Renoprotective Effects of Dapagliflozin Versus Pentoxiphylline in Chronic Kidney Disease Patients

NCT ID: NCT06421870

Last Updated: 2024-05-20

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 210 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-03-01
• Study Completion Date: 2025-07-31

Brief Summary

Kidneys have a vital role in glucose homeostasis by various mechanisms, one of the major mechanisms is through SGLT2. This role was commonly overlooked till development of the new SGLT2 inhibitors. (Ni, L., et al 2020) The SGLT2 inhibitor class of glucose-lowering agents has recently shown beneficial effects to reduce the onset and progression of renal complications in people with and without diabetes, through slow the decline in glomerular filtration rate (GFR), delaying the onset of microalbuminuria and slow or reverse the progression of proteinuria. (Nespoux, J., & Vallon, V. 2020) The drug pentoxifylline is a methyl-xanthine derivative and a nonselective phosphodiesterase inhibitor with anti-inflammatory, antiproliferative and antifibrotic actions currently indicated for peripheral artery disease. (Panchapakesan U et al.,2018) Chronic kidney disease is a progressive disorder in which patients are treated according to complications presented such as hypocalcemia, hyperkalemia, anemia and metabolic acidosis.

Detailed Description

It is only in recent years that the attention was drawn on the key role of the kidney in glucose homeostasis. Nevertheless, along with the liver, the kidney has a key role in ensuring the energy needs during fasting periods. This organ has a vital role in absorbing the entire quantity of the filtered glucose. Having a glomerular filtration rate of 180 litres per day, it filters approximately 180 grams of glucose per day, bringing its contribution in maintaining normal fasting plasma glucose (FPG) levels. (Cersosimo, E.et al 2014) The reabsorption of glucose is ensured by the sodium-glucose cotransporter (SGLT) 2, responsible for the reabsorption of 90% of glucose, and SGLT1, that reabsorbs the remaining glucose. (Mota, M., et al 2015) Glomerular hyperfiltration is a common pathway of kidney injury both in diabetic and non-diabetic settings and is associated with progression of kidney function decline. (Hoogeveen, E. K. 2022) Sodium-glucose co-transporter-2 (SGLT2) inhibitors are glucose-lowering agents that eliminate excess glucose through a glucosuric effect by reducing glucose reabsorption from the renal filtrate (Thomson, S. C., et al. 2019) It is indicated that the expression of high mobility group box 1 (HMGB1) increased in patients with kidney disease, and may result in renal injury through the activation of nuclear factor- κB (NF- κB) and an increase in receptor for advanced glycation end products (RAGE) expression. It is suggested that Dapagliflozin achieves its reno-protective status through its antioxidative stress and anti-inflammatory action via inhibition of the HMGB1 - RAGE - NF- κB signalling pathway. (Yao, D et al., 2018) SGLT2 is found almost exclusively in the luminal membranes of epithelial cells lining the first and second segments of the proximal tubules, where it mediates reabsorption of most (typically ≥ 90%) of filtered glucose. (Mudaliar S, et al. 2015) By inhibiting SGLT2 beneficial kidney effects are thought to be mediated by various mechanisms, including restoration of tubule-glomerular feedback leading to a reduction in intraglomerular pressure and hyperfiltration. Both conditions are considered core components of the pathophysiology contributing to progression of diabetic as well as nondiabetic CKD. Reductions in intraglomerular pressure, as shown by agents blocking the renin-angiotensin system, are frequently accompanied by a hemodynamic acute decrease in GFR, which is reversible after treatment cessation. (Wanner et al., 2018).

Common drug side effects of dapagliflozin include urinary tract infections, cystitis, hypotension, dehydration and female genital mycotic infections. Hypoglycemic episodes were reported in 6% to 10% of patients who administer dapagliflozin concurrently with insulin and insulin secretagogues. (Anderson SL et al., 2014) Pentoxifylline (PTF) is a synthetic dimethylxanthine derivative that modulates the rheological properties of blood and has both anti-oxidant and anti-inflammatory properties. PTF has been investigated for its possible use in diverse conditions, including osteoradionecrosis, diabetic kidney disease, and generally any condition associated with fibrosis. (Wen WX et al., 2017) PTF reduces levels of inflammatory markers: high-sensitivity C-reactive protein (hs-CRP), serum fibrinogen and TNF-α, this could reduce albuminuria and slow renal disease progression. (de Morales AM et al, 2019)

Thus, we need to evaluate the effect of Dapagliflozin versus Pentoxifylline on GFR among CKD non-diabetic patients.

Conditions

Chronic Kidney Diseases

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dapagliflozin arm

70 patients will take dapagliflozin 10 mg per day for 1 year in addition to standard management for chronic kidney disease

Group Type: ACTIVE_COMPARATOR

Dapagliflozin 10mg Tab

Intervention Type: DRUG

Patients will be given dapagliflozin 10 mg once daily

Pentoxiphylline arm

70 patients will take pentoxifylline 400 mg twice daily for 1 year in addition to standard management for chronic kidney disease

Group Type: ACTIVE_COMPARATOR

Pentoxifylline 400 MG

Intervention Type: DRUG

Patients will be given pentoxyifylline 400 mg twice daily

Control

70 patients won't take either dapagliflozin or pentoxiphylline but they will continue their standard management for chronic kidney disease

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Dapagliflozin 10mg Tab

Patients will be given dapagliflozin 10 mg once daily

Intervention Type: DRUG

Pentoxifylline 400 MG

Patients will be given pentoxyifylline 400 mg twice daily

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• CKD stage 2 and 3

Exclusion Criteria

• Diabetes mellitus
• History of recurrent or recent genitourinary infections
• Immunosuppressive medications
• Malignancy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ain Shams University

OTHER

Sponsor Role: lead

Responsible Party

nahla mohamed elsayed teama

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Saeed A Saeed, Professor

Role: STUDY_DIRECTOR

Ain Shams University

Locations

Ain Shams University

Cairo, , Egypt

Site Status: RECRUITING

Countries

Egypt

Central Contacts

Mohamed A Mohamed, MSc

Role: CONTACT

Mohammed.Ashraf@med.asu.edu.eg

1119090018 ext. +20

Facility Contacts

Mohamed A Mohamed, MSc

Role: primary

Mohammed.Ashraf@med.asu.edu.eg

1119090018 ext. +20

References

Ni L, Yuan C, Chen G, Zhang C, Wu X. SGLT2i: beyond the glucose-lowering effect. Cardiovasc Diabetol. 2020 Jun 26;19(1):98. doi: 10.1186/s12933-020-01071-y.

Reference Type: BACKGROUND

PMID: 32590982 (View on PubMed)

Nespoux J, Vallon V. Renal effects of SGLT2 inhibitors: an update. Curr Opin Nephrol Hypertens. 2020 Mar;29(2):190-198. doi: 10.1097/MNH.0000000000000584.

Reference Type: BACKGROUND

PMID: 31815757 (View on PubMed)

Panchapakesan U, Pollock C. Drug repurposing in kidney disease. Kidney Int. 2018 Jul;94(1):40-48. doi: 10.1016/j.kint.2017.12.026. Epub 2018 Apr 6.

Reference Type: BACKGROUND

PMID: 29628139 (View on PubMed)

Cersosimo E, Solis-Herrera C, Triplitt C. Inhibition of renal glucose reabsorption as a novel treatment for diabetes patients. J Bras Nefrol. 2014 Jan-Mar;36(1):80-92. doi: 10.5935/0101-2800.20140014.

Reference Type: BACKGROUND

PMID: 24676619 (View on PubMed)

DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012 Jan;14(1):5-14. doi: 10.1111/j.1463-1326.2011.01511.x.

Reference Type: BACKGROUND

PMID: 21955459 (View on PubMed)

Other Identifiers

MD277/2023

Identifier Type: -

Identifier Source: org_study_id