AtherosclerosisALFANCT06126367
Assessment of Lipoprotein(a) and Endogenous Fibrinolysis in Atherosclerotic Cardiovascular Disease/Aortic Valve Disease
An observational study of Atherosclerosis and Aortic Valve Disease, run by East and North Hertfordshire NHS Trust at 1 site in United Kingdom.
Trial summary
Prior studies have shown that impaired endogenous fibrinolysis is a novel, independent cardiovascular risk factor in patients with myocardial infarction and there is currently no known chronic treatment to enhance endogenous fibrinolysis. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Atherosclerosis, Aortic Valve Disease
- What is being tested?
- Thrombotic assessment and Measurement of Lp(a)
- How many people
- 180 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 20 Oct 2023to 1 Oct 2027
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: 1) Male and female patients aged 18 years or over. 2) i) Patients identified as eligible for treatment with either a PCSK9i or inclisiran ii) Patients diagnosed with moderate or severe calcific aortic stenosis based on non enhanced Cardiac CT scan
Who may be able to join
- 1) Male and female patients aged 18 years or over
- 2) i) Patients identified as eligible for treatment with either a PCSK9i or inclisiran ii) Patients diagnosed with moderate or severe calcific aortic stenosis based on non-enhanced Cardiac CT scan
- 3) Willing and able to understand the Participant Information Sheet and provide informed consent
- 4) The patient must agree to comply with the drawing of blood samples for the assessments
- 5) The patient does not meet any of the exclusion criteria
Who cannot join
- Inability to provide valid informed consent
- Male and female patients aged < 18 years of age
- The patient has, in the opinion of the investigator, significant neurological, hepatic, renal, endocrine, gastrointestinal, pulmonary, haemorrhagic, metabolic or other disease likely to confound the study requirements or analyses
- The patient has a history of substance abuse or demonstrates signs or clinical features of active substance abuse or psychiatric disease
- Alcohol consumption above recommended safe levels (i.e., more than 14 units per week) due to the potential effects of high alcohol levels on platelet reactivity
- Any illness deemed significant by the investigator during the four (4) weeks preceding the screening period of the study
- Any major bleeding diathesis or blood dyscrasia (platelets < 70 x 109/l, Hb < 8 g/dl, INR > 1.4, APTT > x 2 upper normal limit, leucocyte count < 3.5 x 109/l, neutrophil count < 1 x 109/l)
- Currently enrolled in an investigational device or non-licensed drug trial
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United Kingdom1 site, 1 recruiting
- Recruiting
East and North Herts NHS Trust
Stevenage
Toral Odedra, 07918360060, grantapplications.enh-tr@nhs.net
Diana A Gorog
About this study
Prior studies have shown that impaired endogenous fibrinolysis is a novel, independent cardiovascular risk factor in patients with myocardial infarction and there is currently no known chronic treatment to enhance endogenous fibrinolysis.
To date, no therapies have been able to sufficiently reduce Lp(a) and therefore it was considered to be a non-modifiable cardiovascular risk factor. New data, however, has shown that PCSK9 inhibitors and inclisiran (medication that you have been deemed eligible for in order to help further reduce your cholesterol levels) to reduce Lp(a) levels by approximately 20-25%.
Read more
The aim of this study to is to assess:
- if there is an association between raised Lp(a) level in blood and the effectiveness of endogenous fibrinolysis (lysis time).
- whether lowering Lp(a) with PCSK9i or inclisiran can enhance endogenous fibrinolysis
Read the detailed description
The risk of a clot forming in a blood vessel, which can cause a heart attack or stroke, is determined partly by how "sticky" the blood is and partly by the effectiveness of the natural defences in the blood in dissolving any clots that start forming (clot lysis, or "fibrinolysis").
In the last few years, using new blood testing techniques, we and other groups, have shown that individuals who have less effective natural clot lysis, have a much higher risk of heart attack, stroke and death, even despite current best medications.
Therefore, we would like to find medications that can make clot lysis more effective, in such individuals, to reduce their risk of stroke and heart attack. Unfortunately, most blood thinning tablets for long term use do not improve clot lysis. Earlier, our group has shown that the anticoagulant apixaban, mildly improved clot lysis
Elevated concentration of Lp(a) in the blood is a risk factor for the development of cardiovascular disease including coronary artery disease and narrowing of the aortic valve. Lp(a) may exert its adverse effects by impairing fibrinolysis. Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, including fibrin clots. Lp(a) has a high degree of homology to plasminogen (a pro-enzyme that is cleaved to form plasmin) and may cause thrombosis by competitively inhibiting t-PA-mediated plasminogen activation and tPA-mediated clot lysis. Furthermore, Lp(a) stimulates the activity of PAI-1, which is the major inhibitor of the fibrinolytic system.
Until recently, Lp(a) has been considered a non-modifiable cardiovascular risk factor as few therapies are available to sufficiently reduce Lp(a) levels. New data, however, have shown that novel cholesterol lowering treatments, namely PCSK9 inhibitors and inclisiran (a long-acting silencing RNA) can reduce Lp(a) levels by approximately 20-25%.
Given Lp(a) is a causal risk factor for cardiovascular outcomes, it is important to know if a reduction in Lp(a) can favourably modify endogenous fibrinolysis.
If Lp(a) level is directly related to the effectiveness of endogenous fibrinolysis, then medications that reduce Lp(a) (currently PCSK9i and/or inclisiran, and others in development) could be used as targeted treatment for patients who despite optimal antithrombotic therapy, demonstrate impaired endogenous fibrinolysis.
- Conditions
- Atherosclerosis, Aortic Valve Disease
- Being tested
- Thrombotic assessment, Measurement of Lp(a)
- Keywords
- Lipoprotein (a), Global thrombosis test, Endogenous fibrinolysis
- Medical subject headings
- Atherosclerosis, Aortic Valve Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Thrombotic assessmentDiagnostic test
The Global Thrombosis Test (Thromboquest Limited, UK) is an in vitro method imitating high shear stress conditions akin to that which exist in a severely stenosed artery. The test measures platelet reactivity (occlusion time) and endogenous fibrinolysis time (lysis time).
Thromboelastography is a technique that assesses the whole process of clotting and its viscoelastic properties, from the initial activation and aggregation of platelets, to the role of thrombin and finally the stability of the formed clot, as a measure of fibrinolytic resistance.
Plasma will be stored for subsequent analysis of other thrombotic, fibrinolytic, inflammatory and coagulation markers as deemed appropriate.
For patients deemed eligible for treatment with either a PCSK9i or inclisiran, this will be assessed prior to commencing treatment and also 3-6 months after starting treatment.
This will only be assessed once for patients with moderate or severe aortic valve calcification.
Measurement of Lp(a)Diagnostic test
Lp(a) will be measured by particle enhanced immunotubidimetricassay. Human lipoprotein (a) agglutinates with latex particles coated with anti-Lp(a) antibodies. The precipitate is determined turbidimetrically at 800 / 660 nm. The platform employed will be the Roche® Immunoassay Analyser (Roche Diagnostics GmbH, Sandhofer Strasse 116, D-68305 Mannheim). Traceability: This method has been standardized against the IFCC (International Federation of Clinical Chemistry) reference material SRM2B for nmol/L.
For patients deemed eligible for treatment with either a PCSK9i or inclisiran, this will be assessed prior to commencing treatment and also 3-6 months after starting treatment.
This will only be assessed once for patients with moderate or severe aortic valve calcification.
| Study group | Role | What they receive |
|---|---|---|
| Patients identified as eligible for treatment with either a PCSK9i or inclisiran | Not described Receives: Diagnostic Test: Thrombotic assessment; Diagnostic Test: Measurement of Lp(a) | |
| Patients with moderate or severe aortic calcification identified by non-enhanced cardiac CT scan | Not described Receives: Diagnostic Test: Thrombotic assessment; Diagnostic Test: Measurement of Lp(a) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Thrombotic status
Change in thrombotic status as measured by Lysis Time (LT) using the GTT from baseline to 6-months post initiation of PCSK9i or inclisiran
Measured: 3-6 months
Lipoprotein(a) levels
Change in lipoprotein(a) levels from baseline to 6-months post initiation of PCSK9i or inclisiran
Measured: 3-6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Nov 2023
- Study start20 Oct 2023
- Primary completion1 Oct 2027 (estimated)
- Study completion1 Oct 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AtherosclerosisStudies 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
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 180 participants (estimated)
Sponsor and investigators
- Lead sponsor
- East and North Hertfordshire NHS Trust
- Sponsor type
- Other government
- Responsible party
- Principal investigator, Prof Diana Gorog, University of Hertfordshire
- Investigators
- Diana A Gorog, MD, PhD, Principal investigator, East and North Hertfordshire NHS Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06126367
- Sponsor's protocol ID
- RD2023-43
- Acronym
- ALFA
- Status last verified
- Nov 2023
- First submitted
- 6 Nov 2023
- Last updated
- 13 Nov 2023
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Assessment of Lipoprotein(a) and Endogenous Fibrinolysis in Atherosclerotic Cardiovascular Disease/Aortic Valve Disease
- ClinicalTrials.gov ID
- NCT06126367
- Acronym / sponsor ID
- ALFA / RD2023-43
- Conditions
- Atherosclerosis, Aortic Valve Disease
- Keywords
- Lipoprotein (a), Global thrombosis test, Endogenous fibrinolysis
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 180 participants (estimated)
- Lead sponsor
- East and North Hertfordshire NHS TrustOther government
- Study start
- 20 Oct 2023 (actual)
- Primary completion
- 1 Oct 2027 (estimated)
- Study completion
- 1 Oct 2027 (estimated)
- First posted
- 13 Nov 2023 (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.
Prior studies have shown that impaired endogenous fibrinolysis is a novel, independent cardiovascular risk factor in patients with myocardial infarction and there is currently no known chronic treatment to enhance endogenous fibrinolysis.
To date, no therapies have been able to sufficiently reduce Lp(a) and therefore it was considered to be a non-modifiable cardiovascular risk factor. New data, however, has shown that PCSK9 inhibitors and inclisiran (medication that you have been deemed eligible for in order to help further reduce your cholesterol levels) to reduce Lp(a) levels by approximately 20-25%.
The aim of this study to is to assess:
- if there is an association between raised Lp(a) level in blood and the effectiveness of endogenous fibrinolysis (lysis time).
- whether lowering Lp(a) with PCSK9i or inclisiran can enhance endogenous fibrinolysis
Detailed description
The risk of a clot forming in a blood vessel, which can cause a heart attack or stroke, is determined partly by how "sticky" the blood is and partly by the effectiveness of the natural defences in the blood in dissolving any clots that start forming (clot lysis, or "fibrinolysis").
In the last few years, using new blood testing techniques, we and other groups, have shown that individuals who have less effective natural clot lysis, have a much higher risk of heart attack, stroke and death, even despite current best medications.
Therefore, we would like to find medications that can make clot lysis more effective, in such individuals, to reduce their risk of stroke and heart attack. Unfortunately, most blood thinning tablets for long term use do not improve clot lysis. Earlier, our group has shown that the anticoagulant apixaban, mildly improved clot lysis
Elevated concentration of Lp(a) in the blood is a risk factor for the development of cardiovascular disease including coronary artery disease and narrowing of the aortic valve. Lp(a) may exert its adverse effects by impairing fibrinolysis. Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, including fibrin clots. Lp(a) has a high degree of homology to plasminogen (a pro-enzyme that is cleaved to form plasmin) and may cause thrombosis by competitively inhibiting t-PA-mediated plasminogen activation and tPA-mediated clot lysis. Furthermore, Lp(a) stimulates the activity of PAI-1, which is the major inhibitor of the fibrinolytic system.
Until recently, Lp(a) has been considered a non-modifiable cardiovascular risk factor as few therapies are available to sufficiently reduce Lp(a) levels. New data, however, have shown that novel cholesterol lowering treatments, namely PCSK9 inhibitors and inclisiran (a long-acting silencing RNA) can reduce Lp(a) levels by approximately 20-25%.
Given Lp(a) is a causal risk factor for cardiovascular outcomes, it is important to know if a reduction in Lp(a) can favourably modify endogenous fibrinolysis.
If Lp(a) level is directly related to the effectiveness of endogenous fibrinolysis, then medications that reduce Lp(a) (currently PCSK9i and/or inclisiran, and others in development) could be used as targeted treatment for patients who despite optimal antithrombotic therapy, demonstrate impaired endogenous fibrinolysis.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Patients identified as eligible for treatment with either a PCSK9i or inclisiran | – | Diagnostic Test: Thrombotic assessment, Diagnostic Test: Measurement of Lp(a) |
| Patients with moderate or severe aortic calcification identified by non-enhanced cardiac CT scan | – | Diagnostic Test: Thrombotic assessment, Diagnostic Test: Measurement of Lp(a) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- 1) Male and female patients aged 18 years or over. 2) i) Patients identified as eligible for treatment with either a PCSK9i or inclisiran ii) Patients diagnosed with moderate or severe calcific aortic stenosis based on non enhanced Cardiac CT scan
Key inclusion criteria (5 listed)
- 1) Male and female patients aged 18 years or over
- 2) i) Patients identified as eligible for treatment with either a PCSK9i or inclisiran ii) Patients diagnosed with moderate or severe calcific aortic stenosis based on non-enhanced Cardiac CT scan
- 3) Willing and able to understand the Participant Information Sheet and provide informed consent
- 4) The patient must agree to comply with the drawing of blood samples for the assessments
- 5) The patient does not meet any of the exclusion criteria
Key exclusion criteria (8 listed)
- Inability to provide valid informed consent
- Male and female patients aged < 18 years of age
- The patient has, in the opinion of the investigator, significant neurological, hepatic, renal, endocrine, gastrointestinal, pulmonary, haemorrhagic, metabolic or other disease likely to confound the study requirements or analyses
- The patient has a history of substance abuse or demonstrates signs or clinical features of active substance abuse or psychiatric disease
- Alcohol consumption above recommended safe levels (i.e., more than 14 units per week) due to the potential effects of high alcohol levels on platelet reactivity
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 |
|---|---|---|
| Thrombotic assessmentThe Global Thrombosis Test (Thromboquest Limited, UK) is an in vitro method imitating high shear stress conditions akin to that which exist in a severely stenosed artery. The test measures platelet reactivity (occlusion time) and endogenous fibrinolysis time (lysis time). Thromboelastography is a technique that assesses the whole process of clotting and its viscoelastic properties, from the initial activation and aggregation of platelets, to the role of thrombin and finally the stability of the formed clot, as a measure of fibrinolytic resistance. Plasma will be stored for subsequent analysis of other thrombotic, fibrinolytic, inflammatory and coagulation markers as deemed appropriate. For patients deemed eligible for treatment with either a PCSK9i or inclisiran, this will be assessed prior to commencing treatment and also 3-6 months after starting treatment. This will only be assessed once for patients with moderate or severe aortic valve calcification. | Diagnostic test | Patients identified as eligible for treatment with either a PCSK9i or inclisiran, Patients with moderate or severe aortic calcification identified by non-enhanced cardiac CT scan |
| Measurement of Lp(a)Lp(a) will be measured by particle enhanced immunotubidimetricassay. Human lipoprotein (a) agglutinates with latex particles coated with anti-Lp(a) antibodies. The precipitate is determined turbidimetrically at 800 / 660 nm. The platform employed will be the Roche® Immunoassay Analyser (Roche Diagnostics GmbH, Sandhofer Strasse 116, D-68305 Mannheim). Traceability: This method has been standardized against the IFCC (International Federation of Clinical Chemistry) reference material SRM2B for nmol/L. For patients deemed eligible for treatment with either a PCSK9i or inclisiran, this will be assessed prior to commencing treatment and also 3-6 months after starting treatment. This will only be assessed once for patients with moderate or severe aortic valve calcification. | Diagnostic test | Patients identified as eligible for treatment with either a PCSK9i or inclisiran, Patients with moderate or severe aortic calcification identified by non-enhanced cardiac CT scan |
Primary outcome
Thrombotic status
Time frame: 3-6 months
Change in thrombotic status as measured by Lysis Time (LT) using the GTT from baseline to 6-months post initiation of PCSK9i or inclisiran
Lipoprotein(a) levels
Time frame: 3-6 months
Change in lipoprotein(a) levels from baseline to 6-months post initiation of PCSK9i or inclisiran
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Nov 2023.
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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.
Diana A Gorog, MD, PhD principal investigator
East and North Hertfordshire NHS Trust
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Atherosclerosis and Aortic Valve Disease, run by East and North Hertfordshire NHS Trust at 1 site in United Kingdom.
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 5 inclusion and 8 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: looking for participants now, as of the sponsor's last update on 13 Nov 2023. 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 United Kingdom. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Joshua H Leader, MBChB, BSc (07376188768, joshua.leader@nhs.net), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Thrombotic status (time frame: 3-6 months). The study lists 2 primary outcomes in all. 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 13 Nov 2023.