD5 1# QOD.)
Drug: Valsartan
Other Name: Diovan
Drug: Placebo (for Pentoxifylline)
Sugar pill manufactured to mimic Pentoxifylline 400mg tablet

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 Diovan 80-160 mg 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 Diovan (160 mg/day) for more than 8 weeks, randomization will be started after recruitment. For patients taking submaximal, fixed dose of Diovan (< 160 mg/day) for ≥ 8 weeks, with good BP, i.e., ≤ 130/80 mmHg, randomization can also be started after recruitment. However, for patients taking submaximal dose of Diovan with suboptimal BP, i.e., >130/80 mmHg, patients can be recruited but will not be randomized until the dose of Diovan has been fixed for ≥ 8 weeks, or a maximal dose of Diovan (160 mg/day) has been administered for ≥ 8 weeks.The recruited CKD 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 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 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 > 130 mmHg and/or DBP > 80 mmHg, it is necessary to adjust the other antihypertensive drugs. However, the following medications are not allowed during the study: ARB; ACE 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 stages and diabetic/non-diabetic status. CKD includes stage 3 and 4. CKD stage 3 is further divided to 3A and 3B 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 formula. All blood and urine analyses will be performed by the Department of Laboratory Medicine, NTUH. 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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men and women (18-80 years) having diabetic or non-diabetic CKD at stages 3 to 4, as defined by the National Kidney Foundation definition, USA.
  • Renal replacement therapy is not expected within the forthcoming 12 months.
  • Currently under Diovan therapy for at least 8 weeks, with systolic blood pressure<150 mmHg, diastolic blood pressure <90 mmHg irrespective of the magnitude of proteinuria.
  • Renal function has been stable for at least 8 weeks (fluctuation<25% of baseline) at the time of screening

Exclusion Criteria:

  • Patients with history of allergy to pentoxifylline or methylxanthine derivatives (such as caffeine, theophylline).
  • 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.
  • 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).
  • Severe uncontrolled hypertension with SBP ≥ 200 mmHg or DBP ≥ 110 mmHg.
  • Poor glycemic control (HbA1c>8.5%) [Barnett et al, 2004].
  • Liver cirrhosis or hepatic dysfunction as defined by the following laboratory parameters: ALT or AST > 2 times the upper limit of the normal range.
  • Biliary obstructive disorders (e.g., cholestasis).
  • Active malignancy or infectious diseases.
  • Systolic blood pressure<110 mmHg.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01377285

Contacts
Contact: Yung-Ming Chen, Professor 00886-2-23123456 ext 66046 chenym@ntuh.gov.tw

Locations
Taiwan
National Taiwan University Hospital Recruiting
Taipei, Taiwan, 100
Contact: Tun-Jun Tsai, M.D.; PhD    00886-2-23123456 ext 63953    tjtsai@ntuh.gov.tw   
Contact: Yung-Ming Chen, M.D.    00886-2-23123456 ext 65993    chenym@ntuh.gov.tw   
Principal Investigator: Tun-Jun Tsai, M.D.; PhD         
Sponsors and Collaborators
National Taiwan University Hospital
Far Eastern Memorial Hospital
Mackay Memorial Hospital
Taipei Medical University Hospital
Shin Kong Wu Ho-Su Memorial Hospital
Cathay General Hospital
Investigators
Principal Investigator: Yung-Ming Chen, M.D.; PhD National Taiwan University Hospital
  More Information

No publications provided

Responsible Party: National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT01377285     History of Changes
Other Study ID Numbers: 200809041M
Study First Received: June 8, 2010
Last Updated: October 25, 2013
Health Authority: Taiwan: Department of Health

Keywords provided by National Taiwan University Hospital:
chronic kidney disease
pentoxifylline
valsartan

Additional relevant MeSH terms:
Kidney Diseases
Kidney Failure, Chronic
Renal Insufficiency
Renal Insufficiency, Chronic
Urologic Diseases
Pentoxifylline
Valsartan
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Antihypertensive Agents
Antioxidants
Cardiovascular Agents
Enzyme Inhibitors
Free Radical Scavengers
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Phosphodiesterase Inhibitors
Physiological Effects of Drugs
Platelet Aggregation Inhibitors
Protective Agents
Radiation-Protective Agents
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on October 21, 2014