Efficacy of Pentoxifylline on Rapidly Progressive Glomerulonephritis

NCT ID: NCT00354198

Last Updated: 2012-11-14

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-08-31
• Study Completion Date: 2010-06-30

Brief Summary

We have recently demonstrated that pentoxifylline (PTX) has the potential to treat severe glomerular inflammation in a rat model of accelerated anti-glomerular basement membrane (GBM) glomerulonephritis. This study aims to investigate the therapeutic effects of combined PTX and conventional immunosuppressive regimens on patients with rapidly progressive glomerulonephritis.

Detailed Description

Corticosteroids and cytotoxic agents such as cyclophosphamide remain the most commonly used regimens for crescentic glomerulonephritis. However, their use is often limited by adverse effects, most notably life-threatening opportunistic infections due to generalized immunosuppression. Over the past decade, a number of novel experimental therapeutic agents have been shown to ameliorate the severity of experimental crescentic glomerulonephritis. Unfortunately, none of these measures is currently available for clinical use. Other potential agents such as mycophenolate, cyclosporin, and tacrolimus , while clinically available, share similar adverse effects with corticosteroid- and cyclophosphamide-based regimens. PTX is a methylxanthine phosphodiesterase inhibitor that has been widely used to treat peripheral vascular diseases and cerebrovascular disorders. In addition to its well-known hemorheologic activity, accumulating evidence suggests that PTX also possesses potent anti-inflammatory and/or immunoregulatory activities. For examples, PTX has shown its efficacy in different animal models of renal diseases where tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein (MCP)-1, or intercellular adhesion molecule-1 is involved. Moreover, clinical trials in patients with diabetic nephropathy and membranous glomerulonephritis have shown that PTX can lower endogenous TNF-alpha and attenuate proteinuria. These data raise the possibility that PTX may have promise as an anti-inflammatory agent via its ability to antagonize inflammatory mediators. Consistent with this idea, we have demonstrated this potential usefulness of PTX in a rat model of accelerated anti-GBM glomerulonephritis. More recently, we have reported that PTX is capable of inhibiting proteinuria via renal MCP-1 production in subnephrotic primary glomerular diseases. In this study, we aim to investigate the potential benefit of combined PTX and conventional immunosuppressive regimens, compared to conventional immunosuppressive therapy, in patients with rapidly progressive glomerulonephritis.

This study is a randomized, open-label, comparative study. Group A is treated by three monthly standard intravenous pulse-dose methylprednisolone (15 mg/kg/day or a maximum of 1 g/day from days 1 to 3) followed by oral prednisolone 0.5-1.0 mg/kg/day (from days 4-30). Group B is treated by the same corticosteroid regimen plus intravenous PTX (0.33-0.66 mg/kg/h from days 1 to 7) followed by oral PTX 400-800 mg/day (from days 8-90). The dose of intravenous PTX will be determined by estimated GFR, patients whose GFRs are 30-59 ml/min/1.73 m2 will be given 0.66 mg/kg/h, and those below 30 ml/min/1.73 m2 will be given 0.33 mg/kg/h. The oral dose of PTX will also be determined by estimated GFR. Patients whose estimated glomerular filtration rates (GFRs) are between 30-59 ml/min/1.73 m2 will be given 800 mg/day, and those below 30 ml/min/1.73 m2 will be given 400 mg/day. If the patients cannot tolerate oral medications, either PTX or corticosteroids can be administered intravenously until patients can resume oral intakes. Serum and single-voided urine specimens will be collected at the hospital before initiation of therapy (day 0), and at days 8, 15, 30, and 90 after the commencement of therapy. Renal function will be calculated by Cockcroft-Gault and simplified Modification of Diet in Renal Disease formula. 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 using commercial ELISA kits.

Conditions

Glomerulonephritis

Keywords

rapidly progressive glomerulonephritis; pentoxifylline

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

corticosteroids

\[intravenous pulse methylprednisolone (15 mg/kg/day or a maximum of 1 g/day) x 3 days + oral prednisolone (0.5-1.0 mg/kg/day) for 27 days\] x 3 courses

Group Type: ACTIVE_COMPARATOR

corticosteroids

Intervention Type: DRUG

intravenous methylprednisolone (15 mg/kg/day or a maximum of 1 g/day) x 3 days + oral prednisolone (0.5-1.0 mg/kg/day) for 27 days\] x 3 courses

pentoxifylline + corticosteroids

\[intravenous pulse methylprednisolone (15 mg/kg/day or a maximum of 1 g/day) x 3 days + oral prednisolone (0.5-1.0 mg/kg/day) for 27 days\] x 3 courses + intravenous infusion of pentoxifylline (0.33-0.66 mg/kg/h) x 7 days + oral pentoxifylline (400-800 mg/day) from days 8 to 90

Group Type: EXPERIMENTAL

pentoxifylline

Intervention Type: DRUG

intravenous pentoxifylline (0.33-0.66 mg/kg/h from days 1 to 7) followed by oral pentoxifylline 400-800 mg/day (from days 8-90). The dose of intravenous pentoxifylline will be determined by estimated GFR, patients whose GFRs are 30-59 ml/min/1.73 m2 will be given 0.66 mg/kg/h, and those below 30 ml/min/1.73 m2 will be given 0.33 mg/kg/h. The oral dose of pentoxifylline will also be determined by estimated GFR. Patients whose estimated GFRs are between 30-59 ml/min/1.73 m2 will be given 800 mg/day, and those below 30 ml/min/1.73 m2 will be given 400 mg/day.

corticosteroids

Intervention Type: DRUG

intravenous methylprednisolone (15 mg/kg/day or a maximum of 1 g/day) x 3 days + oral prednisolone (0.5-1.0 mg/kg/day) for 27 days\] x 3 courses

Interventions

pentoxifylline

intravenous pentoxifylline (0.33-0.66 mg/kg/h from days 1 to 7) followed by oral pentoxifylline 400-800 mg/day (from days 8-90). The dose of intravenous pentoxifylline will be determined by estimated GFR, patients whose GFRs are 30-59 ml/min/1.73 m2 will be given 0.66 mg/kg/h, and those below 30 ml/min/1.73 m2 will be given 0.33 mg/kg/h. The oral dose of pentoxifylline will also be determined by estimated GFR. Patients whose estimated GFRs are between 30-59 ml/min/1.73 m2 will be given 800 mg/day, and those below 30 ml/min/1.73 m2 will be given 400 mg/day.

Intervention Type: DRUG

corticosteroids

intravenous methylprednisolone (15 mg/kg/day or a maximum of 1 g/day) x 3 days + oral prednisolone (0.5-1.0 mg/kg/day) for 27 days\] x 3 courses

Intervention Type: DRUG

Other Intervention Names

Trental; Solu-medrol, Predonin

Eligibility Criteria

Inclusion Criteria

• biopsied-proved crescentic glomerulonephritis, with rapidly progressive renal failure

Exclusion Criteria

• Anti-GBM disease, Dialysis-dependency or pulmonary hemorrhage, History of allergy to pentoxifylline, Females are nursing or pregnant, Congestive heart failure, 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 or diabetes, Liver cirrhosis or hepatic dysfunction as defined by liver enzymes > 2 times the upper limit of the normal range, Biliary obstructive disorders, Active malignancy or infection

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Science and Technology Council, Taiwan

OTHER_GOV

Sponsor Role: collaborator

National Taiwan University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Yung-Ming Chen, M.D.

Role: PRINCIPAL_INVESTIGATOR

NTUH

Locations

National Taiwan University Hospital

Taipei, , Taiwan

Countries

Taiwan

Other Identifiers

941008

Identifier Type: -

Identifier Source: org_study_id