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A Multicenter, Double-blind, Randomized, Parallel Group Study to Assess the Effect of NCX4016 vs Placebo on Walking Distance in Patients With Peripheral Arterial Occlusive Disease at Leriche-Fontaine Stage II

Design of the study This was a prospective, randomized, double-blind, parallel-groups, placebo-controlled study conducted in fortythree clinical sites throughout Europe. 442 patients with peripheral arterial occlusive disease (PAD) at Leriche-Fontaine stage II were treated with NCX 4016 800 mg bid or with an indistinguishable placebo for 6 months. The dosage of 800 mg bid was selected based on previous clinical studies, which demonstrated a good safety profile and a good tolerability in the gastro intestinal tract. Compliance was checked by counting dispensed versus returned study medication.

All patients received 100 mg aspirin once daily for cardiovascular prevention, standard for this patient population at the time of study design.

Inclusion criteria were: male and female patients between 40 and 80 years with Leriche-Fontaine stage II PAD presenting symptoms of intermittent claudication stable for at least 6 months, an ankle/brachial index <0.9, an absolute claudication distance (ACD) <500 m and an initial claudication distance (ICD) >50 m on a standardized treadmill test (3% incline, 3 km/hr), and clinical stability before inclusion (i.e. changes in ACD not exceeding 25% in two standardized treadmill tests during run-in). All patients gave their written informed consent.

Exclusion criteria were: unstable symptoms and/or rapid deterioration of PAD during the previous 3 months; presence of clinically significant renal or hepatic failure, or insulin-dependent type 1 diabetes; uncontrolled type 2 diabetes, arterial hypertension or dyslipidemia; any clinical condition limiting the patient's exercise ability (angina pectoris, congestive heart failure, respiratory disease, bone and joint disease, neurological disorders); active peptic ulcer during the previous 6 months; any hemorrhagic condition or history of bleeding; acute coronary syndrome or acute cerebrovascular episodes during the previous 6 months; previous revascularization procedures during the last 6 months or indication for vascular surgery; ischemic rest pain; life expectancy <12 months; pregnancy or lactation; participation to other investigational trials within 3 months prior to inclusion; history of hypersensitivity or any form of allergic reaction or contraindications to NSAIDs, aspirin, and NO-donating drugs. The following treatments were not allowed for the period of the study: continuative use (>7 days) of NSAIDs or nitrovasodilating drugs; phosphodiesterase type 5 inhibitors, anticoagulants, heparin, ticlopidine, clopidogrel, indobufen, defibrotide, mesoglycan, picotamide, pentoxyfylline, carnitine, sulodexide. All other concomitant treatments were kept constant as much as possible during the study period.

Primary end-point of the study was the ACD on a constant treadmill test; secondary end-points were ICD; responder rates, i.e. the proportion of patients showing a >=28% or a >=50% improvement of ACD in comparison with baseline; quality of life questionnaire Short-Form 36 (SF-36); the variations of the ankle/brachial index (ABI) between baseline and 6 months and the modifications of the intimal medial thickness (IMT) of the common right carotid artery at 6 months as compared with baseline.

Common right carotid artery was examined by B-mode ultrasound in the longitudinal view, 1-1.5 cm proximally to the bifurcation. The measurement of IMT was obtained according to the Mannheim carotid intima-media thickness consensus with one modification: instead of acquiring the vascular wall image only with the lateral probe incidence, images were acquired also with the anterior and posterior incidence, in order to obtain a triplicate number of measurements to be used for comparisons. Each position was visualized and recorded for at least 15 sec. with simultaneous taking of the ECG tracing. Images of the far wall of the distal 1 cm of the right common carotid artery were obtained. IMT was calculated from each of the three projections and the final value was calculated from the average of all measurements with the use of standardized ultrasonography settings. The baseline carotid ultrasonographic examinations were used to localize the site of interest at follow-up. Digitized still images from an electrocardiographically defined diastolic frame were analyzed offline. A single observer who was unaware of the treatment assignments and the identities of the patients measured the mean carotid intima media thickness. Focal atherosclerotic plaques were excluded from the measurements. All measurements were performed with the use of an automated border detection system. A number of measurements not inferior to 30 for each of the three image acquisition incidences was carried out in the 1cm segment of the carotid artery assessed. For each subject the same ultrasound system and transducer and the same operator were used throughout the study. Images were centrally analyzed at the coordinating center by a dedicated, automated computerized edge detection system for the measurement of common carotid far wall intima-media using the software M'ATH 2.0 (Metris Argenteuil, France).