Official Title: “Clinical Efficacy of Pentoxifylline on Patients With Primary Nephrotic Syndrome”

We aim to investigate (1) the effects of combined pentoxifylline and corticosteroids, compared to that of corticosteroids, on patients with primary nephrotic syndrome; and (2) the effects of pentoxifylline monotherapy on patients with primary nephrotic syndrome not suitable for or intolerance of standard corticosteroid therapy.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: July 2010

Pentoxifylline (PTX) is a phosphodiesterase inhibitor that is used clinically to treat patients with peripheral vascular disorders. In addition to its hemorheologic activity, PTX possesses potent anti-inflammatory and immunomodulatory properties. In vivo, PTX has shown its ability to attenuate nephrotic syndrome secondary to membranous glomerulonephritis and lupus nephritis, and to reduce subnephrotic proteinuria of early and advanced diabetic nephropathy. However, the anti-proteinuric effect of PTX has been traditionally attributed to down-regulation of TNF-alpha. Whether or not other inflammatory mediators are also affected by PTX has never been studied. Our previous works have shown that PTX can inhibit cytokine or albumin-induced MCP-1 production in vitro, and attenuate proteinuria in association with suppression of renal MCP-1 mRNA expression in experimental glomerulonephritis.

More recently, we have found that PTX lowers proteinuria by modulating renal MCP-1 production in a subgroup of human glomerular diseases. In this study, we aim to investigate whether combination of PTX and corticosteroids results in additive reduction in proteinuria, and higher remission rates in patients with primary nephrotic syndrome. The secondary objective is to study whether PTX monotherapy can be effective in patients with primary nephrotic syndrome not suitable for or intolerant of corticosteroid therapy.

The part A study is a prospective, open-labeled, comparative study including primary nephrotic patients randomized into 2 groups. Group A receives oral pentoxifylline plus oral prednisolone, whereas group B receives oral prednisolone alone. The treatment duration is 1 year for both subgroups. The dose for pentoxifylline will be 1,200 mg/day for 1 year. The dose for prednisolone will be 1 mg/kg/day for the initial 3 months, then the dose will be gradually tapered, thus by 6 months the dose will be 0.5 mg/kg/day, and at 12 months the dose will be reduced to around 5-10 mg/day. Part B of the study consists of primary nephrotic patients not considered suitable for (eg., chronic HBV or HCV infection), or intolerance of (eg., concomitant diabetes mellitus, active peptic ulcer disease) standard corticosteroid therapy. Pentoxifylline 1,200 mg/day will be administered to these patients for a total of

1 year. For either part of the study, serum and urine specimens will be collected before initiation of therapy (day 0), and at month 1, 3, 6, and 12 after the commencement of therapy. Glomerular filtration rates will be calculated by Cockcroft-Gault and simplified MDRD formula. Urinary protein excretion will be quantitated by spot urine protein/creatinine ratio and 24-hour urinary protein measurement. All biochemical and immunological analyses will be performed by the Department of Laboratory Medicine, National Taiwan University Hospital. Serum and urine samples will be measured for inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, MCP-1, CX3CL1 (fractalkine), IL-8 by using commercial ELISA kits.

Intervention(s) in this Clinical Trial

• Drug: pentoxifylline
  • The dose for pentoxifylline will be 1,200 mg/day (400 mg three times a day) for 1 year.

Primary Measures

• changes from baseline in urinary protein excretion
  • Time Frame: 12 months
    Safety Issue?: Yes

Secondary Measures

• change from baseline in serum CRP, creatinine and estimated creatinine clearance, as well as urinary NAG, TNF-alpha and MCP-1
  • Time Frame: 12 months
    Safety Issue?: Yes

Inclusion Criteria:

• biopsied-proved primary glomerular diseases, and nephrotic syndrome

Exclusion Criteria:

• History of allergy to pentoxifylline, Females are nursing or pregnant, Congestive heart failure (New York Heart Association functional class III or IV), Unstable angina, myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention, within the past 6 months prior to signing the informed consent form, Cerebral hemorrhage within the past 6 months prior to signing the informed consent form, Retinal hemorrhage within the past 6 months prior to signing the informed consent form, Known or suspected secondary hypertension, Uncontrolled hypertension with SBP > 200 mmHg and/or DBP > 110 mmHg, Liver cirrhosis, Biliary obstructive disorders, Active malignancy or infection, Uncontrolled diabetes mellitus, Glomerular filtration rate ≦ 60 ml/min/1.73 m2

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 20 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: National Taiwan University Hospital

Overall Clinical Trial Officials and Contacts

Yung-Ming Chen, M.D. Principal Investigator NTUH  

Overall Contact: Yung-Ming Chen, M.D. 886-2-23123456 ymchen@ha.mc.ntu.edu.tw

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00354731

Study ID Number: 941103

ClinicalTrials.gov Identifier: NCT00354731

Health Authority: Taiwan: Department of Health