Conditions: Venous Thromboembolism
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
This is a pilot, randomized, open-labelled study. Eligible patients will be enrolled and randomized 1:1 into "anticoagulation" arm or "anticoagulation plus atorvastatin" arm, with atorvastatin given at 40 mg orally daily for 3 months. The targeted total accrual is 80 patients, with 40 in each arm. Patients will be recruited from the hospitals and clinics at The Ohio State University Wexner Medical Center. Follow up visits are planned at enrollment, 3 months, and 9 months after randomization. At each follow up, blood will be obtained and assessments will include structured interviews of signs and symptoms of recurrent venous thromboembolism (VTE), bleeding, post thrombotic syndrome, and adverse events from study drugs.

Detailed description:
VTE is a potentially life-threatening disease, with an estimated incidence of 1-2 per 1000. Despite anticoagulation as standard of care, many patients still suffer from its complications: 30% will have VTE recurrence after an unprovoked VTE, and 25-50% will develop post-thrombotic syndrome. Therefore, there is an urgent need for effective therapies to reduce long-term VTE morbidities. Limitations in our understanding of the underlying pathophysiology of VTE and the absence of accurate biomarkers are significant problems. Without this knowledge, improvement in treatment is unlikely. Therefore, the overall objective of the study is to determine important biomarker changes in acute VTE and the actions of innovative adjunct therapy on those biomarkers. The rationale of the study is that, once the biomarker changes following acute VTE and the actions of therapies are established, treatment for acute VTE could be improved.

Statins are effective in the prevention of arterial thrombosis. Recently, arterial and venous thromboses are shown to share common pathophysiological mechanisms, and effective therapies for arterial thrombosis could provide benefits in VTE. Several observational studies and the JUPITER trial, a large, randomized, placebo-controlled study, have demonstrated that statins significantly reduce the risk of first VTE by 40%. Additionally, as few as 3 days of atorvastatin increase plasma fibrin clot permeability and susceptibility to lysis. Statins have been commonly prescribed for many other medical conditions such as coronary artery diseases and hyperlipidemia, and have demonstrated good safety profiles. These promising results, as well as their safety profiles, make statins an attractive potential addition to the standard anticoagulation for treating acute VTE, in an effort to reduce long-term morbidity. The effects of statins on thrombin generation in patients with acute VTE have not been studied. A study in patients with atrial fibrillation on warfarin showed a 40% reduction in endogenous thrombin potential with only three months of intensive cholesterol-lowering treatment including statins. Similar effects could be seen in patients with acute VTE. In addition, previous studies evaluating the effects of statins on the reduction of D-dimer or inflammatory cytokines revealed promising results but were not focused on patients with acute VTE. Therefore, this study will generate important information for acute VTE patients. This is a pilot, randomized, open-labelled study. Eligible patients will be enrolled and randomized 1:1 into "anticoagulation" arm or "anticoagulation plus atorvastatin" arm, with atorvastatin given at 40 mg orally daily for 3 months. The targeted total accrual is 80 patients, with 40 in each arm. Patients will be recruited from the hospitals and clinics at The Ohio State University Wexner Medical Center. Follow up visits are planned at enrollment, 3 months, and 9 months after randomization. At each follow up, blood will be obtained and assessments will include structured interviews of signs and symptoms of recurrent venous thromboembolism (VTE), bleeding, post thrombotic syndrome, and adverse events from study drugs. The primary objective of the study is to determine the reduction of thrombin peak concentration and/or endogenous thrombin potential measured by Thrombin Generation Assay (TGA) at 3 months in the "anticoagulation +atorvastatin" arm as compared to the "anticoagulation" arm. The secondary objectives are to determine the chronological changes of hemostatic, inflammatory, and lipidomic biomarker profiles in patients with acute VTE receiving anticoagulation as standard of care, with and without statins. The biomarker profile of interest, in addition to thrombin generation, include: D-dimer, Interleukin- 6 (IL-6), Interleukin-8 (IL-8), tumor necrosis factor (TNF)-α, high sensitivity C-reactive protein, free fatty acids, lipoprotein-associated phospholipase A2 , pro- inflammatory eicosanoids. The ultimate goal is to study the mechanisms of VTE and use of statin in VTE patients. Other secondary objectives include determination of relevant clinical outcomes such as VTE recurrence, VTE related mortality, arterial thrombosis, hemorrhage, post thrombotic syndrome, and residual vein obstruction in patients receiving standard of care versus standard of care plus statins.

Arms:
arm 1: Patients will be treated with warfarin with dose adjusted to goal International Normalized Ratio (INR) of 2-3 or rivaroxaban standard dose (15 mg twice daily for 3 weeks then 20 mg daily) arm 2: In addition to standard anticoagulation, patients will be given concurrent atorvastatin 40 mg daily for the study period of 9 months, starting from the time of enrollment

Interventions: intervention 1: Atorvastatin intervention 2: Anticoagulation Therapy
Intervention descriptions: intervention 1: Atorvastatin belongs to the "statin" class of drugs, and is routinely used for prevention of cardiovascular diseases and/or reduction of cholesterol levels. It has been shown to decrease the risk of first venous thromboembolism in an otherwise healthy population with elevated high-sensitivity C-reactive protein (hs-CRP). intervention 2: Warfarin is a standard anticoagulation in the treatment for venous thromboembolism. The dose will be adjusted to goal INR of 2-3.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
A pilot study of using statins in patients with acute venous 
thromboembolism 
 
 
Coordinating Center:  
 
The Ohio State University 
 
 
 
 
Principal Investigator:  
 
Tzu-Fei Wang 
 
A340 Starling Loving Hall 
 
320 W 10th Avenue 
 
Phone: 614-293-2887 
 
Fax: 614-293-7529 
 
Email: Tzu-Fei.Wang@osumc.edu 
 
 
Study drug(s):                                   Atorvastatin 
  
 
Clinical Trials.gov #:                        NCT02331095 
 
 
 
 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
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Schema 
 
 
 
1.0 
Objectives 
 
This will be a single-center, open-labelled, pilot study.  This study has the following objectives:  
1.1     Primary Objective 
 
1.1.1  To determine the  reduction  of  thrombin  peak  concentration  and/or endogenous 
thrombin potential measured by Thrombin Generation Assay (TGA) at 3 months in the 
“anticoagulation +atorvastatin” arm as compared to the “anticoagulation” arm. 
 
 
 1.2      Secondary Objectives 
 
1.2.1  To determine the composite rate of recurrent VTE and VTE related mortality in patients 
in the statin arm as compared to no statin arm. 
 
1.2.2  To determine the rate of arterial thrombotic events in patients in the statin arm as 
compared to no statin arm. 
 
1.2.3  To determine the rate of major, non-major, and all hemorrhages defined by the ISTH 
(International Society on Thrombosis and Haemostasis) criteria (see section 7.3) in 
patients in the statin arm as compared to no statin arm. 
 
Atorvastatin 40 mg 
Atorvastatin  


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
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1.2.4  To evaluate the changes in proposed hemostatic, inflammatory, and lipidomic 
biomarkers at 3 and 9 months compared to upon enrollment in patients in both arms.  
 
1.2.5  To determine the rate of residual vein obstruction by Doppler ultrasound at 3 months in 
patients in the statin arm as compared to no statin arm. 
 
1.2.6  To determine the rate of clinical post-thrombotic syndrome (PTS), as objectively 
evaluated with Villalta scoring system in patients in the statin arm as compared to no 
statin arm. 
 
 
2.0      Background 
 
Venous thromboembolism (VTE) refers to the formation of pathological blood clots in 
extremity veins (deep vein thrombosis, DVT) and/or pulmonary arteries (pulmonary 
embolism, PE). VTE is common, with an estimated incidence of 1-2 per 1000 in the 
general population, and increases to over 1% in the elderly.1 VTE is a considerable public 
health threat. Approximately  300,000-600,000  patients  develop  VTE  in  the  United  
States  each  year, accounting for 60,000-100,000 deaths. According to the Healthcare Cost 
and Utilization Project, about 350,000 hospital admissions were due to VTE, costing over 
three billion dollars in 2011 alone. In addition, approximately one third of patients die within 
one year of their initial VTE, and one third of survivors suffer from long-term morbidity. 
 
Anticoagulation is the current standard o f  care for acute VTE. However, even 
after a course of anticoagulation, 30% patients have VTE recurrence in 10 years after an 
unprovoked VTE,2 and 25-50% patients will develop post-thrombotic syndrome (PTS), 
causing long-term morbidity. 3,4 Therefore, there is significant room for improvement. To 
accomplish this, it is crucial to have a better understanding of the pathophysiology of VTE 
and its complications. Although some important biomarkers in VTE were identified, 12-14 
the detailed hemostatic, inflammatory, and lipidomic biomarker profiles in patients after an 
acute VTE and their evolution and interplay in relation to treatments are unclear. A better 
understanding can help to identify promising targets to develop novel therapy. 
 
The first aim of the study is to investigate important biomarkers in acute VTE as below: 
 
1)  Hemostatic profile: 
In acute VTE, patients’ pro-coagulation, anti-coagulation, and fibrinolytic systems are 
highly activated. The routine clinical coagulation assays such as prothrombin time and 
activated partial thromboplastin time terminate at initial clot formation, and are inadequate for 
comprehensive assessment of the coagulation system. In contrast, thrombin generation assays 
are increasingly used to assess the global hemostatic status. High thrombin generation potential 
or high thrombin peak concentration was correlated with increased risk of first and 
recurrent VTE.15-17 However, the thrombin generation profiles in acute VTE and their changes 
with anticoagulation have not been solidified. Therefore, thrombin generation will be used as 
our primary biomarker of interest. Secondly, a product of fibrinolysis, D-dimer, indicates 
ongoing fibrin formation and degradation. Elevated D-dimer after the completion of 
anticoagulation has been shown to predict increased risk of recurrent VTE.18,19 Therefore, 
we will also follow D- dimer during and after acute VTE. Thirdly, tissue factor (TF) and 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
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tissue factor pathway inhibitor (TFPI) play essential roles in the initiation and modulating of 
blood coagulation cascade and are of interest in the process of venous thrombosis. We 
therefore plan to study these biomarkers in our patient population as well.36  
 
2)  Inflammatory profiles: 
Inflammation and coagulation are closely interwined.20 Inflammatory diseases are 
associated with increased risk of VTE,21 and thrombosis is associated with release of 
inflammatory cytokines. 22However, their changes in relates to anticoagulation and statins are 
unclear, and therefore selected inflammatory biomarkers including IL-6, IL-8, tumor necrosis 
factor (TNF)-α, high sensitivity C-reactive protein (hs-CRP) will be evaluated. 
 
 
3)  Lipidomic profiles: 
Serum phospholipids play crucial roles in inflammation and serve as the substrate 
for phospholipase A2 (PLA2 ), which subsequently liberates arachidonic acid for 
cyclooxygenase (COX) and lipoxygenase (LOX) to generate eicosanoids.23In addition, these 
bioactive phospholipids play a major role in inflammation and repair.24 However, the 
quantification of these bioactive lipids and the process of their modulation of inflammation 
during acute VTE are unclear, and this study intends to clarify it. Lipid biomarkers of 
inflammation that will be analyzed in the study include free fatty acids and eicosanoids. 
 
Statins are effective in the prevention of arterial thrombosis.25 Recently, arterial and 
venous thrombosis are shown to share common pathophysiological mechanisms,26 and 
effective therapies for arterial thrombosis could provide benefits in VTE. Several observational 
studies and the JUPITER trial, a large, randomized, placebo-controlled study, demonstrates 
that statins significantly reduce the risk of first VTE by 40-50%.7, 27-30 Additionally, as few as 3 
days of atorvastatin  increase  plasma  fibrin  clot  permeability  and  susceptibility  to  
lysis.31These promising results, as well as their safety profiles, make statins an attractive 
potential addition to the standard anticoagulation for treating acute VTE, in an effort to reduce 
long-term morbidity. 
Our second aim is to determine the actions of statins on the proposed biomarkers in 
acute VTE because: First, the effects of statins on thrombin generation in patients with acute 
VTE have not been studied. A study in patients with atrial fibrillation on warfarin showed a 
40% reduction in endogenous thrombin potential with only three months of intensive 
cholesterol-lowering treatment including statins.8 Similar effects could be seen in patients with 
acute VTE. In addition, previous studies evaluating the effects of statins on the reduction of 
D-dimer or inflammatory cytokines revealed promising results but were not focused on 
patients with acute VTE.32,33 Therefore, this study will generate important information for 
acute VTE patients. 
 
3.0      Patient Selection 
 
 
3.1      Inclusion of Women and Minorities 
 
Entry to this study is open to both men and women ages 18 and older, of all racial and 
ethnic subgroups. This study will be conducted in accordance with the International 
Conference on Harmonisation and Helsinki Guidelines. 
 
 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
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3.2      Inclusion Criteria 
 
 
3.2.1 At least 18 years old 
 
3.2.2    A diagnosis of proximal DVT (proximal to and including popliteal vein), with or 
without PE, confirmed by objective imaging studies, such as Doppler ultrasound, 
venograms (for DVT) and/or computer tomography, angiograms, ventilation-perfusion 
scan (for PE) 
 
 
3.2.3 Treated with warfarin or rivaroxaban as anticoagulation (short-term bridging with 
heparin or lovenox, if needed is allowed) 
 
3.3      Exclusion Criteria 
 
 
3.3.1   Thrombolysis within 6 weeks prior to enrollment 
 
3.3.2    Patients with statin use within 6 weeks of enrollment  
 
3.3.3 Patients with known allergy or intolerance to statins or statins are contraindicated for any 
other reasons 
 
3.3.4 Patients with baseline aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
or total bilirubin ≥2.0 x ULN (upper limit of normal) 
 
3.3.5    Pregnant or breastfeeding females are excluded  
 
3.3.6    Any  malignancy  diagnosed  within  the  preceding  2  years,  except  for  squamous  
cell carcinoma or basal cell carcinoma of skin treated with local resection only, or 
carcinoma in situ of the cervix 
 
3.3.7 Incarcerated patients are excluded from the study due to the inherent difficulties in 
maintaining close follow-up for study purposes in patients who are incarcerated.   
 
3.4      Enrollment/registration of patients 
 
3.4.1 Patients must give written informed consent prior to enrollment on this study.  Informed 
consent may be obtained by the principal investigator, co-investigators, or one of their 
designees.  
 
4.0      Randomization of Patients 
 
 
 
 
Patients will be randomized at the time of registration/enrollment on this clinical trial via 
contact with the study nurse/coordinator at the time of the initial registration of the 
subject.  The study nurse/coordinator will conduct the randomization on the REDCap 
Data Capture system and relay this information to the treating/enrolling physician so that 
the appropriate medication (atorvastatin) can be started.   
 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
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5.0      Treatment plan: atorvastatin vs placebo 
 
 
After randomization, patients on the statin arm will start the assigned study drug 
(atorvastatin) for a total of 9 months, in addition to the standard of care (anticoagulation). 
Atorvastatin will be prescribed through patients’ pharmacy of choice. It will be taken 
once a day in a tablet form. Pill count and patient self-report compliance diary will be 
reviewed at each visit. All the attempts will be made to continue atorvastatin for entire 9 
months, however, if a patient needs to stop atorvastatin prior to the intended period for 
any reasons (for example, side effects), it will be documented, but they are allowed to 
remain in the study for blood tests and clinical follow up. At the end of the study, the 
decision of whether patients should remain on atorvastatin or not will be left to the 
treating physicians.   
 
6.0       Study calendar 
 
 
Initial visit 
3 month1 
9 month1 
Singed informed 
consent 
x 
 
 
Medical/treatment 
history 
x 
x 
x 
Physical examination 
x 
x 
x 
Vital signs 
x 
x 
x 
CBC with diff2 
x 
x 
x 
Chemistry3, including 
liver function tests 
x 
x 
x 
Fasting lipid profiles 
x 
x 
x 
hs-CRP 
x 
x 
x 
D-dimer 
x 
x 
x 
Urine β-hCG4 
x 
 
 
Thrombin generation 
assay 
x 
x 
x 
IL-6, IL-8, TNF-α 
x 
x 
x 
Lipidomic profiles5 
x 
x 
x 
Doppler ultrasound of 
bilateral lower 
extremities 
 
x 
 
Prescription of statins6 x 
x 
 
1All scheduled visits are allowed a window of +/- 21 days  
2CBC includes: white blood cells with differential, hemoglobin, red blood cells, and platelets  
3Chemistry and liver function tests include: sodium, potassium, carbon dioxide, glucose, BUN, creatinine, calcium, 
total protein, albumin, bilirubin, alkaline phosphatase, AST and ALT  
4Required only in women of child-bearing potential 
5Lipidomic profiles includes free fatty acids, lipoprotein-associated phospholipase A2, pro-inflammatory 
eicosanoids 
6Prescription of statins only in the statin arm 
 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
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7.0      Outcome Criteria 
 
7.1      Recurrent venous thromboembolism 
 
7.1.1   Recurrent pulmonary embolism will be diagnosed when: 
  
a) New filling defect(s) is/are seen in CT angiogram of chest or pulmonary 
angiography 
b) A new high probability on ventilation-perfusion lung scan. 
 
7.1.2   Recurrent deep vein thrombosis will be diagnosed when: 
  
         
a)    New filling defect(s) is/are seen in venography or new uncompressible segments 
seen on vascular Doppler ultrasound in a previously uninvolved limb 
          
b)    In the limb with a previous VTE, new filling defect(s) in venography or new 
uncompressible segments in vascular Doppler ultrasound that is clearly extending 
from the prior thrombosis or involving a new venous segment 
 
7.2      Arterial thromboembolism 
 
7.2.1 Myocardial infarction: 
 
          Myocardial infarction will be diagnosed if at least two of the following criteria are met: a 
history of typical ischemic pain lasting for at least 20 minutes and unresponsive to 
sublingual nitrates (if given), new elevation of cardiac enzymes (creatinine kinase or its 
MB fraction) to more than twice the ULN or troponin value, new EKG changes including 
new persistent ST/T changes, new bundle branch block or new Q waves in at least two 
consecutive leads.  
 
7.2.2   Cerebral vascular accidents: 
 
          Cerebral vascular accidents (CVA) is a clinical syndrome of rapid development of focal or 
global loss of brain function, lasting more than 24 hours, thought to be vascular in origin, 
and/or leading to neurological damages or early death. It is expected that CT or MRI scans 
will be performed to confirm the diagnosis in most cases.  
 
7.3      Bleeding 
 
 
7.3.1 Major bleeding will be defined as: 
 
                      a) Bleeding into critical organs such as central nervous system, retroperitonium 
                      b) Bleeding requiring emergent intervention or surgery for hemostasis 
                      c) Bleeding requiring at least 2 units of packed red blood cell transfusion 
                      d) Bleeding leading to at least 2 points drop in hemoglobin from baseline 
                      e) Bleeding requiring hospital admission for intervention 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
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7.3.2 Non-major bleeding is defined as any other bleeding reported by patients but not 
otherwise meeting the above listed criteria for major bleeding 
 
8.0      Treatment after Recurrences of VTE 
 
 
Patients suffering a recurrent VTE on either arm will stop study drugs and but will 
continue to be followed on the study. The management of recurrent VTE will be left to 
the discretion of the treating physician.  
9.0      Correlative Studies 
9.1       Laboratory Studies at Enrollment  
9.1.1 The initial laboratory tests will be obtained at the time of enrollment on this study. Blood 
will be collected after overnight fasting for at least 9 hours. Laboratory tests will include: 
 
 CBC (complete blood count) 
 chemistry panel (Na, K, Cl, CO2, Cr, BUN, Ca, and glucose),  
 liver function tests (AST, ALT, ALP, total and direct bilirubin) 
 D-dimer 
 high-sensitivity C-reactive protein (hs-CRP) 
 fasting lipid profiles (LDL, HLD, TG, total cholesterol 
 β-hCG is required only in women of child-bearing potential 
             
 
Research labs: 
 thrombin generation assay 
 IL-6, IL-8, tumor necrosis factor (TNF)-α 
 lipidomic profiles including free fatty acids, lipoprotein-associated phospholipase A2,  
pro-inflammatory eicosanoids 
 plasma levels and RNA expression of tissue factor (TF), tissue factor pathway 
inhibitor (TFPI), and other clotting factors  
9.2    Subsequent Follow-up and Correlative Laboratory Studies 
 
9.2.1 All enrolled patients will be seen on enrollment and at month 3 and 9.   
 
9.2.2 The following laboratory studies will be obtained at each follow-up visit: 
 
 CBC (complete blood count), platelet count  
 chemistry panel (Na, K, Cl, CO2, Cr, BUN, Ca, and glucose),  
 liver function tests (AST, ALT, ALP, total and direct bilirubin) 
 d-dimer 
 high-sensitivity C-reactive protein (hs-CRP) 
 fasting lipid profiles (LDL, HLD, TG, total cholesterol) 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
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Research labs:  
 thrombin generation assay 
 IL-6, IL-8, tumor necrosis factor (TNF)-α 
 lipidomic profiles including free fatty acids, lipoprotein-associated phospholipase A2, 
pro-inflammatory eicosanoids 
 plasma levels and RNA expression of tissue factor (TF), tissue factor pathway 
inhibitor (TFPI), and other clotting factors  
 
9.2.3 A follow up Doppler ultrasound will be obtained at month 3 as standard of care in all 
patients to evaluate residual vein thrombosis.  
 
10.0     Outpatient Visits 
 
Patients will be seen in the outpatient thrombosis clinic at least on enrollment, month 3, 
and month 9 (conclusion of the study), at each time side effects of drugs, symptoms of 
bleeding and recurrent VTE, post thrombotic syndrome will be assessed. Pill count and 
drug compliance will be assessed as well. Enrollees will be given $6 dollar food vouchers 
to be used in the cafeteria for each of the scheduled study visit (enrollment, 3 and 9 
months) to compensate their efforts of fasting prior to lab drawn.  
 
11.0    Safety Monitoring During Study 
 
11.1 
To ensure the safety of all patients enrolled on this study, careful monitoring and follow-
ups for all patients will be important aspects of this study. Patients will be monitored 
closely with laboratory and clinical evaluations at regular intervals defined in the study 
protocol. 
 
11.2     At each visit (enrollment, 3 and 9 months), patients will be evaluated by physicians and 
study personnel for side effects of statins and anticoagulation. The management of side 
effects from statins will follow the routine practice for patients who are prescribed with 
statins for other medical problems, and will be left to the discretion of the treating 
physicians, but the study team and PI will be available for any assistance if questions of 
the optimal management of adverse events were to arise. Live function tests will be 
obtained prior to and at each follow-up visit. Creatitine kinase (CK) test will not be 
collected without symptoms, but will be collected if patients were to develop symptoms 
of muscle pain or weakness. Patients with new onset of transaminitis or CK above three 
times of upper limit of normal or significant symptoms will be taken off statins. Their 
abnormal laboratory tests will be monitored at least every 2 weeks, more frequently if 
needed, until the abnormalities resolve. Patients will only resume statins if their 
symptoms resolve, blood tests normalize, and if patients are willing to resume treatment. 
Recurrent test abnormality or symptoms will require permanent discontinuation of 
statins. 
 
 
 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
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12.0  Adverse Events/Severe Adverse Events 
 
12.1    Definition: Adverse events as defined in the International Council on Harmonisation 
Guidelines for Good Clinical Practice are described as “an untoward medical occurrence 
in a patient or clinical investigation administered a pharmaceutical product that does not 
necessarily have a causal relationship with this treatment.”  
 
12.2     A serious adverse event is an adverse event that: 
 Is fatal 
 Is life threatening (places the subject at immediate risk of death) 
 Results in inpatient hospitalization or prolonged existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Includes other significant hazard 
 
12.3      Grading of Adverse Events – Events will be graded by using the Common Terminology 
Criteria for Adverse Events (CTCAE) Criteria version 4.0. 
 
12.4       Attribution – the determination and documentation of whether an adverse event is related 
to a medical procedure. 
 
Attribution Categories: 
1. Not Related –Event clearly related to other factors (e.g., clinical state, other therapies; 
concomitant drugs) 
2. Possible Related – Sequence of event is compatible with study drug, device, or 
procedure, but could have been produced by other factors 
3. Probably Related - Sequence of event is compatible with study drug, or procedure and 
cannot be explained by other factors without much doubt 
4. Definitely Related - Sequence of event is compatible with study drug, or procedure 
and beyond doubt cannot be explained by other factors 
 
12.5  Reporting of Adverse Events: Adverse events must be recorded within 7 days of the 
occurrence using the “Adverse Event” form (see Appendix).  The principal investigator 
will review all adverse event forms every month or more frequently if needed. All serious 
or unexpected adverse events must be communicated to the principal investigator 
immediately and will be reported to the IRB within 24 hours of learning of the event’s 
occurrence by phone, email, or SAE for regardless of attribution. Using these 
mechanisms of rapid reporting, we will be able to rapidly evaluate and minimize the 
potential risks to patients from the occurrence of these events.  Subjects will be instructed 
to report any adverse event(s) during the study and post-study. The investigator will 
notify the IRB of any unanticipated death or adverse event occurring after a participant 
has discontinued or terminated study participation that may reasonably be related to the 
study.  
 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
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12.6  Follow-up of Adverse Events: Patients experiencing an adverse event will continue to be 
followed and carefully monitored until the resolution of the adverse event.  This applies 
whether the patient continues on study or is removed from the study for any reason. 
 
12.7  While no formal stopping rules are deemed necessary due to the well-known safety and 
tolerability of statins, the PI will be informed of any SAE immediately, determine 
correlation, and report to IRB.  The PI is responsible to continuously evaluate the safety 
for study continuation based on regular review of AE reports.  
 
13.0    Sample Procurement  
 
 
Both plasma and blood samples will be taken as a part of this protocol.  Theses samples 
will be obtained at the same time that standard clinical samples or procedures are being 
performed so patients will not be exposed to additional venipunctures or procedures by 
their participation in this study.   
 
14.0     Sample Storage and Handling 
  
 
At the time of enrollment and registration with the coordinating institution, arrangements 
will be made for the research blood samples to be delivered to the laboratory of Dr. Bryce 
Kerlin, Dr. Mark Hall, and Dr. Kenneth Riedl for processing and analysis. Research 
blood samples will be labeled with a unique identification number so that the data 
obtained may be correlated with the patient’s clinical course by the investigators at the 
end of the study, while the laboratory personnel performing the research testing will not 
be able to identity each individual patient.  This will help ensure patient confidentiality, 
as the investigators will be the only people to know the patient name and medical record 
number that correspond with the identification number.  Samples to be used for future 
study will be frozen at -80C and be stored in the benign hematology research office at 
the James Cancer Hospital, and in the laboratory of Dr. Kerlin, depending on the 
designated research testing to be done: thrombin generation assays will be performed in 
Dr. Kerlin’s laboratory at Nationwide Children’s. Inflammatory markers will be done in 
Dr. Mark Hall’s laboratory at Nationwide Children’s and lipidomic profiles will be 
performed at Dr. Kenneth Riedl’s laboratory at Ohio State. At the end of the study, at 
least one aliquot of each plasma and RNA samples will be delivered to Dr. Alan Mast’s 
laboratory at the Blood Center of Wisconsin for testing including TF, TFPI, and other 
clotting factors. Samples will be sent on dry ice via commercial carriers overnight.  
 
15.0    Risks Associated with Testing of Patient Samples 
 
 
A breach of confidentiality is the most serious risk which patients may be exposed to 
regarding to research testing of biologic samples. Confidentiality will be maintained by 
labeling the patient samples with only an identification number and not their name or 
medical record number.  By using this approach, patient samples may be tied to clinical 
information by the investigators but will preserve the confidentiality of patients.  Only the 
principal investigator, co-investigator, and the study nurse/coordinator will have access to 
both the study number and the corresponding patient identification information.  Clinical 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
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information or laboratory data used for publication will not identify patients in any way 
that could potentially breach patient confidentiality.  The samples sent to BloodCenter of 
Wisconsin will be coded and all PHI will be removed so the laboratory personnel there 
will have no access to the PHI. The samples need to be coded and not de-identified, so 
the principal and co-investigators can correlate clinical with research laboratory findings. 
Even though more research laboratory tests are planned in this protocol amendment, it 
will be accomplished within the same amount of blood that was originally planned to be 
drawn and therefore expose no additional risks to subsequent enrollees.  
 
16.0   Thrombin generation assay 
 
Blood samples for measurement of thrombin generation will be drawn in vacutainer tubes 
containing 3.2% sodium citrate with and without corn trypsin inhibitor (CTI) and be 
processed appropriately within an hour prior to storage. Blood samples will be 
centrifuged at 2500g (relative centrifugal force) for 15 minutes (min). Plasma will be 
transferred into plastic tubes, and re-centrifuged at 2500g for 15 min. Plasma will be 
decanted again after second spin and stored in aliquots of 0.2 mL (platelet poor plasma). 
The platelet poor plasma will then be snap frozen and stored at -70°C until testing as bulk 
at the end of the study. 
The thrombin generation assays will be performed using a commercial kit 
(TECHNOTHROMBIN® TGA, Technoclone, Vienna, Austria) according to the 
manufacturer’s instructions in Dr. Kerlin’s laboratory. The assays are performed based on 
monitoring the fluorescence generated by thrombin cleavage of a fluorogenic substrate 
over time, after the activation of the coagulation cascade by tissue factor. At least two 
reagents will be used. Parameters that will be recorded include: lag phase, time to peak 
thrombin concentration, peak thrombin concentration, and endogenous thrombin potential 
(measured by area under the curve). 
 
17.0    Inflammatory marker assessment 
 
Serum IL-6, IL-8, and TNF-α levels will be measured using commercial enzyme-linked 
immunosorbent assay (ELISA) according to the manufacturer’s instructions in Dr. 
Mark Hall’slaboratory. 
 
18.0    Lipodomic profiles 
 
18.1    Lipidomic profiles will be done in Dr. Riedl’s laboratory. Blood samples for measurement 
of lipidomic profiles will be drawn in two vacutainer tubes, one containing 3.2% sodium 
citrate and the other being a serum separator tube.  
 
After collection, blood will be separated into individual constituents including 
serum. Lipidomic profiles will be collected on blood samples using a triple quadrupole 
mass spectrometry platform called Lipidyzer which is enabled through ion mobility 
hardware. This assay covers 13 different lipid classes and uses 56 stable isotope internal 
standards to provide quantitative results for as many as 1,100 lipid species. A separate 
LCMS panel will be utilized to determine eicosanoid profiles in blood. Both of these 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
- 13 - 
assays will be conducted in the Nutrient & Phytochemical Analytic Shared Resource 
(NPASR) of the OSU Comprehensive Cancer Center under the direction of Acting 
Director, Ken Riedl..  
 
19.0    Plasma levels and RNA expression of tissue factor (TF), tissue factor pathway 
inhibitor (TFPI), and other clotting factors 
 
19.1    These tests will be done in Dr. Alan Mast’s laboratory at BloodCenter of Wisconsin 
according to their standard protocol. The plasma samples will be frozen and stored at -
80°C at the Ohio State University until the end of the study, when samples will be 
delivered to Dr. Mast’s lab to perform the research testing. 
 
19.2     After plasma was removed from each tube as per protocol above, the buffy coats in the 
tubes will be collected as much as possible and stored in RNAlater® reagent as per 
manufacturer’s protocol. These buffy coats will be used for analysis of RNA expression in 
Dr. Mast’s laboratory at the end of the study, according to their standard protocol.  
 
20.0  Statistical Analysis 
 
 
At least 66 evaluable patients will be randomized (1:1 allocation, 33 evaluable patients 
in each arm) into “anticoagulation” versus “anticoagulation +atorvastatin” arms. The 
primary endpoints are thrombin peak and thrombin generation. Based on the published 
data,8,9 we anticipate an 80% power to detect an effect size of 0.7 standard deviations in 
the reduction of thrombin peak or thrombin generation between the two arms with two-
side alpha of 0.05 using a two-sample t test. An overall alpha of 0.1 for this pilot study 
was split into 0.05 for each endpoint (thrombin peak and thrombin generation) using 
Bonferroni method. Considering possible drop-outs, our target enrollment will be 80 
patients, with 40 on each arm. 
 
All data will be collected on study-approved data collection forms and entered into 
Research Electronic Data Capture (REDCap), which is a secure, web-based application 
designed to support data capture for research studies by building and managing online 
surveys and databases. The system was built with the help of the OSU Research 
Informatics Services. 
 
Descriptive statistics (i.e. means, standard deviations, 95% confidence intervals for 
continuous variables, and frequencies for discrete data) and graphical analyses will be 
used for all clinical outcomes, demographics, VTE related events, laboratory results, and 
adverse events for each arm. The secondary endpoints will be compared between the 
two arms using chi- square test or Fisher’s exact test, whichever is appropriate. The 
associations between treatment type and the change in biomarkers will be evaluated 
using two-sample t test. Log-transform will be used if necessary. Linear mixed models 
will be used to study the associations between the primary endpoints and treatment, and 
trend across time. The interaction term “arm x time” will be included in the model to 
study whether the two treatment arms have different “behavior” across time. Potential 
confounders will be included in the models. Thrombin peak concentration and 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
- 14 - 
endogenous thrombin potential at 9 months will be compared between the patients on 
anticoagulation and those off anticoagulation. 
 
21.0     Costs of the Study 
 
 
Given the fact that all patients will be receiving standard therapy for VTE 
(anticoagulation), either the patient or their insurance carrier will be responsible for all of 
the medical expenses associated with the treatment and follow up of their VTE. The costs 
associated with the research laboratory studies will be paid by the study researchers and 
will not be passed on to patients or their insurance carriers. The cost of atorvastatin will 
be reimbursed by the study researchers. Patients enrolled on this study will not incur any 
additional expenses as a result of enrolling on this protocol. 
 
22.0 
References 
 
1. Cushman M et al. Deep vein thrombosis and pulmonary embolism in two cohorts: 
the longitudinal investigation of thromboembolism etiology. Am J Med. 
2004;117:19-25. 
2. Heit J et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism. A 
population-based cohort study. Arch Intern Med.2000;160:761-768. 
3. Prandoni P et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern 
Med. 1996;125:1-7. 
4. Kahn SR et al. Determinants of health-related quality of life during the 2 years following 
deep vein thrombosis. J Thromb Haemost. 2008;149:698-707. 
5. Kahn SR et al. Compression stockings to prevent post-thrombotic syndrome: a 
randomized placebo-controlled trial. Lancet. 2014; 383:880-888. 
6. Prandoni P et al. Residual venous thrombosis as a predictive factor of recurrent 
venous thromboembolism. Ann Intern Med. 2002;137:955-960. 
7. Glynn RJ et al. A randomized trial of rosuvastatin in the prevention of 
venous thromboembolism. N Engl J Med. 2009;360:1851-1861. 
8. Van Kuilenburg J et al. Persisting thrombin activity in elderly patients with atrial 
fibrillation on oral anticoagulation is decreased by anti-inflammatory therapy with intensive 
cholesterol- lowering treatment. Journal of Clinical Lipidology. 2011;5:273-280. 
9. Macchia A et al. Statins but not aspirin reduce thrombotic risk assessed by thrombin 
generation in diabetic patients without cardiovascular events: The RATIONAL trial. PLoS 
ONE 2012;7:e32894. 
10. Heit  et al. Venous thromboembolism epidemiology: implications for 
prevention and management. Semin Thromb Hemost 2002;28:suppl 2:3-13. 
11. Heit J et al. Predictors of survival after deep vein thrombosis and pulmonary embolism. A 
population-based cohort study. Arch Intern Med.1999;159:445-453. 
12. Adam  SS  et   al.   D-dimer  antigen:  current  concepts  and  future  prospects.  
Blood. 
2009;113:2878-2887. 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
- 15 - 
13. Fitzpatrick JW et al. Eicosanoids and venous thromboembolism. J Am Osteopath 
Assoc. 
1983;83:301-306. 
14. Kaaja  R  et  al.  Increased  thromboxane  production  in  women  with  a  history  of  
venous thromboembolic event: effect of heparins. British J Hematol. 2001;114:655-659. 
15. Van Hylckama Vlieg A et al. Elevated endogenous thrombin potential is associated 
with an increased risk of first deep venous thrombosis but not with the risk of recurrence. 
Brit J Haematology. 2007;138:769-774. 
16. Tripodi A et al. High thrombin generation measured in the presence of 
thrombomodulin is associated with an increased risk of recurrent venous 
thromboembolism. J Thromb Haemost. 
2008;6:1327-1333. 
17. Besser M. et al. High rate of unprovoked recurrent venous thrombosis is associated 
with high thrombin-generating potential in a prospective cohort study. J Thromb 
Haemost. 
2008;6:1720-1725. 
18. Palareti G et al. D-dimer testing to determine the duration of anticoagulation therapy. N 
Engl 
J Med. 2006;355:1780-1789. 
19. Bruinstroop E et al. Elevated D-dimer levels predict recurrence in patients with 
idiopathic venous thromboembolism: a meta-analysis. J Thromb Haemost. 2009;7:611-
618. 
20. Levi M, et al. Bidirectional relation between inflammation and coagulation. Circulation. 
2004;109:2698-2704. 
21. Vladimir Tichelaar YIG et al. Infections and inflammatory diseases as risk factors for 
venous thrombosis. Thromb Haemost 2012;107:827-837. 
22. Rodriquez AL et al. Statins, inflammation, and deep vein thrombosis: a systematic review. 
J Thromb Thrombolysis. 2012;33:371-382. 
23. Rosenson RS et al. Phospholipase A2 enzymes and the risk of atherosclerosis. Eur Heart J. 
2012;33:2899-2909. 
24. Kotha SR et al. Bioactive phospholipid mediators of inflammation. In Chronic 
inflammation: Nutritional and therapeutic interventions. Editors: Roy S, Bagchi D, 
Raychaudhuri SP. CRC Press, Boca Raton, USA. 2013. 
25. Baigent C et al. Efficacy and safety of cholesterol-lowering treatment: prospective 
meta- analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 
2005;366:1267-1278. 
26. Ageno W et al. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. 
Circulation. 2008;117:93-102. 
27. Ray JG et al. Use of statins and the subsequent development of deep vein thrombosis. Arch 
Intern Med. 2001;161:1405-1410. 
28. Herrington DM et al. Statin therapy, cardiovascular events, and total mortality in the 
Heart and estrogen/Progestin Replacement Study (HERS). Circulation. 2002;105:2962-
2967. 


A Pilot Study of Using Statins in Patients with Acute Venous Thromboembolism (VTE) 
IRB Protocol Number: 2014H0262 
 
Approval Date: 11/15/2017 
 
- 16 - 
29. Ramcharan AS et al. HMG-CoA reductase inhibitors, other lipid-lowering medication, 
antiplatelet therapy, and the risk of venous thrombosis. J Thromb Haemost. 2009;7:514-
520. 
30. Sorensen HT et al. Arterial cardiovascular events, statins, low-dose aspirin and subsequent 
risk of venous thromboembolism: a population based case-control study. J Thromb Haemost. 
2009;7:521-528. 
31. Zolcinski M et al. Effects of atorvastatin on plasma fibrin clot properties in apparently 
healthy individuals and patients with previous venous thromboembolism. Thromb Haemoast 
2012;107:1180-1182. 
32. Squizzato A et al. Why should statins prevent venous thromboembolism? A 
systemic literature search and a call for action. J Thromb Haemost. 2006;4:1925-1927. 
33. Zolcinski M et al. Atorvastatin favorably modulates proinflammatory cytokine 
profile in patients following deep vein thrombosis. Thrombosis Research 2013;132:e31-
35. 
34. Furugohri T et al. Antithrombin-independent thrombin inhibitors, but not direct factor 
Xa inhibitors, enhance thrombin generation in plasma through inhibition of thrombin- 
thrombimodulin-protein C system. Thromb Haemost 2011;106:1076-1083. 
35. Piovella F et al. Normalization rates of compression ultrasonography in patients with a 
first episode of deep vein thrombosis of the lower limbs: association with recurrence and 
new thrombosis. Haematologica. 2002;87:515-522. 
36. Wood JP et al. Biology of tissue factor pathway inhibitor. Blood 2014;123:2934-2943. 

ICF_001.pdf: 
CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014H0262 
IRB Approval date:  11/15/2017 
Version:  6 
 
 
Page 1 of 9 
Form date: 02/10/12  
 
 
1 
The Ohio State University Combined Consent to Participate in 
2 
Research and HIPAA Research Authorization 
3 
 
4 
 
5 
Study Title:  
A pilot study of using statins in patients with acute venous 
thromboembolism 
Principal Investigator: 
Tzu-Fei Wang 
Sponsor:  
 The Ohio State University Wexner Medical Center Department 
of Internal Medicine 
 
6 
 This is a consent form for research participation.  It contains important information 
7 
about this study and what to expect if you decide to participate.  Please consider the 
8 
information carefully. Feel free to discuss the study with your friends and family and 
9 
to ask questions before making your decision whether or not to participate. 
10 
 Your participation is voluntary.  You may refuse to participate in this study.  If you 
11 
decide to take part in the study, you may leave the study at any time.  No matter what 
12 
decision you make, there will be no penalty to you and you will not lose any of your 
13 
usual benefits.  Your decision will not affect your future relationship with The Ohio 
14 
State University.  If you are a student or employee at Ohio State, your decision will 
15 
not affect your grades or employment status. 
16 
 You may or may not benefit as a result of participating in this study.  Also, as 
17 
explained below, your participation may result in unintended or harmful effects for 
18 
you that may be minor or may be serious depending on the nature of the research. 
19 
 You will be provided with any new information that develops during the study 
20 
that may affect your decision whether or not to continue to participate.  If you 
21 
decide to participate, you will be asked to sign this form and will receive a copy of the 
22 
form.  You are being asked to consider participating in this study for the reasons 
23 
explained below.   
24 
 
25 
1.   Why is this study being done? 
26 
Patients who have had blood clots in their leg veins (deep vein thrombosis, DVT) can 
27 
have long term problems after their initial blood clots, such as chronic swollen and 
28 
painful legs called post-thrombotic syndrome or the blood clots could come back. How to 
29 
decrease these long term problems is not well-known.  
30 
 
31 
Statin drugs are commonly used medications to treat high cholesterol and heart diseases. 
32 
Some evidence showed that statin drugs can potentially help prevent blood clots from 
33 
coming back. However, how they work is unclear. 
34 
 
35 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014H0262 
IRB Approval date:  11/15/2017 
Version:  6 
 
 
Page 2 of 9 
Form date: 02/10/12  
 
In this study, we will study the role of statins in patients with new DVT, by measuring 
36 
important blood tests in patients who are taking blood thinners with or without statins as 
37 
treatment for their DVT. 
38 
 
39 
2.   How many people will take part in this study? 
40 
We plan to enroll 80 people in this study at OSU. 
41 
 
42 
3.   What will happen if I take part in this study? 
43 
If you decide to take part in this study, you will be randomly assigned (like the flip of a 
44 
coin) to one of two groups. You have an equal chance of receiving blood thinners alone 
45 
or blood thinners plus atorvastatin, a commercially available statin drug.  You and your 
46 
treating doctors will know which group you are in, and side effects from both atorvastatin 
47 
and the blood thinner will be discussed with you and closely monitored. 
48 
 
49 
You will also be asked to give a sample of your blood at three time points: at enrollment, 
50 
3 months later, and 9 months later. The 3-month and 9-month blood collection will occur 
51 
in conjunction with your regularly scheduled follow-up visits for your DVT. On average, 
52 
these visits last 1-2 hours. The research procedures during these visits will only last 10-15 
53 
minutes. A total of 40 mL (8 teaspoons) of blood will be obtained at each visit (half are 
54 
for standard laboratory tests and half are purely for research purposes).  We ask that you 
55 
fast for 9 hours prior to these blood draws. Your blood sample will be assigned a number, 
56 
and no personally identifiable information will be shown on your sample. At each visit 
57 
we will also ask you about any medications you are taking or have started to take in the 
58 
time between visits. For your safety, participants may only take warfarin or rivaroxaban 
59 
to be included in this study. Thus, you should remain on the drug you are randomized to 
60 
throughout your time on anticoagulation and not switch to other oral anticoagulants 
61 
during the study period.  
62 
 
63 
If you are a woman of childbearing potential, a urine pregnancy test will be done at the 
64 
initial visit, the 3 month visit, and the 9 month visit. You cannot be in this study if you 
65 
are pregnant. If you become pregnant while you are in the study, you will no longer be 
66 
able to participate and you will be excluded from the study. 
67 
 
68 
A Doppler ultrasound of your legs will be done at the 3 month visit as typically done for 
69 
your type of blood clot. A Doppler ultrasound is used to measure the flow of blood 
70 
through your blood vessels using high-frequency sound waves. You will lie on a 
71 
cushioned table and gel will be applied to your skin. A hand-held device that sends and 
72 
receives ultrasound signals will be moved over your legs. This will take approximately 30 
73 
minutes.  
74 
 
75 
Your blood samples will be sent to participating laboratories at Nationwide Children’s 
76 
Hospital (NCH) for the study related blood tests. Some of your blood samples will be 
77 
sent to the Blood Center of Wisconsin (BCW) for analysis. The sample will be coded, 
78 
meaning no personally identifiable information will be sent with your blood to NCH or 
79 
BCW. 
80 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014H0262 
IRB Approval date:  11/15/2017 
Version:  6 
 
 
Page 3 of 9 
Form date: 02/10/12  
 
 
81 
4.   How long will I be in the study? 
82 
You will be in the study for a total of 9 months from the time of study participation. If 
83 
you are assigned to the atorvastatin group, you will need to take atorvastatin for 9months 
84 
(it may be stopped early if side effects happen but you will be able to remain in the 
85 
study). Your doctors will monitor you and obtain necessary blood tests for the rest of the 
86 
time, even after stopping atorvastatin and/or blood thinners.  
87 
 
88 
5. Can I stop being in the study? 
89 
You may leave the study at any time.  If you decide to stop participating in the study, you 
90 
can call the study coordinator Melanie Heinlein at 614-293-5176 to request to be taken 
91 
off the study. There will be no penalty to you, and you will not lose any benefits to which 
92 
you are otherwise entitled.  Your decision will not affect your future relationship with 
93 
The Ohio State University.   
94 
 
95 
If you decide that you no longer wish to have your samples stored, the research lab will 
96 
discard all of your stored samples and no further research will be done with the samples. 
97 
 
98 
6.   What risks, side effects or discomforts can I expect from being in the study? 
99 
Statin drugs, while commonly used for other diseases, can cause some side effects, 
100 
including elevation of liver enzymes, muscle soreness and pain, joint pain, headache, 
101 
nausea and rarely, severe muscle damage leading to kidney failure. However, this is very 
102 
rare (less than 1%) and more commonly happens with a higher dose of statins compared 
103 
to the amount that is given for the study. You and your doctor will know if you are going 
104 
to be taking the statin drugs or not, which will allow close monitoring of these symptoms 
105 
and early intervention if needed to be.  
106 
 
107 
Taking blood from a vein may cause some pain, infection, bleeding, or bruising at the 
108 
needle stick site, and rarely cause fainting. Blood tests for this study will be done at the 
109 
same time as routine blood draws whenever possible. The total amount of blood needed 
110 
for this study is about 24 teaspoons, which will be separated into three time blood drawn 
111 
3 months and 6 months apart (8 teaspoons at each visit), so this amount will not harm you 
112 
in any way. 
113 
 
114 
The other risk is the violation of patient confidentiality. We will assign a number to your 
115 
blood samples, not your name. This will allow researchers to relate clinical information 
116 
to the laboratory data without violating your confidentiality.  In addition, while results 
117 
from this study are intended to be published in the future, you will not be identified in 
118 
any manner in publications or presentations that could arise from this work.  Any future 
119 
discoveries arising from these studies which could potentially impact the treatment of 
120 
your disease will be discussed with you.  You will be told of any new information that 
121 
may influence your willingness to continue to participate in this study. 
122 
 
123 
7.   What benefits can I expect from being in the study? 
124 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014H0262 
IRB Approval date:  11/15/2017 
Version:  6 
 
 
Page 4 of 9 
Form date: 02/10/12  
 
You may not have direct immediate benefits from being in the study. However, by 
125 
studying important blood tests and their changes during the time course of DVT, and the 
126 
potential benefits of these commonly used, well-tolerated statin drugs, we can understand 
127 
the disease of DVT better and identify better treatment for it to prevent long term 
128 
complications. In the future, patients with DVT can be treated more effectively. 
129 
 
130 
8.   What other choices do I have if I do not take part in the study? 
131 
You may choose not to participate without penalty or loss of benefits to which you are 
132 
otherwise entitled. 
133 
 
134 
9.   Will my study-related information be kept confidential? 
135 
Efforts will be made to keep your study-related information confidential.  However, there 
136 
may be circumstances where this information must be released.  For example, personal 
137 
information regarding your participation in this study may be disclosed if required by state 
138 
law.   
139 
 
140 
Also, your records may be reviewed by the following groups (as applicable to the 
141 
research): 
142 
 
Office for Human Research Protections or other federal, state, or international 
143 
regulatory agencies; 
144 
 
U.S. Food and Drug Administration; 
145 
 
The Ohio State University Institutional Review Board or Office of Responsible 
146 
Research Practices; 
147 
 
The sponsor supporting the study, their agents or study monitors; and 
148 
 
Your insurance company (if charges are billed to insurance). 
149 
 
150 
If this study is related to your medical care, your study-related information may be placed 
151 
in your permanent hospital, clinic, or physician’s office records. Authorized Ohio State 
152 
University staff not involved in the study may be aware that you are participating in a 
153 
research study and have access to your information.  
154 
 
155 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
156 
required by U.S. law.  This website will not include information that can identify you.  At 
157 
most, the website will include a summary of the results.  You can search the website at 
158 
any time.  
159 
 
160 
10. What are the costs of taking part in this study? 
161 
There are no direct costs of taking part in this study.  However, the medications 
162 
(anticoagulation), routine medical care, laboratory tests, and imaging studies for the 
163 
routine care of your DVT will be billed to your insurance company and you may be 
164 
responsible for co-payment (if needed as dictated by your insurance plan).  Since statins 
165 
are not currently considered routine care for patients with blood clot, it may not be 
166 
covered by your insurance company, and the cost of statins if you are assigned to the 
167 
statin arm will be reimbursed to you by the study, so you will not have extra cost to 
168 
participate in the study.  
169 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014H0262 
IRB Approval date:  11/15/2017 
Version:  6 
 
 
Page 5 of 9 
Form date: 02/10/12  
 
 
170 
 
171 
 
172 
11. Will I be paid for taking part in this study? 
173 
Yes, you will be given a $6 dollar food voucher to be used in the cafeteria for each of the 
174 
scheduled study visit (enrollment, 3 and 9 months) to compensate your efforts of fasting 
175 
prior to laboratory tests. 
176 
 
177 
12. What happens if I am injured because I took part in this study? 
178 
If you suffer an injury from participating in this study, you should notify the researcher or 
179 
study doctor immediately, who will determine if you should obtain medical treatment at 
180 
The Ohio State University Medical Center.   
181 
 
182 
The cost for this treatment will be billed to you or your medical or hospital insurance. The 
183 
Ohio State University has no funds set aside for the payment of health care expenses for 
184 
this study.  
185 
 
186 
13. What are my rights if I take part in this study? 
187 
If you choose to participate in the study, you may discontinue participation at any time 
188 
without penalty or loss of benefits.  By signing this form, you do not give up any personal 
189 
legal rights you may have as a participant in this study. 
190 
 
191 
You will be provided with any new information that develops during the course of the 
192 
research that may affect your decision whether or not to continue participation in the 
193 
study. 
194 
 
195 
You may refuse to participate in this study without penalty or loss of benefits to which 
196 
you are otherwise entitled. 
197 
 
198 
An Institutional Review Board responsible for human subjects research at The Ohio State 
199 
University reviewed this research project and found it to be acceptable, according to 
200 
applicable state and federal regulations and University policies designed to protect the 
201 
rights and welfare of participants in research. 
202 
 
203 
14.  HIPAA AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR 
204 
       RESEARCH PURPOSES  
205 
 
206 
I. What information may be used and given to others? 
207 
 
208 
 Past and present medical records; 
209 
 Research records; 
210 
 Records about phone calls made as part of this research; 
211 
 Records about your study visits; 
212 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014H0262 
IRB Approval date:  11/15/2017 
Version:  6 
 
 
Page 6 of 9 
Form date: 02/10/12  
 
 Information that includes personal identifiers, such as your name, or a number 
213 
associated with you as an individual; 
214 
 Records about any study drug you received; 
215 
 
216 
II. Who may use and give out information about you? 
217 
 
218 
Researchers and study staff.   
219 
 
220 
III. Who might get this information? 
221 
 
222 
 The sponsor of this research.  “Sponsor” means any persons or companies that are: 
223 
 working for or with the sponsor; or  
224 
 owned by the sponsor. 
225 
 Authorized Ohio State University staff not involved in the study may be aware that 
226 
you are participating in a research study and have access to your information; 
227 
 If this study is related to your medical care, your study-related information may be 
228 
placed in your permanent hospital, clinic or physician’s office record; 
229 
 
230 
IV. Your information may be given to: 
231 
  
232 
 The U.S. Food and Drug Administration (FDA), Department of Health and Human 
233 
Services (DHHS) agencies, and other federal and state entities; 
234 
 Governmental agencies in other countries; 
235 
 Governmental agencies to whom certain diseases (reportable diseases) must be 
236 
reported; and  
237 
 The Ohio State University units involved in managing and approving the research 
238 
study including the Office of Research and the Office of Responsible Research 
239 
Practices. 
240 
 
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V. Why will this information be used and/or given to others? 
242 
 
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 To do the research;  
244 
 To study the results; and  
245 
 To make sure that the research was done right.   
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VI. When will my permission end? 
248 
 
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There is no date at which your permission ends. Your information will be used 
250 
indefinitely. This is because the information used and created during the study may be 
251 
analyzed for many years, and it is not possible to know when this will be complete. 
252 
 
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VII. May I withdraw or revoke (cancel) my permission? 
254 
 
255 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014H0262 
IRB Approval date:  11/15/2017 
Version:  6 
 
 
Page 7 of 9 
Form date: 02/10/12  
 
Yes. Your authorization will be good for the time period indicated above unless you 
256 
change your mind and revoke it in writing. You may withdraw or take away your 
257 
permission to use and disclose your health information at any time. You do this by 
258 
sending written notice to the researchers. If you withdraw your permission, you will not 
259 
be able to stay in this study. When you withdraw your permission, no new health 
260 
information identifying you will be gathered after that date. Information that has already 
261 
been gathered may still be used and given to others. 
262 
 
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VIII. What if I decide not to give permission to use and give out my health 
264 
information? 
265 
 
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Then you will not be able to be in this research study and receive research-related 
267 
treatment.  However, if you are being treated as a patient here, you will still be able to 
268 
receive care. 
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270 
IX. Is my health information protected after it has been given to others? 
271 
 
272 
There is a risk that your information will be given to others without your permission. Any 
273 
information that is shared may no longer be protected by federal privacy rules. 
274 
 
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X. May I review or copy my information? 
276 
 
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Signing this authorization also means that you may not be able to see or copy your study-
278 
related information until the study is completed.   
279 
 
280 
 
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15. Who can answer my questions about the study? 
282 
For questions, concerns, or complaints about the study you may contact the coordinator 
283 
for the study Melanie Heinlein at 614-293-5176. 
284 
 
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For questions related to your privacy rights under HIPAA or related to this research 
286 
authorization, please contact HIPPA Privacy Officer, Suite E2140, 600 Ackerman Road, 
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Columbus, Ohio 43202, or by phone at 614-293-4477. 
288 
 
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For questions about your rights as a participant in this study or to discuss other study-
290 
related concerns or complaints with someone who is not part of the research team, you 
291 
may contact Ms. Sandra Meadows in the Office of Responsible Research Practices at 1-
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800-678-6251. 
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If you are injured as a result of participating in this study or for questions about a study-
295 
related injury, you may contact Dr. Tzu-Fei Wang at 614-293-9441. 
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CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014H0262 
IRB Approval date:  11/15/2017 
Version:  6 
 
 
Page 8 of 9 
Form date: 02/10/12  
 
 
300 
 
301 
 
302 
 
  
 
 
 
                Signing the consent form 
303 
 
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I have read (or someone has read to me) this form and I am aware that I am being asked to 
305 
participate in a research study.  I have had the opportunity to ask questions and have had them 
306 
answered to my satisfaction.  I voluntarily agree to participate in this study.  
307 
 
308 
I am not giving up any legal rights by signing this form.  I will be given a copy of this form. 
309 
 
310 
 
 
 
 
Printed name of subject 
 
Signature of subject 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
 
 
 
 
Printed name of person authorized to consent for subject 
(when applicable) 
 
Signature of person authorized to consent for subject  
(when applicable) 
 
 
 
 
 
AM/PM 
Relationship to the subject 
 
Date and time 
 
 
311 
 
312 
 
313 
Investigator/Research Staff 
314 
 
315 
I have explained the research to the participant or his/her representative before requesting the 
316 
signature(s) above.  There are no blanks in this document.  A copy of this form has been given 
317 
to the participant or his/her representative. 
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319 
 
 
 
 
Printed name of person obtaining consent 
 
Signature of person obtaining consent 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
320 
Witness(es) - May be left blank if not required by the IRB 
321 
 
322 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014H0262 
IRB Approval date:  11/15/2017 
Version:  6 
 
 
Page 9 of 9 
Form date: 02/10/12  
 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
323