Ignite Creation Date:
2024-05-06 @ 12:45 PM
Last Modification Date:
2024-10-26 @ 1:04 PM
Study NCT ID:
NCT03844113
Status:
UNKNOWN
Last Update Posted:
2020-12-29
First Post:
2019-02-12
Brief Title:
Carnosine for Peripheral Vascular Disease
Sponsor:
Monash University
Organization:
Monash University
Study Overview
Official Title:
Carnosine for Peripheral Vascular Disease
Status:
UNKNOWN
Status Verified Date:
2020-12
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Car-PVD
Brief Summary:
The investigators hypothesise that a home-based standardised exercise intervention with 2g of carnosine daily for 6 months will improve walking endurance in 104 patients with PVD aged 40-80 years compared to placebo and exercise through stabilisation of HIF1-α in the ischaemic leg
Aims
Aim 1 Determine whether in patients with PVD carnosine in addition to exercise improves
1 walking endurance 6-min walk test primary outcome
2 initial claudication distance ICD and absolute claudication distance ACD treadmill cadence resting and exercise ABI and
3 central blood pressure endothelial function arterial aortic stiffness lipid profile and
4 quality of life as determined by EuroQol-5D all secondary outcomes
5 Improve cognitive function global cognitive score formed by a composite of 7 cognitive tests
Aim 2 Delineate the mechanisms by which carnosine improves walking endurance
1 protein expression of pro-angiogenic and carnosine related genes including carnosine transporters in the skeletal muscle biopsies EPCs in peripheral blood and quantitative proteomic studies
2 other mechanisms demonstrated in animal studies including plasma inflammatory markers serum and urinary advanced glycation AGE and lipoxidation ALE end-products tertiary outcomes
This trial will provide evidence for use of carnosine as a therapeutic intervention for PVD patients and if positive will have immediate clinical application
Aims
Aim 1 Determine whether in patients with PVD carnosine in addition to exercise improves
1 walking endurance 6-min walk test primary outcome
2 initial claudication distance ICD and absolute claudication distance ACD treadmill cadence resting and exercise ABI and
3 central blood pressure endothelial function arterial aortic stiffness lipid profile and
4 quality of life as determined by EuroQol-5D all secondary outcomes
5 Improve cognitive function global cognitive score formed by a composite of 7 cognitive tests
Aim 2 Delineate the mechanisms by which carnosine improves walking endurance
1 protein expression of pro-angiogenic and carnosine related genes including carnosine transporters in the skeletal muscle biopsies EPCs in peripheral blood and quantitative proteomic studies
2 other mechanisms demonstrated in animal studies including plasma inflammatory markers serum and urinary advanced glycation AGE and lipoxidation ALE end-products tertiary outcomes
This trial will provide evidence for use of carnosine as a therapeutic intervention for PVD patients and if positive will have immediate clinical application
Detailed Description:
Peripheral vascular disease PVD has high prevalence of 10-15 in Australia and is caused by atherosclerotic occlusion of the arteries supplying the lower extremities which reduces blood flow and leads to intermittent claudication and critical limb ischaemia No effective medication is currently available Although surgical or endovascular revascularisation are available treatments not all patients are suitable for the procedure and grafts can fail and dilated arteries can restenose Structured exercise both supervised and home-based improves walking endurance in patients with PVD to a similar extent as revascularisation and effects are longer lasting but the pain associated with exercise is a major limitation Therefore there is a need to develop safe interventions synergistic with exercise that can prompt revascularisation and preserve limb viability
Angiogenesis plays an essential role for recovery from critical limb ischaemia Hypoxia inducible factor 1α HIF1-α a master regulator of angiogenic genes has been implicated Under normal conditions HIF1-α is targeted for proteasomal degradation through the activity of prolyl hydroxylases PHDs PHDs require iron for their activity and their inactivation by metal chelators or pharmacological inhibitors stabilises HIF1-α and has been shown to improve blood flow in the ischaemic limb However metal chelators cannot be used as an intervention due to their toxicity
Recent studies have shown that supplementation of carnosine β-alanyl-L-histidine a naturally occurring histidyl dipeptide in skeletal muscle with an excellent safety profile improves exercise performance in athletes as well as in patients with chronic heart failure The investigators and others have shown that carnosine supplementation also improves cardiometabolic risk factors No clinical trial has yet to investigate whether carnosine improves walking endurance in patients with PVD Carnosine has anti-inflammatory antioxidative anti-glycating and anti-atherosclerotic properties It also has the ability to chelate metals form conjugates with reactive aldehydes and has lactate buffering capacity In addition carnosine has been found to be very effective in reducing ischaemia-reperfusion damage in several organs Our preliminary results using a murine model of hind limb ischaemia HLI showed that administration of carnosine over 21 days increased HIF1-a and VEGF levels in the ischaemic muscle and improved tissue perfusion Furthermore mobilisation of pro-angiogenic endothelial progenitor cells EPCs and the ambulatory movement were increased in carnosine treated HLI mice compared to controls The investigators propose a randomised clinical trial to investigate whether administration of carnosine for 6-month in addition to exercise could improve walking endurance and quality of life in patients with PVD compared to placebo and exercise
Angiogenesis plays an essential role for recovery from critical limb ischaemia Hypoxia inducible factor 1α HIF1-α a master regulator of angiogenic genes has been implicated Under normal conditions HIF1-α is targeted for proteasomal degradation through the activity of prolyl hydroxylases PHDs PHDs require iron for their activity and their inactivation by metal chelators or pharmacological inhibitors stabilises HIF1-α and has been shown to improve blood flow in the ischaemic limb However metal chelators cannot be used as an intervention due to their toxicity
Recent studies have shown that supplementation of carnosine β-alanyl-L-histidine a naturally occurring histidyl dipeptide in skeletal muscle with an excellent safety profile improves exercise performance in athletes as well as in patients with chronic heart failure The investigators and others have shown that carnosine supplementation also improves cardiometabolic risk factors No clinical trial has yet to investigate whether carnosine improves walking endurance in patients with PVD Carnosine has anti-inflammatory antioxidative anti-glycating and anti-atherosclerotic properties It also has the ability to chelate metals form conjugates with reactive aldehydes and has lactate buffering capacity In addition carnosine has been found to be very effective in reducing ischaemia-reperfusion damage in several organs Our preliminary results using a murine model of hind limb ischaemia HLI showed that administration of carnosine over 21 days increased HIF1-a and VEGF levels in the ischaemic muscle and improved tissue perfusion Furthermore mobilisation of pro-angiogenic endothelial progenitor cells EPCs and the ambulatory movement were increased in carnosine treated HLI mice compared to controls The investigators propose a randomised clinical trial to investigate whether administration of carnosine for 6-month in addition to exercise could improve walking endurance and quality of life in patients with PVD compared to placebo and exercise
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None