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Investigational and Comparative Study in the Management of Diabetic Nephropathy

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ClinicalTrials.gov Identifier: NCT05487755
Recruitment Status : Not yet recruiting
First Posted : August 4, 2022
Last Update Posted : August 4, 2022
Sponsor:
Information provided by (Responsible Party):
Walla Ahmed Amaar, Tanta University

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.

Condition or disease Intervention/treatment Phase
Diabetic Nephropathy Type 2 Drug: Tadalafil 20Mg Oral Tablet Drug: Pentoxifylline 400 MG Oral Tablet Phase 3

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: Investigational and Comparative Study to Assess Safety and Effectiveness of Tadalafil and Pentoxifyllin in the Management of Diabetic Nephropathy
Estimated Study Start Date : September 2022
Estimated Primary Completion Date : October 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
No Intervention: control group
: (n=30) control group will receive traditional therapy blood glucose lowering agent +RAAS blockade ACEI or ARBs for six months.
Experimental: Tadalafil group
:( n=30) will receive traditional therapy +tadalafil PO 20 mg every other day for six months
Drug: Tadalafil 20Mg Oral Tablet
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
Other Name: cialong

Experimental: pentoxifylline group
:( n=30) will receive traditional therapy+ pentoxifylline PO 400 mg twice daily for six months.
Drug: Pentoxifylline 400 MG Oral Tablet
Pentoxifylline is a methyl xanthine derivative, non selective phosphodiesterase enzyme inhibitor used mainly to treat peripheral vascular diseases by improve blood flow
Other Name: Pental SR




Primary Outcome Measures :
  1. Change in Urinary albumin/creatinine ratio (ACR) [ Time Frame: Change between baseline and six months after ]
    Measurement of Urinary albumin/creatinine ratio (ACR) using colorimetric technique

  2. Change in Hemoglobin A1C (HbA1c). [ Time Frame: Change between baseline and six months after ]
    Measurement of Hemoglobin A1C

  3. Change in Sr Cr [ Time Frame: Change between baseline and six months after ]
    Measurement of serum creatinine using colorimetric technique

  4. Change in Fasting blood glucose. [ Time Frame: Change between baseline and six months after ]
    Measurement of Fasting blood glucose.

  5. Change in serum (TNF-α) [ Time Frame: Change between baseline and six months after ]
    Measurement of serum tumor necrosis factor -α (TNF-α) using ELISA technique

  6. Change in serum malondialdehyde (MDA ) [ Time Frame: Change between baseline and six months after ]
    Measurement of serum malondialdehyde (MDA ) using ELISA technique

  7. Change in BUN (blood urea nitrogen ) [ Time Frame: Change between baseline and six months after ]
    Measurement of blood urea nitrogen using colorimetric technique


Secondary Outcome Measures :
  1. Change in 2- Hours Postprandial blood glucose. [ Time Frame: Change between baseline and six months after ]
    Measurement of serum 2- Hours Postprandial blood glucose.

  2. Change in Urinary NGAL (uNGAL). [ Time Frame: Change between baseline and six months after ]
    Measurement of urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL)using ELISA technique:

  3. Change in Lipid profile (TC, TG, LDL, and HDL). [ Time Frame: Change between baseline and six months after ]
    Measurement of serum lipid profile (TC,TG,HDL,LDL)using Enzymatic Colorimetric Method

  4. Change in Creatinine clearance. [ Time Frame: Change between baseline and six months after ]
    Measurement of creatinine clearance(Cockcroft-Gault Equation)The formulas are as follows: CrCl (male) = ([140-age] × weight in kg) / (serum creatinine × 72)



Information from the National Library of Medicine

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Ages Eligible for Study:   35 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05487755


Contacts
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Contact: Walla A Amaar, pharmacist 01003735367 walaa.amar81@gmail.com
Contact: Sahar K Hegazy, professor 01225471985 S_hgz@yahoo.com

Sponsors and Collaborators
Tanta University
Investigators
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Study Chair: Wafaa S Hegab, Lecturer National Institute of Diabetes and Endocrinology
Publications:
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Responsible Party: Walla Ahmed Amaar, clinical pharmacist, Tanta University
ClinicalTrials.gov Identifier: NCT05487755    
Other Study ID Numbers: DN mangement
First Posted: August 4, 2022    Key Record Dates
Last Update Posted: August 4, 2022
Last Verified: August 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Kidney Diseases
Diabetic Nephropathies
Urologic Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Tadalafil
Pentoxifylline
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents
Platelet Aggregation Inhibitors
Radiation-Protective Agents
Protective Agents
Physiological Effects of Drugs
Free Radical Scavengers
Antioxidants