Ignite Creation Date:
2024-05-05 @ 11:51 AM
Last Modification Date:
2024-10-26 @ 9:15 AM
Study NCT ID:
NCT00157508
Status:
TERMINATED
Last Update Posted:
2015-04-09
First Post:
2005-09-08
Brief Title:
Renal and Systemic Effects of NCX4016 in Patients With Type 2 Diabetes and Early Nephropathy
Sponsor:
Mario Negri Institute for Pharmacological Research
Organization:
Mario Negri Institute for Pharmacological Research
Study Overview
Official Title:
A Pilot Randomised Double-blind Cross-over Study to Assess the Renal and Systemic Effects of NCX4016 in Patients With Type 2 Diabetes and Early Nephropathy
Status:
TERMINATED
Status Verified Date:
2005-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Aspirin is commonly used for treatment of painful and inflammatory diseases and in the prevention of the cardiovascular disease A major drawback of aspirin treatment is the well recognized gastrointestinal toxicity Recent research indicate that coupling a nitric oxide NOderivate to the aspirin moiety retains its therapeutic effects while avoiding its undesirable gastrointestinal side effects NO has cytoprotective effects such as blood flow modulation mucus release and repair of mucosal injury NCX4016 a NO-releasing derivative of acetylsalicilic acid has been shown to retain the analgesic anti-inflammatory and antithrombotic activity of aspirin but with less gastrointestinal toxicity In addition preliminary data suggested that NCX4016 may restore insulin sensitivity in eNOS deficient mice
This study was aimed to evaluate the activity of NCX4016 compared to aspirin on albuminuria insulin sensitivity and cardiac and renal hemodynamic in patients with type 2 diabetes mellitus The patients after one month of placebo treatment entered two 1-month treatments periods with equivalent doses 800 mg of NCX4016 325 mg of aspirin of NCX4016 or aspirin
This study was aimed to evaluate the activity of NCX4016 compared to aspirin on albuminuria insulin sensitivity and cardiac and renal hemodynamic in patients with type 2 diabetes mellitus The patients after one month of placebo treatment entered two 1-month treatments periods with equivalent doses 800 mg of NCX4016 325 mg of aspirin of NCX4016 or aspirin
Detailed Description:
Nitric oxide-releasing non-steroidal anti-inflammatory drugs NO-NSAIDs are new chemical entities obtained by adding a nitric oxide-releasing moiety to the parent NSAID via a short-chain ester linkage NCX4016 Nitro-aspirin a acetoxy-benzoate 2-2-nitroxymethyl-phenyl ester of acetylsalicylic acid is one of these novel compounds developed with the dual aim to expand the pharmacological properties of the parent drug and to spare some of its side effects in particular on the gastrointestinal mucosa Decreased NO synthesis may contribute to some of the abnormalities associated with diabetes such as decreased insulin activity impaired endothelium-dependentinsulin-induced vasodilatation increased sympathetic vasoconstrictor outflow and increased platelet activation that may result in increased vascular resistance and arterial hypertension and in the long term to an increased risk of micro- and macrovascular complications
Low-dose aspirin represents the antiplatelet drug of choice for prevention of vascular complications in diabetes Preclinical data on NCX4016 support the possibility that Nitro-aspirin may shear with aspirin the antithrombotic activity and may offer the additional benefits related to increased NO bioavailability Actually NCX4016 inhibits cyclooxygenase COX activity in platelets both in vitro and ex vivo and similar to aspirin prevents the release of thromboxane TX A2 and arachidonic acid-induced platelet aggregation Moreover Nitro-aspirin inhibits aspirin-insensitive platelet aggregation and adhesion possibly by inhibiting the expression of platelet adhesion molecules by a specific COX-independent mechanism probably NO-mediated that is not show by the parent compound Therefore Nitro-aspirin can exceed the cardioprotective action of the parent compound by adding the aspirin-like moiety and the NO-releasing moiety which both contribute to its benefits effects such as multiple anti-thrombotic and possibly anti-atherosclerotic activities restoration of insulin-related metabolic and vascular effect and finally blood pressure reduction Moreover experimental and clinical data suggest that Nitro-aspirin will offer significant safety advantages by its NO moiety that may limit aspirin gastrotoxicity by preventing the vasocontriction of the mucosal microvasculature
In the present randomised double-blind cross-over study we evaluated the efficacy and safety profile of Nitro-aspirin 800 mg bid and of an equiactive dose of aspirin 325 mg od as compared to placebo in thirteen patients with type 2 diabetes and micro or macro-albuminuria overnight albumin excretion rate 20 µgmin for at least 6 months without overt renal insufficiency serum creatinine concentration 2 mgdl and no specific controindication to aspirin therapy Eligible patients who provided written informed consent withdrew any previous treatment with NSAIDs or aspirin and after a 4-week placebo run-in period entered two consecutive 4-week treatment periods with Nitro-aspirin plus aspirin placebo or Nitro-aspirin placebo plus aspirin in a random order Primary efficacy variables were changes in urinary albumin excretion UAE and in insulin activity at the end of Nitro-aspirin treatment as compared to baseline UAE mean of three overnight urine collection insulin sensitivity glucose disposal rate as measured by an hyperinsulinemic euglycemic clamp cardiac haemodynamics evaluated by echocardiography NO bioavailability and oxidative stress measured as nitritenitrate plasma levels and other clinical and laboratory variables were measured at baseline and at the end of each treatment periods
Low-dose aspirin represents the antiplatelet drug of choice for prevention of vascular complications in diabetes Preclinical data on NCX4016 support the possibility that Nitro-aspirin may shear with aspirin the antithrombotic activity and may offer the additional benefits related to increased NO bioavailability Actually NCX4016 inhibits cyclooxygenase COX activity in platelets both in vitro and ex vivo and similar to aspirin prevents the release of thromboxane TX A2 and arachidonic acid-induced platelet aggregation Moreover Nitro-aspirin inhibits aspirin-insensitive platelet aggregation and adhesion possibly by inhibiting the expression of platelet adhesion molecules by a specific COX-independent mechanism probably NO-mediated that is not show by the parent compound Therefore Nitro-aspirin can exceed the cardioprotective action of the parent compound by adding the aspirin-like moiety and the NO-releasing moiety which both contribute to its benefits effects such as multiple anti-thrombotic and possibly anti-atherosclerotic activities restoration of insulin-related metabolic and vascular effect and finally blood pressure reduction Moreover experimental and clinical data suggest that Nitro-aspirin will offer significant safety advantages by its NO moiety that may limit aspirin gastrotoxicity by preventing the vasocontriction of the mucosal microvasculature
In the present randomised double-blind cross-over study we evaluated the efficacy and safety profile of Nitro-aspirin 800 mg bid and of an equiactive dose of aspirin 325 mg od as compared to placebo in thirteen patients with type 2 diabetes and micro or macro-albuminuria overnight albumin excretion rate 20 µgmin for at least 6 months without overt renal insufficiency serum creatinine concentration 2 mgdl and no specific controindication to aspirin therapy Eligible patients who provided written informed consent withdrew any previous treatment with NSAIDs or aspirin and after a 4-week placebo run-in period entered two consecutive 4-week treatment periods with Nitro-aspirin plus aspirin placebo or Nitro-aspirin placebo plus aspirin in a random order Primary efficacy variables were changes in urinary albumin excretion UAE and in insulin activity at the end of Nitro-aspirin treatment as compared to baseline UAE mean of three overnight urine collection insulin sensitivity glucose disposal rate as measured by an hyperinsulinemic euglycemic clamp cardiac haemodynamics evaluated by echocardiography NO bioavailability and oxidative stress measured as nitritenitrate plasma levels and other clinical and laboratory variables were measured at baseline and at the end of each treatment periods
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None