Pentoxifylline in Lupus Nephritis

Summary

Glomerulonephritis is an important manifestation in about 1/2 of patients with Systemic Lupus Nephritis (SLE; lupus). Despite recent national guidelines recommending use of induction therapy with high-dose corticosteroids and immunosuppressive agents, followed by prolonged maintenance therapy, up to 1/3 of these patients continue to have active nephritis and ongoing protein in the urine (proteinuria). It has long been recognized that both the level and chronicity of proteinuria in patients with lupus nephritis are associated with disease severity and with long-term prognosis, including the possibility of progression to complete kidney failure, which may occur in about 1/4 of patients. Pentoxifylline (PTX) is an oral medication introduced 45 years ago for treatment of vascular insufficiency. It has also recently been found to reduce proteinuria in patients with diabetic nephropathy. The mechanism of this unexpected and intriguing finding is not certain, but may in part involve inhibiting the production of TNF-alpha, an inflammatory cytokine known to be present in urine and kidneys of patients with lupus nephritis. Our hypothesis is that this inexpensive, generic drug, PTX, can significantly reduce proteinuria in patients with lupus nephritis.

To test this hypothesis, we plan to initiate a 6-month, double-blind, placebo-controlled randomized clinical trial of PTX or placebo in 40 patients with active lupus nephritis. This trial will include 6-8 patients from each of 5 different academic medical centers that specialize in the treatment of lupus nephritis. Our primary objective of this trial will be to measure urine protein each month to determine the extent to which PTX is able to reduce urine protein, and how rapidly this occurs.

Concurrently, we will carefully follow these patients each month to determine whether PTX administration is also associated with stabilization of renal function, or with improvement in other manifestations of lupus, such as clinical disease activity or abnormal laboratory findings. A major secondary objective will be to explore the possible mechanism(s) whereby PTX reduces proteinuria. For this purpose, we will use the monthly urine specimens to measure TNF-alpha, and levels of several other proteins (IL-1, IL-6, IL-2, MCP-1, TGF-beta, PDGF, and IFN-alpha) that have been shown to contribute to inflammation and scarring in lupus nephritis. Comparison of levels of these inflammatory proteins with level of protein in the urine should help us to determine whether one or more of these proteins is a contributor to the severity or persistence of lupus nephritis.

This information may also allow us to learn whether repeated measurements of these proteins can serve as biomarkers to assist in the ongoing management of patients with lupus nephritis. Finally, we hope to eventually measure levels of these inflammatory proteins in blood samples from the patients, to determine if PTX treatment can suppress (or enhance) such levels, and whether these changes are associated with reduced lupus disease activity, or improvement in other manifestations of lupus. Ultimately, it is our hope that the data from this clinical trial using a generic repurposed drug will permit us to conclusively confirm that PTX can significantly reduce proteinuria in patients with lupus nephritis, which would be of great benefit for the thousands of people who suffer with this most severe type of lupus.

Conditions

• Lupus Nephritis

Interventions

DRUG

Pentoxifylline

Pentoxifylline (PTX) is a methylxanthine derivative that is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). This enzyme, which has at least 5 subtypes, is responsible for inactivation of the important second messengers, Cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP)

DRUG

Placebos

Placebo

Sponsors & Collaborators

• Ohio State University

  collaborator OTHER

• The Research Foundation for the State University of New York

  collaborator UNKNOWN

• Yale University

  collaborator OTHER

• MetroHealth Medical Center

  lead OTHER

Principal Investigators

• Stanley Ballou, MD · MetroHealth Medical Center

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

90 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-09-01

Primary Completion

2021-12-31

Completion

2022-12-31

Countries

• United States

Study Locations