| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Peripheral arterial disease (intermittent claudication) Fontaine stage II |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10022562 |
| E.1.2 | Term | Intermittent claudication |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To investigate in patients suffering from intermittent claudication due to Fontaine stage II PAD whether a 24-week treatment by SL650472 OD on top of clopidogrel may result in an improvement of walking capacity, by comparing three doses of SL650472 to placebo, and to calibrate such effect versus cilostazol. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the effects of such therapeutic regimens on the functional/quality of life status of the study population.
To compare the safety and tolerability of those therapeutic regimens.
Pharmacokinetics:
To build a population PK model in patients.
To detect influence of covariates on PK parameters. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria at screening visit:
Diagnosis of intermittent claudication
1. Patient with stable symptoms of intermittent claudication of the lower extremities, secondary to chronic occlusive arterial disease from atherosclerosis origin (symptoms present for 6 months or longer and not significantly changed within the past 3 months);
2. ICD of 30 to 200 m at screening constant workload treadmill test.
Confirmation of underlying PAD
3. Doppler-measured pre-treadmill ABI of 0.90 or lower after 10 minutes of rest or, for patients with an ABI of greater than 1.3 (non-compressible arteries), a Toe-Brachial Index (TBI) of less than 0.7.
Appropriate background therapy
4. Patient following a supervised or unsupervised program of exercise training and smoking cessation (if smoker) for at least 3 months prior to screening, and accepting to continue it for the entire study duration;
5. Patient who can be treated by clopidogrel 75 mg OD from screening visit to 24-week visit.
Inclusion criteria at randomization:
Confirmation of symptoms stability
6. Mean ICD of 30 to 200 m calculated by averaging the constant workload treadmill test performed at the end of the run-in phase and the previous one performed 14 to 17 days before;
7. Percent change less than or equal to 25 % between those two ICD measurements, as per international recommendation.
Compliance to investigational products administration
8. At least 80 % of clopidogrel and 80 % of placebo tablets/capsules taken during the run-in phase. |
|
| E.4 | Principal exclusion criteria |
Exclusion criteria at screening/randomization visits
1. Patient not having provided written informed consent.
2. Patient previously screened for or included in this study.
Potentially non-atherosclerotic and/or severe stage disease not amenable to medical therapy
3. Age below 40 years and/or onset of symptoms of PAD before the age of 40 years;
4. Non-atherosclerotic vascular disease (e.g. Buerger’s disease, popliteal entrapment syndrome);
5. Limb-threatening (grades III and IV) chronic limb ischemia, manifested by ischemic rest pain, ulceration, or gangrene.
Current (or within the 3 months prior to screening) pharmacological treatment likely to interfere with study endpoints
6. Recent initiation or discontinuation of treatment by vasoactive agents (including cilostazol, naftidrofuryl, pentoxyfilline, beraprost sodium, papaverine, isoxsuprine, nylidrin, cyclandelate, and niacin derivatives), or high-dose atorvastatin (80 mg OD) or warfarin/coumadin.
Recent (within 3 months prior to screening or during the run-in phase) changes in local and/or general conditions likely to interfere with study endpoints
7. Recent lower-extremity surgical or endovascular arterial reconstructions or sympathectomy, or recent deep venous thrombosis;
8. Recent change in the level of compliance to supervised or unsupervised program of exercise training and smoking cessation (whatever the grade of compliance, it should remain the same during this period);
9. Recent occurrence of at least one of the following: acute myocardial infarction (MI), unstable angina (UA), coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI) transient ischemic attack (TIA) or stroke;
Presence of medical and/or social problems (at screening or during the run-in phase) that would either interfere with participation in the trial, or lead to inability to complete the trial
10. Conditions other than claudication likely to jeopardize completion and/or safety of the treadmill testing, including angina, electrocardiographic or clinical evidence of significant myocardial ischemia (ischemic ST-segment depression greater than 0.2 mV in any lead) or QT prolongation (QTc ≥ 500 ms), dyspnea, fatigue, orthopedic, or rheumatologic symptoms, severe obesity (BMI ≥35), uncontrolled hypertension (blood pressure greater than 200/100 mm Hg) or significant hypotension (systolic blood pressure less than 90 mm Hg), severe valvular disease, restrictive or hypertrophic cardiomyopathy
11. Planned cardiac or vascular surgery or angioplasty or any major surgery within the next 6 months;
12. Severe concomitant disease such that the patient is not expected to survive 6 months;
13. Receipt of any investigational treatment (drug or device) within the previous 30 days;
14. Previous disabling condition with a severe cerebral deficit, such that the patient is bedridden or demented;
15. Geographic or social factors making study participation impractical;
16. Unable to understand the full meaning of the informed consent.
Contra-indications to the use of cilostazol, or conditions likely to dramatically affect pharmacokinetics of cilostazol and/or SL650472
17. History of congestive heart failure of any severity;
18. History of drug allergy to cilostazol;
19. Pregnant or breast-feeding women, or women planning to become pregnant or breast-feed;
20. Severe hepatic insufficiency;
21. Severe renal failure (serum creatinine greater than 2.5 mg/dL [220 µmol/L] and / or clearance less than 30 mL/min and /or dependency on renal dialysis);
22. Requirement for systemic administration of inhibitors of CYP3A4 such as ketoconazole, itraconazole, erythromycin, cimetidine and diltiazem, as well as inhibitors of CYP2C19 such as omeprazole.
23. Patient with a history of a malignant (i.e. carcinoma) or proliferative breast disease (i.e. breast fibroadenoma, fibrocystic breast disease).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change in initial claudication distance (ICD) measured at the 24-week test, compared with that at baseline |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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