Effect of NCX4016 on Walking Distance in Patients With Peripheral Arterial Occlusive Disease (PAOD)
Condition: Intermittent Claudication
MeSH terms: Intermittent Claudication; Arterial Occlusive Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      Peripheral arterial disease (PAD) is almost invariably associated with a generalized
      atherosclerotic involvement of the arterial tree and endothelial dysfunction. Previous short
      term studies showed improvement of vascular reactivity and walking capacity in PAD patients
      by measures aimed at restoring Nitric Oxide (NO) production. NO is also known to prevent the
      progression of atherosclerosis. We wished to assess whether the prolonged administration of a
      NO-donating agent (NCX 4016) improves the functional capacity of PAD patients and affects the
      progression of atherosclerosis as assessed by carotid intima-media thickness (IMT).

      Four hundred forty two patients with stable intermittent claudication were enrolled in a
      prospective, double blind, placebo-controlled study and randomized to either NCX 4016 800mg
      bid or its placebo for 6 months. The primary study outcome was the absolute claudication
      distance (ACD) on a constant treadmill test (10% incline, 3km/hr); main secondary end-point
      was the change of the mean far-wall right common carotid artery IMT.
    

Detailed description: 
      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).
    

Intervention name(s): NCX-4016; NCX4016 placebo
Intervention type(s): Drug; Drug
Intervention description(s): NCX4016 800 mg b.i.d. for 6 months on top of aspirin 100 mg o.d.; NCX4016 placebo b.i.d. for 6 months
Intervention MeSH terms: Aspirin; Nitroaspirin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: atherosclerosis; carotid intima-media thickness; intermittent claudication; Nitric Oxide / NO