Investigational and Comparative Study in the Management of Diabetic Nephropathy
Primary Purpose
Diabetic Nephropathy Type 2
Status
Active
Phase
Phase 3
Locations
Egypt
Study Type
Interventional
Intervention
Tadalafil 20Mg Oral Tablet
Pentoxifylline 400 MG Oral Tablet
Sponsored by
About this trial
This is an interventional treatment trial for Diabetic Nephropathy Type 2
Eligibility Criteria
Inclusion Criteria:Patients with clinical diagnosis of T2DM.
- Patients on stage 3 DN with evidence of persistent micro-albuminuria (urinary ACR≥30-300mg/g) in 3 consecutive measurements in 3 months period despite treatment with RAAS blockade ACEI or ARBs for at least 3 months period before enrollment in the study at maximum recommended tolerated dose.
Exclusion Criteria:
- Cardiovascular disease: angina, arrhythmias, myocardial Infarction, heart failure (NYHA II -IV), uncontrolled hypertension > (170 \100 mm Hg) severe hypotension < (90\50 mm Hg).
- Hearing problem, vision defect, thyroid disorders, alcohol abuse.
- Hepatic insufficiency (child -Pugh class C), (ALT or AST>3N), cholestasis.
- Known allergy to tadalafil or methylxanthine.
- Use alpha one blockers, medications strongly alter CYP3A4 inducer or inhibitor, use of nitrates, other PDEI drug.
- Bleeding disorders, peptic ulcer, and stroke.
- Pregnancy, lactation.
- Renal disease (acute kidney injury, recent exposure to radio- contrast media, creatinine clearance <30 mL /min.
Sites / Locations
- Faculty of pharmacy
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
No Intervention
Experimental
Experimental
Arm Label
control group
Tadalafil group
pentoxifylline group
Arm Description
: (n=30) control group will receive traditional therapy blood glucose lowering agent +RAAS blockade ACEI or ARBs for six months.
:( n=30) will receive traditional therapy +tadalafil PO 20 mg every other day for six months
:( n=30) will receive traditional therapy+ pentoxifylline PO 400 mg twice daily for six months.
Outcomes
Primary Outcome Measures
Change in Urinary albumin/creatinine ratio (ACR)
Measurement of urine albumin to creatinne ratio by measurement of urine albumin using Turbidimetric immunoassay method and measurement of urine creatinnie by standard by enzymatic colorimetric methods
Change in Hemoglobin A1c (HbA1c).
Measurement of Hemoglobin A1C using (HPLC: ion exchange chromatography)
Change in Fasting blood glucose.
Measurement of Fasting blood glucose by using standard enzymatic colorimetric methods
Change in Sr Cr
Measurement of serum creatinine using colorimetric technique
Change in Creatinine clearance
Creatinine clearance was calculated by (Cockcroft-Gault Formula)
change in 2- Hours Postprandial blood glucose
Measurement 2- Hours Postprandial blood glucose in blood using standard enzymatic colorimetric methods
Secondary Outcome Measures
Change in serum ((TNF-α).
Measurement of serum level of (TNF-α) by Enzyme linked immunosorbent assay (ELISA).
Change in Urinary NGAL (uNGAL).
Measurement of urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL)using by Enzyme linked immunosorbent assay ELISA technique:
Change in Lipid profile (TG, LDL, and HDL).
Measurement of serum lipid profile (TC,TG,HDL,LDL)using Enzymatic Colorimetric Method
Change in serum malondialdehyde (MDA) .
Meaurement of serum malondialdehyde by Enzyme linked immunosorbent assay (ELISA) .
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT05487755
Brief Title
Investigational and Comparative Study in the Management of Diabetic Nephropathy
Official Title
Investigational and Comparative Study to Assess Safety and Effectiveness of Tadalafil and Pentoxifyllin in the Management of Diabetic Nephropathy
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 1, 2022 (Actual)
Primary Completion Date
December 1, 2023 (Anticipated)
Study Completion Date
November 1, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Tanta University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
The objective of this study is to investigate and compare the safety and efficacy of selective (PDE5) enzyme inhibitor; tadalafil and non selective (PDE) inhibitor; pentoxifylline in diabetic nephropathy to improve glucose metabolism, lipid profile and decrease albuminuria.
Detailed Description
Diabetic nephropathy(DN) is one of the major micro- vascular complications of diabetes mellitus and the leading cause of end-stage renal disease (ESRD) that require renal replacement therapies.
The average incidence of diabetic nephropathy is 3% per year during the first 10 to 20 years after diabetes onset. Diabetic nephropathy occurs in 20-40% of all diabetic patients.
Pathogenesis of diabetic nephropathy is complex and multi-factorial in which diabetes mellitus has more than pathway for initiation and progression of the disease.
Metabolic pathway: result in formation of advanced glycation end products (AGEs).
Inflammatory pathway: result in increase serum level of tumor necrosis factor-α(TNF .
Hemodynamic pathway: result in increase serum level of endothelin-1 which result in glomerular hypertension and hyper filtration.
Tadalafil is a phosphodiesterase type 5 enzyme (PDE5) inhibitor used mainly in erectile dysfunction and pulmonary hypertension by a mechanism involving increase(NO-cGMP-PKG) signaling pathway.
Tadalafil is a powerful pleiotropic drug that it can be used in DN as it can target more than pathway involved in pathogenesis of DN include hyperglycemia and endothelial dysfunction through increase (NO-cGMP) signaling pathway as well as hyperlipidemia. Animal studies reported that tadalafil increase significantly total antioxidant capacity(TAC),decrease significantly serum level of inflammatory marker (TNF- α), blood glucose level, serum creatinine ,serum urea and urinary albumin excretion all result in decrease renal inflammation, injury, necrosis and apoptosis.
Pentoxifylline is a methyl xanthine derivative, non selective phosphodiesterase enzyme inhibitor used mainly to treat peripheral vascular diseases by improve blood flow, increase red blood cell flexibility and inhibit platelet aggregation.
Pentoxifylline have been recently widely used in many animal studies and clinical trials to evaluate its efficacy in management of DN and the results were so promising.(14)
Pentoxifylline can slow the decrease in eGFR, and significantly reduce albuminuria in which it can be effective alternative to ACEI in reducing albuminuria as proved by clinical trial.(15) The powerful effect of pentoxifylline in DN as it can affect several pathways implicated in pathogenesis of DN; it has hypoglycemic effect by decrease Significantly blood glucose, HbA1c and serum triglyceride, it also decrease pro inflammatory cytokines (TNF-α, IL-1, IL-6), reduce plasma level of malondialdehyde and increase glutathione level.(16)
Neutrophil Gelatinase-Associated Lipocalin (NGAL): is a 25-kDa protein belong to lipocalin superfamily. The urinary concentration of NGAL increase in renal tubular damage as a result of both diminished reabsorption and increased release from renal tubules into urine indicating both proximal and distal tubular damage respectively.(17) NGAL is not considered a marker of renal function but a marker of structural damage of renal tubules, its level can quantify the degree of tubular damage.(18) NGAL can be used as a precocious marker of therapeutic response by application of NGAL measurement in monitoring the effectiveness of a particular treatment and predicting different clinical outcomes in the course of renal diseases
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetic Nephropathy Type 2
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
This is a randomized, controlled, prospective study.
Ninety diabetic nephropathy patients at stage 3(micro-albuminuria) will be divided into three groups as follow -Group 1: (n=30) control group will receive traditional therapy blood glucose lowering agent +RAAS blockade ACEI or ARBs for six months.
Group 2 :( n=30) will receive traditional therapy +tadalafil PO 20 mg every other day for six months.
Group 3 :( n=30) will receive traditional therapy+ pentoxifylline PO 400 mg twice daily for six months.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
90 (Actual)
8. Arms, Groups, and Interventions
Arm Title
control group
Arm Type
No Intervention
Arm Description
: (n=30) control group will receive traditional therapy blood glucose lowering agent +RAAS blockade ACEI or ARBs for six months.
Arm Title
Tadalafil group
Arm Type
Experimental
Arm Description
:( n=30) will receive traditional therapy +tadalafil PO 20 mg every other day for six months
Arm Title
pentoxifylline group
Arm Type
Experimental
Arm Description
:( n=30) will receive traditional therapy+ pentoxifylline PO 400 mg twice daily for six months.
Intervention Type
Drug
Intervention Name(s)
Tadalafil 20Mg Oral Tablet
Other Intervention Name(s)
cialong
Intervention Description
Tadalafil is a phosphodiesterase type 5 enzyme (PDE5) inhibitor used mainly in erectile dysfunction and pulmonary hypertension by a mechanism involving increase(NO-cGMP-PKG) signaling pathway.(8) Tadalafil is a powerful pleiotropic drug that it can be used in DN as it can target more than pathway involved in pathogenesis of DN include hyperglycemia and endothelial dysfunction through increase (NO-cGMP) signaling pathway as well as hyperlipidemia
Intervention Type
Drug
Intervention Name(s)
Pentoxifylline 400 MG Oral Tablet
Other Intervention Name(s)
Pental SR
Intervention Description
Pentoxifylline is a methyl xanthine derivative, non selective phosphodiesterase enzyme inhibitor used mainly to treat peripheral vascular diseases by improve blood flow
Primary Outcome Measure Information:
Title
Change in Urinary albumin/creatinine ratio (ACR)
Description
Measurement of urine albumin to creatinne ratio by measurement of urine albumin using Turbidimetric immunoassay method and measurement of urine creatinnie by standard by enzymatic colorimetric methods
Time Frame
Change between baseline and six months after
Title
Change in Hemoglobin A1c (HbA1c).
Description
Measurement of Hemoglobin A1C using (HPLC: ion exchange chromatography)
Time Frame
Change between baseline and six months after
Title
Change in Fasting blood glucose.
Description
Measurement of Fasting blood glucose by using standard enzymatic colorimetric methods
Time Frame
Change between baseline and six months after
Title
Change in Sr Cr
Description
Measurement of serum creatinine using colorimetric technique
Time Frame
Change between baseline and six months after
Title
Change in Creatinine clearance
Description
Creatinine clearance was calculated by (Cockcroft-Gault Formula)
Time Frame
Change between baseline and six months after
Title
change in 2- Hours Postprandial blood glucose
Description
Measurement 2- Hours Postprandial blood glucose in blood using standard enzymatic colorimetric methods
Time Frame
Change between baseline and six months after
Secondary Outcome Measure Information:
Title
Change in serum ((TNF-α).
Description
Measurement of serum level of (TNF-α) by Enzyme linked immunosorbent assay (ELISA).
Time Frame
Change between baseline and six months after
Title
Change in Urinary NGAL (uNGAL).
Description
Measurement of urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL)using by Enzyme linked immunosorbent assay ELISA technique:
Time Frame
Change between baseline and six months after
Title
Change in Lipid profile (TG, LDL, and HDL).
Description
Measurement of serum lipid profile (TC,TG,HDL,LDL)using Enzymatic Colorimetric Method
Time Frame
Change between baseline and six months after
Title
Change in serum malondialdehyde (MDA) .
Description
Meaurement of serum malondialdehyde by Enzyme linked immunosorbent assay (ELISA) .
Time Frame
Change between baseline and six months after
10. Eligibility
Sex
All
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
A confirmed with clinical diagnosis of T2DM with duration at least 7 years to ensure established of micro-vascular complication (DKD).
females (post-menopause), males with sufficient erectile function.
Patients on stage 3 DN with evidence of persistent micro-albuminuria. All Abnormal tests of (UACR) must be confirmed in two out of three samples collected over a 6 month period before enrolled in the study.
(urinary ACR≥30-300mg/g) in 3 consecutive measurements in 6 months period despite treatment with RAAS blockade(ramipril 10 mg ) ACEI or for at least 6 months period before enrollment in the study at maximum recommended tolerated dose.
Exclusion Criteria:Cardiovascular disease: angina, arrhythmias, myocardial Infarction, heart failure (NYHA II -IV), uncontrolled hypertension > (170 \100 mm Hg) severe hypotension < (90\50 mm Hg), Hearing problem, vision defect, previous episodes of retinal / cerebral hemorrhage, psychiatric disease, thyroid disorders, alcohol abuse, smoking, Hepatic insufficiency (child -Pugh class C), (ALT or AST>3N), cholestasis, history of chronic inflammatory, immunologic or malignant disease. Acute inflammation or infectious disease in the previous 3 months, taking immunosuppressive treatment, Known allergy to tadalafil or methylxanthine, Use alpha one blockers, use of anti-oxidant drugs three months before enrollment in the study ,medications strongly alter CYP3A4 inducer or inhibitor, use of nitrates, other PDEI drugs, - Renal disease (acute kidney injury, recent exposure to radio- contrast media, creatinine clearance <30 ml/ min /1.73 m2 , bleeding disorders, peptic ulcer, and stroke, Pregnancy, lactation.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wafaa S Hegab, Lecturer
Organizational Affiliation
Tanta University
Official's Role
Study Chair
Facility Information:
Facility Name
Faculty of pharmacy
City
Tanta
Country
Egypt
12. IPD Sharing Statement
Citations:
PubMed Identifier
19200057
Citation
Rivero A, Mora C, Muros M, Garcia J, Herrera H, Navarro-Gonzalez JF. Pathogenic perspectives for the role of inflammation in diabetic nephropathy. Clin Sci (Lond). 2009 Mar;116(6):479-92. doi: 10.1042/CS20080394.
Results Reference
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PubMed Identifier
23075333
Citation
Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci (Lond). 2013 Feb;124(3):139-52. doi: 10.1042/CS20120198.
Results Reference
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Investigational and Comparative Study in the Management of Diabetic Nephropathy
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