Peripheral Arterial DiseasePhase 2Car-PVDNCT03844113
Carnosine for Peripheral Vascular Disease
A Phase 2 study testing Carnosine in people with Peripheral Arterial Disease, run by Monash University at 1 site in Australia.
Trial 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. Read more about this study
- Who is it for?
- Ages 40 to 80 years
- Conditions the study is for
- Peripheral Arterial Disease
- What is being tested?
- Carnosine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 104 participants
- Where
- 1 siteAustralia
- Study dates
- 1 Mar 2019to 31 Dec 2022
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age >=40or <80 years
- Clinical diagnosis Peripheral Vascular disease
- Rutherford Grade 1-3
- No significant kidney, cardiovascular, haematological, respiratory, gastrointestinal, or central nervous system disease, as well as no psychiatric disorders, no active cancer within the last five years; no presence of acute inflammation (by history, physical or laboratory examination)
- Intermittent claudication on treadmill between 30m and 200m
- Ankle Brachial index 0.6-1 at rest with minimum post exercise drop in ABI of 0.1
Who cannot join
- Age < 40 or > 80 years
- Pregnant or lactating
- Limb threatening ischaemia- Rutherford grades 4-6, manifested by ischaemic rest pain, ulceration, or gangrene; acute limb-threatening ischaemia
- lower limb surgical or endovascular interventions in the preceding 6 months
- planned lower limb endovascular or surgical intervention within the next 6 months on either limb
- taking medication for PVD (Cilostazol and Pentoxifylline)
Show all 11Show fewer
- inability to complete the treadmill walking test for reasons other than claudication
- myocardial infarction within last 3 months
- deep vein thrombosis within 3 months
- estimated life expectancy < 1 year
- alcohol and illicit drug abuse.
Trial locations and contacts
1 site in 1 country.
Australia1 site, 1 recruiting
- Recruiting
Monash Centre for Health Research and Implementation
Melbourne, Victoria, 3168
Barbora de Courten, MD,PHD,MPH, +61 3 857 22651, barbora.decourten@monash.edu
Barbora de Courten, MD,PHD,MPH
About this study
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
Read more
Aim 1: Determine whether in patients with PVD, carnosine in addition to exercise improves:
- walking endurance (6-min walk test; primary outcome);
- initial claudication distance (ICD), and absolute claudication distance (ACD; treadmill), cadence, resting and exercise ABI; and
- central blood pressure, endothelial function, arterial (aortic) stiffness, lipid profile; and
- quality of life as determined by EuroQol-5D (all secondary outcomes).
- 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:
- 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.
- 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.
Read the 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.
- Conditions
- Peripheral Arterial Disease
- Being tested
- Carnosine, Placebo
- Keywords
- carnosine, peripheral arterial disease
- Medical subject headings
- Peripheral Arterial Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CarnosineDrug
Also called Pure Carnosine
Each participant will be given a daily oral dose 2 g of carnosine for 6 months
PlaceboDrug
Each participant will be given a daily oral dose 2 g of methycellulose powder for 6 months
| Study group | Role | What they receive |
|---|---|---|
| Intervention | Active comparator | Each participant will be given a daily oral dose 2 g of carnosine for 6 months Receives: Drug: Carnosine |
| Control | Placebo comparator | Each participant will be given a daily oral dose 2 g of placebo for 6 months Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
walking endurance
change in walking endurance (6-min walk test)
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Feb 2019
- Study start1 Mar 2019
- Primary completion31 Dec 2022 (estimated)
- Study completion31 Dec 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Peripheral Arterial DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- parallel assignment
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 104 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Monash University
- Sponsor type
- University, hospital or other
- Collaborators
- Monash Health
- Responsible party
- Principal investigator, Barbora de Courten, Monash University
- Investigators
- Barbora deCourten, MD,PHD,MPH, Principal investigator, Monash University and Monash Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03844113
- Sponsor's protocol ID
- Car-PVD
- Acronym
- Car-PVD
- Status last verified
- Dec 2020
- First submitted
- 12 Feb 2019
- Last updated
- 29 Dec 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Carnosine for Peripheral Vascular Disease
- ClinicalTrials.gov ID
- NCT03844113
- Acronym / sponsor ID
- Car-PVD / Car-PVD
- Conditions
- Peripheral Arterial Disease
- Keywords
- carnosine, peripheral arterial disease
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 104 participants (estimated)
- Lead sponsor
- Monash UniversityUniversity, hospital or other
- Collaborators
- Monash Health
- Study start
- 1 Mar 2019 (actual)
- Primary completion
- 31 Dec 2022 (estimated)
- Study completion
- 31 Dec 2022 (estimated)
- First posted
- 18 Feb 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- walking endurance (6-min walk test; primary outcome);
- initial claudication distance (ICD), and absolute claudication distance (ACD; treadmill), cadence, resting and exercise ABI; and
- central blood pressure, endothelial function, arterial (aortic) stiffness, lipid profile; and
- quality of life as determined by EuroQol-5D (all secondary outcomes).
- 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:
- 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.
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- parallel assignment
| Arm | Type | Receives |
|---|---|---|
| Intervention | Active comparator | Drug: CarnosineEach participant will be given a daily oral dose 2 g of carnosine for 6 months |
| Control | Placebo comparator | Drug: PlaceboEach participant will be given a daily oral dose 2 g of placebo for 6 months |
Who may qualify
- Ages
- 40 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Age >=40or <80 years
- Clinical diagnosis Peripheral Vascular disease
- Rutherford Grade 1-3
- No significant kidney, cardiovascular, haematological, respiratory, gastrointestinal, or central nervous system disease, as well as no psychiatric disorders, no active cancer within the last five years; no presence of acute inflammation (by history, physical or laboratory examination)
- Intermittent claudication on treadmill between 30m and 200m
Key exclusion criteria (11 listed)
- Age < 40 or > 80 years
- Pregnant or lactating
- Limb threatening ischaemia- Rutherford grades 4-6, manifested by ischaemic rest pain, ulceration, or gangrene; acute limb-threatening ischaemia
- lower limb surgical or endovascular interventions in the preceding 6 months
- planned lower limb endovascular or surgical intervention within the next 6 months on either limb
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CarnosineAlso: Pure CarnosineEach participant will be given a daily oral dose 2 g of carnosine for 6 months | Drug | Intervention |
| PlaceboEach participant will be given a daily oral dose 2 g of methycellulose powder for 6 months | Drug | Control |
Primary outcome
walking endurance
Time frame: 6 months
change in walking endurance (6-min walk test)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Dec 2020.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Barbora deCourten, MD,PHD,MPH principal investigator
Monash University and Monash Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Carnosine in people with Peripheral Arterial Disease, run by Monash University at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 29 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Barbora deCourten, MD,PHD,MPH (+610385722651, barbora.decourten@monash.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
walking endurance (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Dec 2020.