Effect of NCX4016 on Walking Distance in Patients With Peripheral Arterial Occlusive Disease (PAOD)

Sponsor

NicOx Research Institute S.r.l. (Industry)

Overall Status

Completed

CT.gov ID

NCT01256775

Collaborator

(none)

442

Enrollment

Location

Arms

Duration (Months)

23.3

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Intermittent Claudication	Drug: NCX-4016 Drug: NCX4016 placebo	Phase 2

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).

Study Design

Study Type:

Interventional

Actual Enrollment :

442 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Sep 1, 2003

Actual Primary Completion Date :

Apr 1, 2005

Actual Study Completion Date :

Apr 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: NCX4016 placebo NCX4016 placebo b.i.d for 6 months	Drug: NCX4016 placebo NCX4016 placebo b.i.d. for 6 months
Active Comparator: NCX4016 ncx4016,800 mg b.i.d., on top of aspirin 100 mg o.d.	Drug: NCX-4016 NCX4016 800 mg b.i.d. for 6 months on top of aspirin 100 mg o.d.

Arm

Intervention/Treatment

Placebo Comparator: NCX4016 placebo

NCX4016 placebo b.i.d for 6 months

Drug: NCX4016 placebo

NCX4016 placebo b.i.d. for 6 months

Active Comparator: NCX4016

ncx4016,800 mg b.i.d., on top of aspirin 100 mg o.d.

Drug: NCX-4016

NCX4016 800 mg b.i.d. for 6 months on top of aspirin 100 mg o.d.

Outcome Measures

Primary Outcome Measures

maximal walking distance evaluated by a constant treadmill test [baseline]
maximal walking distance evaluated by a constant treadmill test [6 months]

Secondary Outcome Measures

pain-free walking distance [baseline, 1-3-6 months]
assessment of carotid artery IMT [baseline and 6 month]

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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
ankle/brachial index <0.9
an absolute claudication distance (ACD) <500 m
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:

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.