Ignite Creation Date:
2024-05-06 @ 12:48 PM
Last Modification Date:
2024-10-26 @ 1:04 PM
Study NCT ID:
NCT03859570
Status:
WITHDRAWN
Last Update Posted:
2021-02-02
First Post:
2019-02-22
Brief Title:
Pentoxifylline in Lupus Nephritis
Sponsor:
MetroHealth Medical Center
Organization:
MetroHealth Medical Center
Study Overview
Official Title:
A Multicenter Double-blind Placebo-controlled Randomized Trial of Pentoxifylline or Placebo in Addition to Standard of Care for Treatment of Proteinuria in Patients With Lupus Nephritis
Status:
WITHDRAWN
Status Verified Date:
2021-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Study not selected to receive funding
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Pentoxifylline
Brief Summary:
Glomerulonephritis is an important manifestation in about 12 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 13 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 14 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 mechanisms 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
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 mechanisms 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
Detailed Description:
Glomerulonephritis occurs in up to one-half of patients with systemic lupus erythematosus SLE and is a major cause of morbidity and mortality Guidelines published by the American College of Rheumatology in 2012 1 suggested a multi-targeted treatment approach that has been shown to lead to clinical remission in up to one-half of patients 23
However at least one-third of patients continue to have active disease many of these individuals may eventually develop renal failure Therefore there is an unmet need for more effective therapeutic approaches for lupus nephritis LN Although the pathogenesis of LN is almost certainly multifactorial the presence and persistence of immune complexes are thought to play a major role in disease pathogenesis by attracting inflammatory cells of the innate immune system such as neutrophils and monocytes resulting in cell activation and secretion of inflammatory cytokines including interferon alpha TGF-beta IL-1 IL-6 and TNF-alpha 6-7 Pentoxifylline PTX is a nonselective phosphodiesterase inhibitor with minimal toxicity It has been in clinical use since 1972 for treatment of patients with intermittent claudication secondary to peripheral vascular disease This generic drug has also recently been increasingly used off-label for several other conditions including patients with diabetic nephropathy in whom the unexpected finding of significant reduction of proteinuria has been repeatedly demonstrated 34-38 The mechanism of this phenomenon is unclear although experimental studies in animals and humans have observed suppression of inflammatory cytokine production following PTX administration 24-28 In LN 2 small uncontrolled observational studies of PTX reported reduction in proteinuria following 2-6 months of treatment with PTX 89 The level and chronicity of proteinuria have long been associated with disease prognosis in patients with LN 10 Thus a novel treatment that could significantly and persistently reduce or even eliminate proteinuria could result in substantial improvement in the long-term outcome of patients with this most serious manifestation of SLE
However at least one-third of patients continue to have active disease many of these individuals may eventually develop renal failure Therefore there is an unmet need for more effective therapeutic approaches for lupus nephritis LN Although the pathogenesis of LN is almost certainly multifactorial the presence and persistence of immune complexes are thought to play a major role in disease pathogenesis by attracting inflammatory cells of the innate immune system such as neutrophils and monocytes resulting in cell activation and secretion of inflammatory cytokines including interferon alpha TGF-beta IL-1 IL-6 and TNF-alpha 6-7 Pentoxifylline PTX is a nonselective phosphodiesterase inhibitor with minimal toxicity It has been in clinical use since 1972 for treatment of patients with intermittent claudication secondary to peripheral vascular disease This generic drug has also recently been increasingly used off-label for several other conditions including patients with diabetic nephropathy in whom the unexpected finding of significant reduction of proteinuria has been repeatedly demonstrated 34-38 The mechanism of this phenomenon is unclear although experimental studies in animals and humans have observed suppression of inflammatory cytokine production following PTX administration 24-28 In LN 2 small uncontrolled observational studies of PTX reported reduction in proteinuria following 2-6 months of treatment with PTX 89 The level and chronicity of proteinuria have long been associated with disease prognosis in patients with LN 10 Thus a novel treatment that could significantly and persistently reduce or even eliminate proteinuria could result in substantial improvement in the long-term outcome of patients with this most serious manifestation of SLE
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None