Aspirin and Renal Disease Progression in Patients With Type 2 Diabetes

NCT02895113 | Unknown Phase 3 DMC

• 1 other identifier: LEDA study
• Study Type: interventional
• Target: 418
• Locations: 1 country
• Sites: 1

Brief Summary

The pathophysiology of diabetes is multifactorial. Beyond genetic susceptibility loci, a lot of acquired risk factors are involved in the development and progression of the disease. Chronic complications of diabetes can be divided into vascular and nonvascular. The risk of developing complications increases with the duration of hyperglycemia, and usually become apparent in the second decade of hyperglycemia. Vascular complications are further subdivided into microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (coronary artery disease, peripheral arterial disease, cerebrovascular disease). It is estimated that the annual decline of estimated glomerular filtration rate (eGFR) in diabetic adults is about 2.1-2.7 ml/min. While there is consolidated evidence about the use of aspirin (ASA) for secondary prevention in diabetic patients, there is no consensus on the use in primary prevention; the use of ASA in these patients is at physician discretion. ASA is an effective antithrombotic agent that inhibits the production of thromboxane (Tx) A2 and other prostaglandins by blocking cyclooxygenase (COX). In patients treated with aspirin, serum TxB₂ level is the most reliable in vivo indicator of COX-1 inhibition than TxA2, due to its short half-life and artifacts associated with platelet activation ex vivo. COX are present in the kidney in the macula densa, in the medulla and in the interstitium. Experimental animals models have demonstrated that COX are involved in regulation of renal blood flow. In particular, in a murine animal model, after the administration of COX inhibitors such as aspirin and celecoxib, it was observed an improvement in renal plasma flow and eGFR, suggesting a role for Tx in the progression of renal damage However, data on the relationship between aspirin and renal function in humans are scarce. In a recent work lead on a large cohort of 800 patients with non-valvular atrial fibrillation, ASA use was associated with a reduced progression of eGFR \<45 ml/min during 2 years of follow-up. Furthermore, basal levels of urinary excretion of TxB2, correlated inversely with the use of aspirin and with the decrease of eGFR at follow-up. The aim of the study is to evaluate the decline in renal function in diabetic patients treated with low-dose aspirin (100 mg/day) vs. untreated diabetic patients.

Conditions

Diabetes

Keywords

Aspirin; Diabetes; Renal function; Thromboxane

Outcome Measures

Primary Outcomes (1)

• Changes in renal function in diabetic patients treated with aspirin

  The aim of our study is to evaluate the decline in renal function in diabetic patients treated with low-dose aspirin (100 mg/day) vs. untreated diabetic patients. In particular, we will evaluate: * The absolute change in eGFR, calculated as the difference between eGFR at 12 months - baseline eGFR; * The rapid decline in renal function, defined as a reduction of eGFR ≥5 ml/min at 1 years. * The change of renal function class (from G1 to G2, from G2 to G3a and so on) at 6 and 12 months.

  1 year

Secondary Outcomes (1)

• Relationship between changes of Thromboxane B2 excretion and renal function in diabetic patients treated with aspirin

  1 year

Study Arms (2)

Aspirin

EXPERIMENTAL

Patients will be treated with aspirin 100 mg/day for one year

Drug: Aspirin

Placebo

PLACEBO COMPARATOR

Patients will be treated with placebo for one year

Other: Placebo

Interventions

Aspirin DRUG

Patients suffering from type 2 diabetes will be randomized to receive 100 mg/day or placebo for one year

Also known as: Cardioaspirin, Acetylsalicylic acid

Aspirin

Placebo OTHER

Patients in this arm will be treated with placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of type 2 diabetes: random blood glucose ≥ 200 mg / dl, fasting blood glucose ≥ 126 mg/dl, blood glucose 2 hours after oral glucose tolerance test (75 g) ≥200 mg/dl, treatment with glucose-lowering agents.

You may not qualify if:

• History of cardiovascular or cerebrovascular events;
• Presence of inadequate glycaemic control (glycosylated haemoglobin ≥8%);
• Clinical diagnosis of type 1 diabetes (diagnosis of diabetes and insulin use before 35 years of age);
• Patients with renal impairment in G4 stage (eGFR \<30 ml/min) at baseline;
• Chronic active infection or evidence of malignancy in the last 5 years;
• Autoimmune systemic disease;
• Cardiac arrhythmia;
• Use of non-steroidal anti-inflammatory drugs, vitamin supplements, or other antiplatelet agents in the previous 30 days;
• Liver Failure (eg cirrhosis);
• Use of anticoagulants;
• Life expectancy \<1 year;
• Known allergy to aspirin.

Sponsors & Collaborators

• University of Roma La Sapienza: lead

Study Sites (1)

Internal and Medical Specialities Department - Policlinico Umberto I

Rome, Rome, 00161, Italy

Location

Related Publications (9)

• Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004 May;27(5):1047-53. doi: 10.2337/diacare.27.5.1047.

  PMID: 15111519 BACKGROUND

• Stevens PE, Levin A; Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013 Jun 4;158(11):825-30. doi: 10.7326/0003-4819-158-11-201306040-00007.

  PMID: 23732715 BACKGROUND

• Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007 Dec 13;357(24):2482-94. doi: 10.1056/NEJMra071014. No abstract available.

  PMID: 18077812 BACKGROUND

• Patrono C, Ciabattoni G, Pinca E, Pugliese F, Castrucci G, De Salvo A, Satta MA, Peskar BA. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res. 1980 Feb 1-15;17(3-4):317-27. doi: 10.1016/0049-3848(80)90066-3. No abstract available.

  PMID: 7368167 BACKGROUND

• Lariviere R, Moreau C, Rodrigue ME, Lebel M. Thromboxane blockade reduces blood pressure and progression of renal failure independent of endothelin-1 in uremic rats. Prostaglandins Leukot Essent Fatty Acids. 2004 Aug;71(2):103-9. doi: 10.1016/j.plefa.2003.12.021.

  PMID: 15207526 BACKGROUND

• Lomnicka M, Karouni K, Sue M, Wessel LA, Bing RJ. Effects of nonsteroidal anti-inflammatory drugs on prostacyclin and thromboxane in the kidney. Pharmacology. 2003 Jul;68(3):147-53. doi: 10.1159/000070172.

  PMID: 12784086 BACKGROUND

• Pastori D, Pignatelli P, Perticone F, Sciacqua A, Carnevale R, Farcomeni A, Basili S, Corazza GR, Davi G, Lip GYH, Violi F; ARAPACIS (Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment-Collaborative Italian Study) study group. Aspirin and renal insufficiency progression in patients with atrial fibrillation and chronic kidney disease. Int J Cardiol. 2016 Nov 15;223:619-624. doi: 10.1016/j.ijcard.2016.08.224. Epub 2016 Aug 14.

  PMID: 27565838 BACKGROUND

• Natale P, Palmer SC, Saglimbene VM, Ruospo M, Razavian M, Craig JC, Jardine MJ, Webster AC, Strippoli GF. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev. 2022 Feb 28;2(2):CD008834. doi: 10.1002/14651858.CD008834.pub4.

  PMID: 35224730 DERIVED

• Violi F, Targher G, Vestri A, Carnevale R, Averna M, Farcomeni A, Lenzi A, Angelico F, Cipollone F, Pastori D. Effect of aspirin on renal disease progression in patients with type 2 diabetes: A multicenter, double-blind, placebo-controlled, randomized trial. The renaL disEase progression by aspirin in diabetic pAtients (LEDA) trial. Rationale and study design. Am Heart J. 2017 Jul;189:120-127. doi: 10.1016/j.ahj.2017.04.005. Epub 2017 Apr 18.

  PMID: 28625368 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus

Interventions

Aspirin

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Francesco Violi, MD

  University of Roma La Sapienza

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Francesco Violi, MD

CONTACT

+390649970893; francesco.violi@uniroma1.it

Daniele Pastori, MD

CONTACT

+390649970893; daniele.pastori@uniroma1.it

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Full professor

Study Record Dates

• First Submitted: September 4, 2016
• First Posted: September 9, 2016
• Study Start: January 1, 2017
• Primary Completion: January 1, 2018
• Study Completion: September 1, 2018
• Last Updated: September 9, 2016

Record last verified: 2016-09

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)