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

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

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.

Study Overview

• Status: Unknown
• Conditions: Type 2 Diabetes Mellitus; Chronic Kidney Disease stage3 and 4
• Intervention / Treatment: Drug: pentoxifylline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 196
• Phase: Phase 4

Contacts and Locations

Study Locations

• Mexico
  • Michoacán
    • Morelia, Michoacán, Mexico, 58290
      • Recruiting
      • Cibimi - Hgz 83 Imss
      • Contact: Oliva Mejía - Rodríguez, PhD; Phone Number: 01 4431853008; Email: oliva.mejia@imss.gob.mx

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. CKD
2. Type 2 diabetes mellitus
3. Microalbuminuria
4. Proteinuria.
5. Creatinine plasma clearance ˂ of 60 mL / min.

Exclusion criteria:

1. History of psychiatric disorders,
2. Immunosuppressants treatment
3. Herbalism Treatment
4. History of chronic alcoholism.
5. Type 1 diabetes mellitus.
6. Chronic obstructive pulmonary disease.
7. Pulmonary fibrosis
8. Heart failure
9. HIV-AIDS.
10. Liver cirrhosis.
11. Chronic hepatitis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo group; 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; 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; Other Names: Trental
Active Comparator: Pentoxifylline group; Pentoxifillyne or experimental group will receive 400 mg of pentoxifylline three times a day with meals, during the following two years.	Drug: pentoxifylline; 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; Other Names: Trental

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Maria Eugenia Galván Plata
• Collaborators: Centro de Investigación Biomédica de Michoacán.; Hospital General Regional N° 1 Instituto Mexicano del Seguro Social.; Hospital General de Zona N° 83 Instituto Mexicano del Seguro Social.; Coordinación Auxiliar Medica de Investigación en Salud. Delegación Michoacán.
• Investigators: Principal Investigator: Oliva Mejía-Rodríguez, PhD, CIBIMI IMSS

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2018
• Primary Completion (Anticipated): July 30, 2019
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: July 25, 2018
• First Submitted That Met QC Criteria: September 6, 2018
• First Posted (Actual): September 10, 2018

Study Record Updates

• Last Update Posted (Actual): February 7, 2019
• Last Update Submitted That Met QC Criteria: February 6, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: quality of life; inflammation; oxidative stress; fibrosis
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Renal Insufficiency; Diabetes Mellitus, Type 2; Kidney Diseases; Renal Insufficiency, Chronic; Diabetic Nephropathies; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Pentoxifylline
• Other Study ID Numbers: CNIC-2015-785-065

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The individual participant data for all primary and secondary outcome measures will be made available
• IPD Sharing Time Frame: Data will be available six months after the end of the study
• IPD Sharing Access Criteria: Data access request will be reviewed by the research institutional board.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• 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