Pentoxifylline Effect in Patients With Diabetic Nephropathy.(PENFOSIDINE STUDY)

Study Overview
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Brief Summary
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One of the purposes of the management of the patient with chronic kidney disease (CKD)is to slow the decline of renal function. The mechanisms by which the renal function declines involve inflammatory and fibrotic responses due in part by the effects of oxidative stress. Pentoxifylline (PTX)is a drug that stimulates adenosine receptors, and produces inhibition of phosphodiesterases, as well as being a dopaminergic modulator through D1 and D2 receptors. Its main effects are inhibition of the inflammatory state by decreasing serum levels of tumor necrosis factor alpha (TNF-ɒ) and monocyte chemo attractant protein 1 (MCP_1), which may slow down the decline of renal function. It also produces diminish of sympathetic activity, with the reduction of circulating levels of norepinephrine (NA), which may contribute to the reduction of glomerulosclerosis in diabetic patients. In the connective tissue increases the activity of the collagenases and decrease of collagen, fibronectin and glucosamine of the fibroblasts as well as inhibition of oxygen free radicals. Due to its antioxidant, anti-inflammatory and anti-fibrotic effects, PTX can result in an excellent therapeutic option for the prevention of CKD in DM2. This work proposes the use of pentoxifylline as treatment CKD in DM2. Its application in patients with CKD will allow a therapeutic management with different targets, for its antioxidant, anti-inflammatory and antifibrotic effects that will be evaluated by means of fibrosis, inflammation and oxidative stress markers. The results will be of great importance in clinical practice, since they will justify the use of a new pharmacological tool, already known, with minimal adverse effects and low cost, accessible to all strata of the population since it is found as generic.

Detailed Description
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Patients will be randomly selected from the outpatient family medicine clinics. Once included, patients will be randomly allocated (by a computer-generated randomization list) to a study or control group. Over a period of 2 years, patients of the study group will receive one PTX tablet (400 mg) orally three times a day (at dinner time), whereas controls will receive one cellulose identical tablet on the same schedule. All patients will continue with their usual treatment prescribed by their family doctor. Monthly visits will be scheduled for clinical and biochemical evaluations. A blood sample will be taken at baseline and every six months up to 24 months, for measurement of complete blood count, urea, creatinine, glucose, albumin, lipids, electrolytes, liver function tests, serum total proteins, (will be measure by usual methods). In serum samples at 0, 6, 12, 18 and 24 months, high sensibility C reactive protein will be measured by nephelometry, Brain natriuretic peptide and Serum Cystatin C will be measured by ELISA. Glomerular filtration rate (GFR) will be calculated based in Cystatin C level Grubb's equations. Vitamin C will be measured by HPLC. A 24 h ambulatory blood pressure monitoring (24 h ABPM), M-mode and two-dimensional echocardiographic, and an analysis of body composition by bioelectrical impedance will be done at baseline 6, 12, 18 and 24 months. To investigate health-related quality of life the short-form 36 (SF-36) questionnaire will be applied. Treatment compliance will be recorded by counting tablets left in the container at the end of each monthly visit and by the Morinsky Green test.

Official Title
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Pentoxifylline Effect on Renal Function, Oxidative Stress, Inflammation, and Fibrosis Markers, and Quality of Life in Patients With Diabetic Nephropathy

Conditions
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Chronic Kidney Disease stage3 and 4, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: pentoxifylline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CKD Type 2 diabetes mellitus Microalbuminuria Proteinuria. Creatinine plasma clearance ˂ of 60 mL / min. Exclusion criteria: History of psychiatric disorders, Immunosuppressants treatment Herbalism Treatment History of chronic alcoholism. Type 1 diabetes mellitus. Chronic obstructive pulmonary disease. Pulmonary fibrosis Heart failure HIV-AIDS. Liver cirrhosis. Chronic hepatitis.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: blinded,multicenter, randomized, pentoxifylline vs placebo controlled clinical trial. Time: two years after the enrollment of the last patient.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo group<br>Placebo group will receive 1 tablet of cellulose pill to mimic pentoxifylline tablets three times a day with meals, during the following two years. | Drug: pentoxifylline<br>* Pentoxifylline or placebo will be prescribed three times a day with meals. All the participants will continue with the usual treatment. Time frame: two years<br>* Other names: Trental;|
| Active Comparator: Pentoxifylline group<br>Pentoxifillyne or experimental group will receive 400 mg of pentoxifylline three times a day with meals, during the following two years. | Drug: pentoxifylline<br>* Pentoxifylline or placebo will be prescribed three times a day with meals. All the participants will continue with the usual treatment. Time frame: two years<br>* Other names: Trental;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the glomerular filtration rate | It will be measure as to duplicate serum creatinine levels from baseline (mg/dL), or to pass from a stage of chronic kidney disease to he next stage (GFR mL/min) | The measurements will be done baseline and every six months up to 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in oxidative stress marker. | The change in vit C level from baseline (normal range 4-8.8mg/ L) | Change is assessed baseline, 6 months, 12 months, 18 months and 24 months. | 
| Change in fibrosis markers. | Change in Nt_ProBNP from the baseline (Normal values up to 381 pg/mL) | Change is assessed baseline, 6 months, 12 months, 18 months and 24 months. | 
| Change in inflammation markers. | To assess inflammation high sensitivity C reactive protein will be measured by nephelometry. (normal value < 5 mg/L | Change is assessed baseline, 6 months, 12 months, 18 months and 24 months. | 
| Change in health-related quality of life | This outcome will be measured by the SF 36 questionnaire, themaximun punctuation is 100, as greater punctuation a better quality of life | The questionnaire will be applied baseline and every six months up to 24 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oxidative stress, fibrosis, inflammation, quality of life