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Pentoxifylline in Lupus Nephritis (Pentoxifylline)

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ClinicalTrials.gov Identifier: NCT03859570
Recruitment Status : Not yet recruiting
First Posted : March 1, 2019
Last Update Posted : March 7, 2019
Sponsor:
Collaborators:
Ohio State University
University of Cincinnati
The Cleveland Clinic
Information provided by (Responsible Party):
Stanley Ballou, MetroHealth Medical Center

Brief Summary:

This is a randomized, double-blind, placebo-controlled clinical trial of pentoxifylline or placebo, administered in addition to standard of care therapy for patients with lupus nephritis at 4 sites to 40 subjects. Hence, this will be an "add-on" clinical trial, in which all patients will continue to receive their usual therapies for lupus nephritis throughout the 6 months of study duration.

This exploratory clinical trial is ultimately intended to inform the scientific basis for a subsequent, larger 12- month, randomized, double-blind, placebo-controlled clinical trial of Pentoxifylline (PTX) involving 100-150 patients with lupus nephritis and persistent proteinuria recruited from about 10-15 US medical centers. A trial of this size would be statistically adequately powered to answer numerous questions related to use of Pentoxifylline (PTX) in patients with lupus


Condition or disease Intervention/treatment Phase
Lupus Nephritis Drug: Pentoxifylline Drug: Placebos Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Contracted biostatistician will be responsible for drug/placebo randomization. He will be able to conduct an early, interim data analysis following initial 30% enrollment, and will permit unblinding of subject data to the Data Safety Monitor (DSM) for reasons of safety assurance, as requested.
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Pentoxifylline or Placebo in Addition to Standard of Care for Treatment of Proteinuria in Patients With Active Lupus Nephritis.
Estimated Study Start Date : December 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pentoxifylline
Pentoxifylline and standard of care therapy
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)
Other Name: Trental

Placebo Comparator: Placebo
Placebo and standard of care therapy
Drug: Placebos
Placebo




Primary Outcome Measures :
  1. Level of proteinuria [ Time Frame: 9 months ]
    Level of proteinuria measured as the protein/creatinine ratio on a morning first void specimen, recorded longitudinally at monthly intervals from baseline to 6 months, and from urine specimens provided monthly for 3 months following the 6 month study termination visit.


Secondary Outcome Measures :
  1. Histopathologic subclass [ Time Frame: 6 months ]
    The effect of Pentoxifylline on proteinuria relative to disease duration and histopathologic subclass.We will stratify these subjects in to 3 groups: class II, class III/IV, and class V. Given the relatively low expected frequency of class II (about 20%) and class V (about 10%), and the small total number of subjects, we will likely only be able to observe trends in responses of proteinuria to Pentoxifylline treatment in the 3 groups, without observing significant differences between groups.

  2. Serum albumin [ Time Frame: 6 months ]
    Longitudinal changes in serum albumin over 6 months

  3. Glomerular Filtration Rate [ Time Frame: 6 months ]
    Longitudinal changes in glomerular filtration rate (GFR)

  4. Serologic markers [ Time Frame: 6 months ]
    Longitudinal changes in serologic markers including anti-DNA, complement component 3 (C3), and complement component 4(C4)

  5. SELENA-Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Instrument Score [ Time Frame: 6 months ]
    Longitudinal changes in SELENA-SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) Instrument Score. This tool is a cumulative and weighted index used to assess disease activity across 24 different disease descriptors in patients with Systemic Lupus Erythematosus.This assessment can be completed to objectively assess the patient's current state of disease. The descriptors with a weight of 8 are seizure, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, cerebrovascular accident, and vasculitis. The descriptors with a weight of 4 are arthritis, myositis, urinary casts, hematuria, proteinuria, and pyuria. The descriptors with a weight of 2 are rash, alopecia, mucosal ulcers, pleurisy, pericarditis, low complement, and increased DNA binding. The descriptors with a weight of 1 are fever, thrombocytopenia, and leukopenia.

  6. Longitudinal changes in patient global activity score [ Time Frame: 6 months ]
    This score measures the disease activity from the patient's perspective. It is measured from 0 to 10 with 10 being the worst.

  7. Longitudinal changes in physician global activity score [ Time Frame: 6 months ]
    This score measures the disease activity from the physician's perspective.It is measured from 0 to 10 with 10 being the worst.

  8. Prednisone dose [ Time Frame: 6 months ]
    Longitudinal changes in prednisone dose (and total cumulative prednisone dose)

  9. Serum and urinary cytokine levels [ Time Frame: 6 months ]
    Correlation between serum and urinary cytokine levels (Tumor necrosis factor(TNF-alpha), Interleukin 1 (IL1), Interleukin 6 (IL6), Interleukin 2 (IL-2), Monocyte chemoattractant protein -1 (MCP-1), Transforming growth factor beta(TGF-beta), Interferon alpha (IFN-alpha), and Platelet-derived growth factor (PDGF) and changes in urinary protein excretion at baseline and at 1, 2, 3, and 6 months



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Patients 18 and older, who meet the 1982 criteria for classification of systemic lupus erythematosus and have established lupus nephritis as documented by any of the following:

    1. Kidney biopsy documenting class II, III, IV, or V (RPS/ISN 2004) lupus nephritis within 3 years or
    2. Abnormal urine protein excretion on ≥ 2 occasions, at least 2 weeks apart, characterized by:> 500 mg urine protein, quantitated either by 24-hour urine collection or by urine protein/creatinine ratio > 0.5 mg/mg measured on a 1st void morning specimen, in the absence of other glomerulopathies; or
    3. Abnormal urine sediment, containing > 5 red blood cell(RBC), >5 white blood cell(WBC), or cellular casts on ≥ 2 occasions, at least 2 weeks apart, in the absence of infection, concurrent menstruation, anatomic genitourinary abnormalities, or pathologic disorders other than lupus nephritis.
  • Absence of changes in immunosuppressive agents and/or dose of immunosuppressive agents administered during the 2 months before enrollment
  • Unless contraindicated, patients will be required to be taking an Angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blockers (ARB), with stable dose for at least 1 month prior to enrollment. Patients with intolerance of Angiotensin-converting enzyme inhibitor or angiotensin II receptor blockers (ACE/ARB) therapies will be eligible to participate, as indicated above.
  • Urine protein > 500 mg/24 hours (= 0.5 mg/mg protein/creatinine ratio) at time of screening.Willingness to remain on stable immunosuppressive drugs for the duration of the study unless safety issues arise.
  • Willingness to remain on stable immunosuppressive drugs for the duration of the study unless safety issues arise.
  • The SELENA-Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) will be measured at screening but no minimal Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score will be required for inclusion.
  • Although kidney biopsy is not required for enrollment in this clinical trial, the standard of care at all four participating institutions is to recommend renal biopsy for all patients with lupus nephritis, and at least 75% of such patients at each institution do have this procedure. Subjects who qualify for this study according to clinical criteria noted in 1b and 1c above must be confirmed to have lupus nephritis, and no other renal disorder, by the site Principal Investigator, prior to enrollment.

Exclusion criteria:

  • History of retinal, cerebral, or peptic ulcer hemorrhage within 3 months prior to enrollment.
  • Current use of warfarin, long-acting heparin, or an oral anti-coagulant (other than low dose aspirin)
  • Pregnancy or currently breast-feeding
  • History of theophylline, pentoxifylline, or caffeine allergy
  • Currently taking theophylline-containing medications
  • Malignancy within 2 years, other than basal cell carcinoma
  • Congestive heart failure, class III or IV
  • Abnormal aspartate aminotransferase/alanine aminotransferase (AST/ALT)
  • Obstructive uropathy
  • Acute kidney injury defined as greater than 50% decrease in Glomerular filtration rate(GFR) in the prior 30 days.
  • Myocardial infarction, percutaneous coronary intervention, coronary bypass graft surgery, or unstable angina in the prior 6 months
  • Blood pressure (BP) greater than 145/95 on 2 measurements using a manual blood pressure (BP) cuff
  • Known diagnosis of diabetes mellitus or hemoglobin A1c greater than 8.0
  • Glomerular filtration rate (GFR) less than 30 mL/min
  • Surgery within 3 months prior to enrollment
  • Concurrent diagnosis of antiphospholipid syndrome (APS), or presence of APS antibodies.

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Responsible Party: Stanley Ballou, Professor of Medicine - Case Western Reserve University, MetroHealth Medical Center
ClinicalTrials.gov Identifier: NCT03859570     History of Changes
Other Study ID Numbers: IRB18-00310
First Posted: March 1, 2019    Key Record Dates
Last Update Posted: March 7, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Lupus Nephritis
Lupus Erythematosus, Systemic
Nephritis
Kidney Diseases
Urologic Diseases
Glomerulonephritis
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Pentoxifylline
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Radiation-Protective Agents
Protective Agents
Physiological Effects of Drugs
Vasodilator Agents
Free Radical Scavengers
Antioxidants