| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Peripheral Arterial Disease: Intermittent Claudication |
|
| E.1.1.1 | Medical condition in easily understood language |
| Occlusive disease in the arteries supplying the legs causing cramping muscle pain on walking due to poor blood flow. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009241 |
| E.1.2 | Term | Claudication intermittent |
| E.1.2 | System Organ Class | 100000004866 |
|
| 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 |
| The principal research objective of this trial is to assess whether the combination of ramipril with Percutaneous Transluminal Angioplasty (PTA) improves maximum walking distance, when compared to PTA alone, in sufferers of Intermittent Claudication (IC). IC is exercise pain due to arterial disease causing impaired blood supply to the muscles. Primary outcome measure for this trial is the Maximum Walking Distance (MWD). Treadmill exercise test will be used to estimate the maximum distance the participant can walk at a speed of 2.5 km/h with a 10 degree incline for a maximum of 15 minutes. This time will be recorded in both placebo and ramipril groups at baseline and at 6 and 24 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Outcome Measures:
1. Other clinical indicators of lower limb ischaemia:
a) Patient Reported Walking Distance (PRWD)- This is a distance, in metres, that the patient estimates that they can walk.
b) Treadmill Intermittent Claudication Distance (ICD) or the distance associated with the onset of claudication pain measured on the same standardised treadmill test
c) Ankle Brachial Pressure Index (ABPI) at rest and following treadmill testing. ABPI is a comparison of pressure in the peripheral arteries of the foot and ankle compared to the blood pressure in their arm as we would routinely measure it. This is a standard diagnostic marker of Peripheral Arterial Disease.
d) Progression of disease: we will monitor how many patients go on to develop worsening disease. This may be indicated by rest pain, gangrene or acute ischaemia. In intermittent Claudication sufferers will experience pain on exertion. With rest pain, the disease is so severe that the pain persists even when t |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Patients listed for elective femoropopliteal PTA for intermittant claudication due to peripheral artery disease
-Patients with unilateral or bilateral intermittent leg claudication which was stable for the last 6 months.
-Patients with ABPI < 0.9 at rest at least in one leg.
-BP ≤ 160/90 and a stable medication regimen for the last 6 months.
-Able to give informed consent
-Able to comply with study protocol |
|
| E.4 | Principal exclusion criteria |
Documented bilateral renal artery stenosis
Diabetes Mellitus types 1 or 2
Unlikely to be compliant with medication or follow up as determined by the recruiting institution.
Patients who had a recent (less than 3 months) angioplasty or bypass surgery
Pregnancy and breast feeding
Patients with critical limb ischemia (This includes patients with ischaemic rest pain and ulceration > 2 weeks and/or a resting ankle pressure < 50mmHg (grades IV, V and VI according to Rutherford et al 1997).
Patients who had a recent (less than 3 months) angioplasty or bypass surgery
Patients who are unable to perform a treadmill test due to a limiting heart, respiratory or arthritic disease.
History of angioneurotic oedema
Currently taking ACE inhibitor or Angiotensin receptor blocker
Contraindication to ACE inhibitor
History of ACE inhibitor intolerance
A creatinine rise of > 30% from baseline and/or Potassium > 5.9 mmol/l
Unwillingness to participate.
Level 1 evidence for ACE inhibitor treatment, including:
a) Documented heart failure, left ventricular dysfunction or ejection fraction <35% on previous echocardiography
b) uncontrolled hypertension, BP > 160mmHg systolic or 100mmHg diastolic on 3 separate readings measured after 10 minutes rest on 2 separate occasions
c) Recent (< 3months) myocardial infarction or stroke
d) Chronic renal impairment (serum creatinine > 250 micromol/l) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure is Maximal Walking Distance (MWD). This will be measured on a treadmill exercise test, lasting 15 minutes, with a walking speed of 2.5km/hr with a 10 degree incline. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Measures will be taken at 6 and 24 weeks following angioplasty and will be compared to a measure prior to angioplasty as a baseline. |
|
| E.5.2 | Secondary end point(s) |
Secondary Outcome Measures:
1. Other clinical indicators of lower limb ischaemia:
a) Patient Reported Walking Distance (PRWD)- This is a distance, in metres, that the patient estimates that they can walk.
b) Treadmill Intermittent Claudication Distance (ICD) or the distance associated with the onset of claudication pain measured on the same standardised treadmill test
c) Ankle Brachial Pressure Index (ABPI) at rest and following treadmill testing. ABPI is a comparison of pressure in the peripheral arteries of the foot and ankle compared to the blood pressure in their arm as we would routinely measure it. This is a standard diagnostic marker of Peripheral Arterial Disease.
d) Progression of disease: we will monitor how many patients go on to develop worsening disease. This may be indicated by rest pain, gangrene or acute ischaemia. In intermittent Claudication sufferers will experience pain on exertion. With rest pain, the disease is so severe that the pain persists even when the individual is not exercising. Gangrene occurs when the blood supply is so poor that there is dead tissue (skin or muscle). Acute ischaemia is when there is a sudden blockage of an artery. This is considered an emergency and can lead to amputation if the blood supply is not restored.
2. Quality of life: This will be assessed using several validated questionnaires. We will look at generic and disease specific quality of life.
a) Generic – measured using the SF36V2, SF6D and EuroQol (EQ5D) instruments
b) Disease specific – measured using the VascuQol
3. Cardiovascular prognosis (risk of heart attacks and strokes and other vascular events) will be assessed using validated scoring systems. These will include Framingham, PROCAM, QRISK and Manchester charts scoring systems. We will also look at certain biochemical and haematological markers in the blood that have been linked with altered cardiovascular risk including - B-type Natriuretic Peptide (BNP) and N- terminal prohormone BNP (NT-proBNP) and a Lipid profile (LDL, HDL, Total Cholesterol, Triglycerides), fibrinogen and CRP.
4. Markers of endothelial function and ischaemia reperfusion – these are tests that are used to assess the blood vessels response to stress. The response to stress is often abnormal in diseased blood vessels. Many of these are analysed from blood / urine tests taken prior to and following treadmill testing including:
a) IL6
b) Soluble Intercellular Adhesion Molecule-1 (sICAM -1)
c) sE selectin
d) Urine Albumin Creatinine Ratio (UACR)
e) tissue factors/ microparticles
How well the blood vessels respond to stress can also be measured using a non-invasive test known as Peripheral Arterial Tonometry (PAT) measured using the EndoPAT technology.
5. Arterial effects: We will be examining whether ramipril affects the stiffness of the arterial system. Primarily, we will do this using two non-invasive tests that examine the speed of conduction of pulse waves. We will also look at markers in the blood that suggest abnormal re-modelling of the structure of the diseased artery wall. Different types of two blood markers will be tested for. These are Matrix metaloproteinases (MMPs) and tissue inhibitors of metaloproteinases (TIMPs).
6. Duplex of the angioplasty site following angioplasty. Duplex is a form of imaging that uses doppler signals and ultrasound images. It can be used to assess blood flow in an artery. Altered blood flow can be used to assess the angioplasty site to see how much it has narrowed up again. This will be measured at the 2 week follow up stage and at the 24 week stage. In order to assess blood flow we must take two measurements. One measurement will be taken 1cm proximal (nearer the heart) than the most proximal narrowing that has been angioplastied. The other will be taken 1cm distal (furthest from the heart) to the most distal narrowing that has been angioplastied.
7. Health economics (cost effectiveness / utility) will be analysed. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All measures will be taken at 6 and 24 weeks following angioplasty except arterial duplex which will be done at 2 and 24 weeks. Measures will be compared to a measure prior to angioplasty as a baseline except duplex which will be compared from between 2 and 24 weeks. |
|
| 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 | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The last visit of the last subject to be enrolled (24 weeks from date of PTA). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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