Type 2 Diabetes MellitusPhase 4NCT01322711
Atorvastatin, Aspirin, Oxidative Stress, Coagulation and Platelet Activation Indexes
A Phase 4 study testing Atorvastatin in people with Type 2 Diabetes Mellitus and Hypercholesterolemia, run by University of Roma La Sapienza at 1 site in Italy.
Trial summary
Primary and secondary prevention trials with statins, as well as with antiplatelet, clearly demonstrated that these drugs are able to reduce cardiovascular events. Even if the principal mechanism of action of statins is to lower cholesterol, other effects, the so-called pleiotropic effects, have been considered as… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Type 2 Diabetes Mellitus, Hypercholesterolemia
- What is being tested?
- Atorvastatin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- 1 siteItaly
- Study dates
- Mar 2011to Dec 2015
- Phase
- Phase 4
- 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 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with polygenic hypercholesterolemia (LDL-C > 160 mg/dl)
- Males and Females
- White race
- Sign of the informed consent
- Patients with T2DM diagnosed according to the American Diabetes Association definition
- Treatment with 100 mg/day aspirin from at least 30 days
Show all 9Show fewer
- Males and Females
- White race
- Sign of the informed consent
Who cannot join
- Liver insufficiency
- Serious renal disorders
- Diabetes mellitus
- Arterial hypertension
- History or evidence of previous myocardial infarction or other atherothrombotic diseases
- Any autoimmune diseases
Show all 16Show fewer
- Cancer
- Present or recent infections
- Patients were taking nonsteroidal antiinflammatory drugs, drugs interfering with cholesterol metabolism, or vitamin supplements
- For T2 Diabetic patients:
- recent history (< 3 months) of acute vascular events
- clinical diagnosis of type 1 DM
- serum creatinine level greater than 2.5 mg/dl
- active infection or malignancy
- cardiac arrhythmia or congestive heart failure
- use of non-steroidal anti-inflammatory drugs, vitamin supplements, or other antiplatelet drugs such as clopidogrel in the previous 30 days
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Effects on Oxidative Stress, Coagulation, Platelet Activation and Inflammatory Indexes of Atorvastatin and/or Aspirin Treatment in Patients at High Risk of Vascular Events
Primary and secondary prevention trials with statins, as well as with antiplatelet, clearly demonstrated that these drugs are able to reduce cardiovascular events. Even if the principal mechanism of action of statins is to lower cholesterol, other effects, the so-called pleiotropic effects, have been considered as adjunctive properties potentially accounting for the anti-atherosclerotic effect of statins.
Inhibition of oxidative stress may be considered an intriguing pleiotropic effect in view of the fact that oxidative stress is thought to be a key event in the initiation and progression of atherosclerotic disease. Reduction of several markers of oxidative stress including isoprostanes, 8-hydroxydeoxyguanosine (8-OHdG), and nitrotyrosine have been observed after statin treatment. NADPH oxidase is among the most important sources of reactive oxygen species involved in atherosclerotic disease. The investigators developed an ELISA to evaluate serum levels of soluble-gp91phox, the catalytic core of phagocyte NADPH oxidase. Recently the investigators showed that statins (30 days treatment) exert an antioxidant effect via inhibition of soluble gp91phox expression.
Read more
The exact mechanism by which atorvastatin reduces NADPH oxidase, however, is unclear. Recent study showed that statin treatment inhibits leukocyte ROCK activity, a protein kinase implicated in the activation of NADPH oxidase, with a mechanism that seems to be independent from lowering cholesterol. To further study the mechanism(s) implicate in gp91phox downregulation by statin the investigators planned the present study in patients with high risk of vascular events such as hypercholesterolemic and Type 2 Diabetes mellitus patients.
In addition the investigators want to evaluate the synergistic role of atorvastatin with aspirin treatment.
Read the detailed description
Primary and secondary prevention trials with statins, as well as with antiplatelet, clearly demonstrated that these drugs are able to reduce cardiovascular events. Even if the principal mechanism of action of statins is to lower cholesterol, other effects, the so-called pleiotropic effects, have been considered as adjunctive properties potentially accounting for the antiatherosclerotic effect of statins.
Inhibition of oxidative stress may be considered an intriguing pleiotropic effect in view of the fact that oxidative stress is thought to be a key event in the initiation and progression of atherosclerotic disease. Reduction of several markers of oxidative stress including isoprostanes, 8-hydroxydeoxyguanosine (8-OHdG), and nitrotyrosine have been observed after statin treatment. NADPH oxidase is among the most important sources of reactive oxygen species involved in atherosclerotic disease. The investigators developed an ELISA to evaluate serum levels of soluble-gp91phox, the catalytic core of phagocyte NADPH oxidase. Recently the investigators showed that statins (30 days treatment) exert an antioxidant effect via inhibition of soluble gp91phox expression.
The exact mechanism by which atorvastatin reduces NADPH oxidase, however, is unclear. Recent study showed that statin treatment inhibits leukocyte ROCK activity, a protein kinase implicated in the activation of NADPH oxidase, with a mechanism that seems to be independent from lowering cholesterol.
Accelerated atherosclerosis is a typical feature of type 2 diabetes mellitus (T2DM). Thus, patients with T2DM have a 2- to 4-fold increased risk of cardiovascular diseases (CAD) and 2- to 6-fold increased risk of stroke.
Platelets play a major role in the etiology of atherosclerotic disease, as shown by the significant decrease of cardiovascular events in patients treated with aspirin, an inhibitor of COX1 that prevents platelet thromboxane (Tx) A2 formation. Despite this, interventional trials with aspirin in diabetic patients failed to show a beneficial effect. It has been previously demonstrated that COX1 inhibition determines a shift in arachidonic acid metabolism towards other pathways, such as the lipooxygenase system. The investigators speculate that COX1 inhibition could also be associated with increased conversion of arachidonic acid to platelet isoprostane formation; the increase of platelet isoprostanes would balance the inhibition of TxA2, thus hampering the antiplatelet effect of aspirin. As reported above, statins have been reported to down-regulate systemic isoprostanes with a mechanism that may involve inhibition of NADPH oxidase,therefore it could be interesting to examine if statins improve the antiplatelet effect of aspirin via inhibition of platelet isoprostanes.
To further study the mechanism(s) implicate in gp91phox downregulation by statin the investigators planned the present study in patients with hypercholesterolemia.
Furthermore, the second part of the study will be addressed to evaluate the synergistic role of atorvastatin with aspirin treatment in Type 2 Diabetes mellitus patients.
- Conditions
- Type 2 Diabetes Mellitus, Hypercholesterolemia
- Being tested
- Atorvastatin, Placebo
- Keywords
- Thromboxane, Aspirin, Atorvastatin, Platelet activation, Thrombin Activation, Oxidative stress
- Medical subject headings
- Diabetes Mellitus, Type 2, Hypercholesterolemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AtorvastatinDrug
Also called Totalip 40 mg, Torvast 40 mg
Atorvastatin 40 mg day
PlaceboDrug
Diet
| Study group | Role | What they receive |
|---|---|---|
| Atorvastatin | Active comparator | Each day accordingly to randomization patients allocated to Atorvastatin received a pill of 40 mg of atorvastatin. In diabetic patients the concomitant aspirin treatment include a previous 30 days treatment with 100 mg daily of aspirin.
All patients followed the diet used in the placebo group. Receives: Drug: Atorvastatin |
| Diet | Placebo comparator | Low-fat diet with mean macronutrient profiles that were close to the present Adult Treatment Panel III guidelines (7% energy from saturated fat and, 200 mg dietary cholesterol per day) Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Evaluation of effect of Atorvastatin Therapy in Hypercholesterolemic Patients (n=30) and Diabetic Patients (n=30)
In Hypercholesterolemic patients (n=30) and in Diabetic patients (n=30) under chronic treatment with low dose aspirin (100 mg daily for at least 30 days), blood and urine samples were taken at each above reported time to evaluate the effect of atorvastatin or no treatment (Diet) on platelet recruitment, platelet and serum isoprostanes, platelet and serum thromboxane A2, platelet and serum NOX2 activation indexes, thrombin activation indexes, urinary excretion of thromboxane and isoprostanes.
Measured: Baseline, 2 hours, 24 hours, 3 days, 7 days, 30 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Mar 2011 (estimated)
- Study startMar 2011
- Primary completionOct 2015 (estimated)
- Study completionDec 2015 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Type 2 Diabetes MellitusStudies of the same condition, open and under way.
- More trials run by University of Roma La SapienzaThe sponsor's other registered studies.
- 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Roma La Sapienza
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Stefania Basili, University of Roma La Sapienza
- Investigators
- Stefania Basili, Prof., Principal investigator, Sapienza-Univerity of Rome
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01322711
- Sponsor's protocol ID
- ATORVASA
- Status last verified
- May 2015
- First submitted
- 24 Mar 2011
- Last updated
- 28 May 2015
- Results posted
- No
- Data monitoring committee
- No
Publications
Carnevale R, Pignatelli P, Di Santo S, Bartimoccia S, Sanguigni V, Napoleone L, Tanzilli G, Basili S, Violi F. Atorvastatin inhibits oxidative stress via adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients. Atherosclerosis. 2010 Nov;213(1):225-34. doi: 10.1016/j.atherosclerosis.2010.08.056. Epub 2010 Aug 19.
PubMed 20832062Pignatelli P, Carnevale R, Cangemi R, Loffredo L, Sanguigni V, Stefanutti C, Basili S, Violi F. Atorvastatin inhibits gp91phox circulating levels in patients with hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):360-7. doi: 10.1161/ATVBAHA.109.198622. Epub 2009 Dec 3.
PubMed 19965781Pignatelli P, Carnevale R, Pastori D, Cangemi R, Napoleone L, Bartimoccia S, Nocella C, Basili S, Violi F. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012 Jul 3;126(1):92-103. doi: 10.1161/CIRCULATIONAHA.112.095554. Epub 2012 May 21.
PubMed 22615342
Study at a glance
From the registry record, last updated by the sponsor on 28 May 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects on Oxidative Stress, Coagulation, Platelet Activation and Inflammatory Indexes of Atorvastatin and/or Aspirin Treatment in Patients at High Risk of Vascular Events
- ClinicalTrials.gov ID
- NCT01322711
- Acronym / sponsor ID
- ATORVASA
- Conditions
- Type 2 Diabetes Mellitus, Hypercholesterolemia
- Keywords
- Thromboxane, Aspirin, Atorvastatin, Platelet activation, Thrombin Activation, Oxidative stress
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- University of Roma La SapienzaUniversity, hospital or other
- Study start
- Mar 2011
- Primary completion
- Oct 2015 (estimated)
- Study completion
- Dec 2015 (estimated)
- First posted
- 25 Mar 2011 (estimated)
- 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.
Primary and secondary prevention trials with statins, as well as with antiplatelet, clearly demonstrated that these drugs are able to reduce cardiovascular events. Even if the principal mechanism of action of statins is to lower cholesterol, other effects, the so-called pleiotropic effects, have been considered as adjunctive properties potentially accounting for the anti-atherosclerotic effect of statins.
Inhibition of oxidative stress may be considered an intriguing pleiotropic effect in view of the fact that oxidative stress is thought to be a key event in the initiation and progression of atherosclerotic disease. Reduction of several markers of oxidative stress including isoprostanes, 8-hydroxydeoxyguanosine (8-OHdG), and nitrotyrosine have been observed after statin treatment. NADPH oxidase is among the most important sources of reactive oxygen species involved in atherosclerotic disease. The investigators developed an ELISA to evaluate serum levels of soluble-gp91phox, the catalytic core of phagocyte NADPH oxidase. Recently the investigators showed that statins (30 days treatment) exert an antioxidant effect via inhibition of soluble gp91phox expression.
The exact mechanism by which atorvastatin reduces NADPH oxidase, however, is unclear. Recent study showed that statin treatment inhibits leukocyte ROCK activity, a protein kinase implicated in the activation of NADPH oxidase, with a mechanism that seems to be independent from lowering cholesterol. To further study the mechanism(s) implicate in gp91phox downregulation by statin the investigators planned the present study in patients with high risk of vascular events such as hypercholesterolemic and Type 2 Diabetes mellitus patients.
In addition the investigators want to evaluate the synergistic role of atorvastatin with aspirin treatment.
Detailed description
Primary and secondary prevention trials with statins, as well as with antiplatelet, clearly demonstrated that these drugs are able to reduce cardiovascular events. Even if the principal mechanism of action of statins is to lower cholesterol, other effects, the so-called pleiotropic effects, have been considered as adjunctive properties potentially accounting for the antiatherosclerotic effect of statins.
Inhibition of oxidative stress may be considered an intriguing pleiotropic effect in view of the fact that oxidative stress is thought to be a key event in the initiation and progression of atherosclerotic disease. Reduction of several markers of oxidative stress including isoprostanes, 8-hydroxydeoxyguanosine (8-OHdG), and nitrotyrosine have been observed after statin treatment. NADPH oxidase is among the most important sources of reactive oxygen species involved in atherosclerotic disease. The investigators developed an ELISA to evaluate serum levels of soluble-gp91phox, the catalytic core of phagocyte NADPH oxidase. Recently the investigators showed that statins (30 days treatment) exert an antioxidant effect via inhibition of soluble gp91phox expression.
The exact mechanism by which atorvastatin reduces NADPH oxidase, however, is unclear. Recent study showed that statin treatment inhibits leukocyte ROCK activity, a protein kinase implicated in the activation of NADPH oxidase, with a mechanism that seems to be independent from lowering cholesterol.
Accelerated atherosclerosis is a typical feature of type 2 diabetes mellitus (T2DM). Thus, patients with T2DM have a 2- to 4-fold increased risk of cardiovascular diseases (CAD) and 2- to 6-fold increased risk of stroke.
Platelets play a major role in the etiology of atherosclerotic disease, as shown by the significant decrease of cardiovascular events in patients treated with aspirin, an inhibitor of COX1 that prevents platelet thromboxane (Tx) A2 formation. Despite this, interventional trials with aspirin in diabetic patients failed to show a beneficial effect. It has been previously demonstrated that COX1 inhibition determines a shift in arachidonic acid metabolism towards other pathways, such as the lipooxygenase system. The investigators speculate that COX1 inhibition could also be associated with increased conversion of arachidonic acid to platelet isoprostane formation; the increase of platelet isoprostanes would balance the inhibition of TxA2, thus hampering the antiplatelet effect of aspirin. As reported above, statins have been reported to down-regulate systemic isoprostanes with a mechanism that may involve inhibition of NADPH oxidase,therefore it could be interesting to examine if statins improve the antiplatelet effect of aspirin via inhibition of platelet isoprostanes.
To further study the mechanism(s) implicate in gp91phox downregulation by statin the investigators planned the present study in patients with hypercholesterolemia.
Furthermore, the second part of the study will be addressed to evaluate the synergistic role of atorvastatin with aspirin treatment in Type 2 Diabetes mellitus patients.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Atorvastatin | Active comparator | Drug: AtorvastatinEach day accordingly to randomization patients allocated to Atorvastatin received a pill of 40 mg of atorvastatin. In diabetic patients the concomitant aspirin treatment include a previous 30 days treatment with 100 mg daily of aspirin. All patients followed the diet used in the placebo group. |
| Diet | Placebo comparator | Drug: PlaceboLow-fat diet with mean macronutrient profiles that were close to the present Adult Treatment Panel III guidelines (7% energy from saturated fat and, 200 mg dietary cholesterol per day) |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Patients with polygenic hypercholesterolemia (LDL-C > 160 mg/dl)
- Males and Females
- White race
- Sign of the informed consent
- Patients with T2DM diagnosed according to the American Diabetes Association definition
Key exclusion criteria (16 listed)
- Liver insufficiency
- Serious renal disorders
- Diabetes mellitus
- Arterial hypertension
- History or evidence of previous myocardial infarction or other atherothrombotic diseases
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 |
|---|---|---|
| AtorvastatinAlso: Totalip 40 mg, Torvast 40 mgAtorvastatin 40 mg day | Drug | Atorvastatin |
| PlaceboDiet | Drug | Diet |
Primary outcome
Evaluation of effect of Atorvastatin Therapy in Hypercholesterolemic Patients (n=30) and Diabetic Patients (n=30)
Time frame: Baseline, 2 hours, 24 hours, 3 days, 7 days, 30 days
In Hypercholesterolemic patients (n=30) and in Diabetic patients (n=30) under chronic treatment with low dose aspirin (100 mg daily for at least 30 days), blood and urine samples were taken at each above reported time to evaluate the effect of atorvastatin or no treatment (Diet) on platelet recruitment, platelet and serum isoprostanes, platelet and serum thromboxane A2, platelet and serum NOX2 activation indexes, thrombin activation indexes, urinary excretion of thromboxane and isoprostanes.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 May 2015.
- Background: PubMed 20832062Carnevale R, Pignatelli P, Di Santo S, Bartimoccia S, Sanguigni V, Napoleone L, Tanzilli G, Basili S, Violi F. Atorvastatin inhibits oxidative stress via adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients. Atherosclerosis. 2010 Nov;213(1):225-34. doi: 10.1016/j.atherosclerosis.2010.08.056. Epub 2010 Aug 19.
- Background: PubMed 19965781Pignatelli P, Carnevale R, Cangemi R, Loffredo L, Sanguigni V, Stefanutti C, Basili S, Violi F. Atorvastatin inhibits gp91phox circulating levels in patients with hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):360-7. doi: 10.1161/ATVBAHA.109.198622. Epub 2009 Dec 3.
- Derived from this study: PubMed 22615342Pignatelli P, Carnevale R, Pastori D, Cangemi R, Napoleone L, Bartimoccia S, Nocella C, Basili S, Violi F. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012 Jul 3;126(1):92-103. doi: 10.1161/CIRCULATIONAHA.112.095554. Epub 2012 May 21.
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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.
Stefania Basili, Prof. principal investigator
Sapienza-Univerity of Rome
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Atorvastatin in people with Type 2 Diabetes Mellitus and Hypercholesterolemia, run by University of Roma La Sapienza at 1 site in Italy.
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 9 inclusion and 16 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 28 May 2015. 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 Italy. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
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?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Evaluation of effect of Atorvastatin Therapy in Hypercholesterolemic Patients (n=30) and Diabetic Patients (n=30) (time frame: Baseline, 2 hours, 24 hours, 3 days, 7 days, 30 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01322711, which also lists 3 linked publications.
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 28 May 2015.