Clinical trial NCT02706249
Conditions: Venous Thormboembolism
Sponsor: Dana-Farber Cancer Institute
Start date: 2016-04-01; Completion date: 2021-06-07
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Hospitalized patients with histologically or cytologically confirmed diagnosis of solid tumor malignancy, lymphoma, or multiple myeloma and who are at high risk for a venous thromboembolism will be randomized to standard dose versus intermediate dose enoxaparin.

Detailed description:
In a phase II trial, high risk hospitalized cancer patients will be enrolled and randomized to standard dose enoxaparin versus intermediate dose (weight adjusted) enoxaparin thromboprophylaxis. Study subjects will be administered enoxaparin during hospitalization in a double-blinded manner. Following completion of 14 days, the study arms will be unblinded and lower extremity ultrasound performed on the standard dose enoxaparin arm in order to more accurately determine the overall cumulative incidence of thrombosis in this group.

Arms: arm 1: Participants will receive Enoxaparin 40 mg subcutaneously once daily. On study Enoxaparin will be administered for up 14 days during hospitalization.

After the day 14 assessment, treatment arms will be un-blinded in order to appropriately schedule a bilateral lower extremity ultrasound for participants enrolled onto Arm A at day 17. arm 2: Participants will receive Enoxaparin at 1mg/kg subcutaneously once daily with maximum dose of 100 mg daily. Participants who weigh more than 100kg will be capped at 100mg.

On study Enoxaparin will be administered for up 14 days during hospitalization.
Interventions: intervention 1: Enoxaparin
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
DF/HCC Protocol #: 15-547 
 
DF/HCC Biomedical Protocol Template: August 28, 2018 
 
 
TITLE: A randomized, phase II study of weight-based versus standard dose enoxaparin 
thromboprophylaxis in high-risk hospitalized cancer patients.  
 
 
Coordinating Center: 
Beth Israel Deaconess Medical Center 
 
*Principal Investigator (PI):      Jeffrey Zwicker, M.D. 
 
Beth Israel Deaconess Medical Center 
 
330 Brookline Ave, Boston, MA 02215 
 
jzwicker@bidmc.harvard.edu 
 
Other Investigators:  
Alok Khorana, M.D. 
 
Cleveland Clinic Foundation 
 
Khorana@ccf.org 
 
 
 
Study is Exempt from IND Requirements per 21 CFR 312.2(b).   
 
 
Protocol Type / Version # / Version Date: 
#8/08.28.18  


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SCHEMA 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................5 
1.1 
Study Design ............................................................................................................5 
1.2 
Primary Objectives...................................................................................................5 
1.3 
Secondary Objectives............................................. Error! Bookmark not defined. 
2. 
BACKGROUND .................................................................................................................5 
2.1 
Study Disease(s).......................................................................................................5 
2.2 
Study Agent (Enoxaparin) .......................................................................................6 
2.3 
Rationale ..................................................................................................................7 
2.4 
Correlative Studies Background ..............................................................................8 
3. 
PARTICIPANT SELECTION .............................................................................................9 
3.1 
Eligibility Criteria ....................................................................................................9 
3.2 
Exclusion Criteria ....................................................................................................9 
3.3 
Inclusion of Women and Minorities ......................................................................10 
4. 
REGISTRATION PROCEDURES ...................................................................................10 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...................................10 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................11 
4.3 
General Guidelines for Other Investigative Sites ..................................................11 
4.4 
Registration Process for Other Investigative Sites.................................................12 
5. 
TREATMENT PLAN ........................................................................................................12 
5.1 
Treatment Regimen ................................................................................................12 
5.2 
Pre-Treatment Criteria ...........................................................................................13 
5.3 
Off treatment procedures (unblinding) ..................................................................13 
5.4 
Agent Administration.............................................................................................14 
5.5 
General Concomitant Medication and Supportive Care Guidelines ......................14 
5.6 
Criteria for Taking a Participant Off Protocol Therapy .........................................14 
5.7 
Duration of Follow Up ...........................................................................................15 
5.8 
Criteria for Taking a Participant Off Study ...........................................................15 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................15 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................17 
7.1 
Definitions .............................................................................................................17 
7.2 
Expected Toxicities ................................................................................................18 
7.3 
Adverse Event Characteristics ...............................................................................19 
7.4 
Expedited Adverse Event Reporting ......................................................................20 
7.5 
Reporting to NHLBI ..............................................................................................20 
7.6 
Expedited Reporting to Hospital Risk Management .............................................21 
7.7 
Routine Adverse Event Reporting .........................................................................21 


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8. 
PHARMACEUTICAL INFORMATION ..........................................................................21 
8.1 
Enoxaparin .............................................................................................................21 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................22 
9.1 
Biomarker Studies ..................................................................................................23 
9.2 
Laboratory Correlative Studies ..............................................................................23 
10. 
STUDY CALENDAR .......................................................................................................25 
11. 
MEASUREMENT OF EFFECT........................................................................................26 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................27 
12.1 
Data Reporting .......................................................................................................27 
12.2 
Data Safety Monitoring..........................................................................................27 
12.3 
Multicenter Guidelines...........................................................................................27 
12.4 
Collaborative Agreements Language:....................................................................28 
N/A 
28 
13. 
STATISTICAL CONSIDERATIONS...............................................................................28 
13.1 
Study Design/Endpoints.........................................................................................28 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................28 
13.3 
Stratification Factors ..............................................................................................29 
13.4 
Interim Monitoring Plan ........................................................................................29 
13.5 
Analysis of Primary Endpoints ..............................................................................29 
13.6 
Analysis of Secondary Endpoints ..........................................................................30 
13.7 
Reporting and Exclusions ......................................................................................31 
14. 
PUBLICATION PLAN .....................................................................................................31 
REFERENCES ..............................................................................................................................32 
15. 
APPENDIX A PERFORMANCE STATUS CRITERIA ..................................................35 
16. 
Appendix B: Specimen Collection Instruction and Shipping Report ................................36 
 
 


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1. OBJECTIVES 
 
 
1.1 
Study Design 
 
This is a 2-arm, randomized, double-blinded multi-center phase II trial to estimate the 
cumulative incidence of venous thromboembolic events (VTE) and major hemorrhage in 
hospitalized cancer patients receiving enoxaparin thromboprophylaxis. Hospitalized cancer 
patients considered to be at high risk of thrombosis (based on malignancy diagnosis and Padua 
risk factors) will be randomized to standard dose enoxaparin daily versus weight-adjusted 
enoxaparin daily for up to 14 days.  
 
1.2 
Primary Objectives 
 The primary objectives of the study are to estimate the cumulative incidence of VTE and 
major hemorrhage in hospitalized cancer patients receiving standard dose or weight-
adjusted enoxaparin.  
 
1.3 
Exploratory Objectives 
 Compare rates of symptomatic VTE between enoxaparin arms at day 14 
 Evaluate the performance of clinical scoring models (ie. Padua, IMPROVE, and Khorana 
Score) in predicting thrombotic risk in hospitalized cancer patients  
 Assess the prognostic value of biomarkers (e.g. D-dimer and microparticles) to predict 
thrombosis in hospitalized cancer patients  
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Venous thromboembolism is estimated to account for up to 5% of all deaths during 
hospitalization.[1] Recognizing the burden on healthcare and the preventable nature of venous 
thromboembolic events during hospitalization, U.S. Government agencies are working to 
improve the rates of prescribed thromboprophylaxis. The Agency for Healthcare Research and 
Quality identified thromboprophylaxis as the number one patient safety practice[2], the Surgeon 
General issued a Call to Action[3], and the Centers for Medicare & Medicaid Services is 
targeting hospital thromboprophylaxis in a national health-care quality initiative. Major 
professional organizations including the American Society of Clinical Oncology, National 
Comprehensive Cancer Network, American College of Chest Physicians, and European Society 
of Medical Oncology have all issued strong recommendations for the prescription of 
pharmacologic thromboprophylaxis of hospitalized cancer patients.[4-7] And yet, despite the 
association between cancer-thrombosis and increased in-hospital cancer mortality, the absolute 
benefit, toxicity and even appropriate dosing of routine thromboprophylaxis in cancer patients is 
unknown. In the three phase III registration trials comparing low molecular weight heparins with 
placebo in hospitalized medical patients, only 6% of patients carried a diagnosis of cancer and 
there was no statistical benefit for thromboprophylaxis in the subgroup analysis of cancer 
patients included in these trials.[8] This phase II trial will establish point estimates on the risk of 


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VTE and hemorrhage in preparation for a planned phase III clinical trial to assess the risks and 
benefits of anticoagulation in cancer patients at increased risk for thrombosis.  
 
Risk factors for thrombosis in hospitalized cancer patients    
In analysis of a large hospital discharge database that included over 1 million cancer patients, the 
overall incidence of venous thromboembolic events (VTE) was 4.1% per hospitalization with 
considerable variation according to presence of concomitant thrombotic risk factors.[9]  For 
instance, in 26,118 patients with pancreatic cancer the rate of VTE was 8.1% per hospitalization 
whereas the rate was 1.4% in the 50,898 patients with head and neck malignancy. Other higher 
risk tumors included ovary (5.6% rate of VTE), lung (5.1%), stomach (4.9%), and non-Hodgkin 
lymphoma (4.6%). Independent risk factors for thrombosis during hospitalization included 
primary site of cancer, age, chemotherapy, and comorbidities (e.g. infection, pulmonary, renal 
disease).  
 
Prediction models have been developed to identify which populations of hospitalized patients are 
at highest risk of thrombosis but these have not been specifically developed for hospitalized 
cancer populations. In the widely cited Padua Prediction Score, independent risk factors for VTE 
include cancer, prior history of VTE, reduced mobility, hereditary thrombophilia, recent surgery 
or trauma, obesity, elderly, and comorbidities (e.g. infection, acute coronary syndrome, 
respiratory failure).[10] Among the 659 low risk patients (Padua Score of <4) not receiving 
pharmacologic thromboprophylaxis, only one patient (0.2%) was diagnosed with VTE during 
hospitalization. By comparison, the rate of thrombosis was 7.5% among the 469 high-risk 
patients (Padua Score > 4).  
 
Risk-benefit assessment for thromboprophylaxis for hospitalized cancer patients 
In a recent systematic review and meta-analysis of cancer patients enrolled in randomized phase 
III clinical trials.[8] Only 307 cancer patients were enrolled among the three major registration 
clinical trials involving low molecular weight heparins (or fondaparinux) versus placebo. The 
pooled relative risk of VTE was 0.91 (95% CI, 0.21-4.0) with two trials demonstrating a non-
significant reduction of thrombosis in cancer patients while the third trial demonstrated a 
statistically significant increase in thrombosis in patients receiving thrombopropylaxis with 
fondaparinux. Fondaparinux has been shown previously in randomized clinical trials to prevent 
thrombosis following cancer surgery and thus these results are unlikely to point simply to the 
ineffectiveness of a single thromboprophylactic agent. In all studies the incidence of thrombosis 
was higher in the cancer subgroup receiving thromboprophylaxis compared with non-cancer 
patients. It is evident that anywhere from 1 in 5 to 1 in 20 hospitalized cancer patients are 
diagnosed with VTE despite receiving recommended thromboprophylaxis.  
 
2.2 
Study Agent (Enoxaparin) 
 
Enoxaparin is a low molecular weight heparin with antithrombotic properties approved by the 
Federal Drug Administration for prevention of deep vein thrombosis following abdominal or 
orthopedic surgery and in medical patients with restricted mobility during acute illness. 
 
Enoxaparin administered subcutaneously achieves steady-state activity levels predicted by 
single-dose pharmacokinetics. After repeated subcutaneous administration of 40mg once daily, 


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the steady state is reached on day 2 with an average exposure ratio of 15% higher than after a 
single dose. Enoxaparin is primarily metabolized in the liver by desulfation and/or 
depolymerization to lower molecular weight species with much reduced biological potency. 
Renal clearance of active fragments represents about 10% of the administered dose and total 
renal excretion of active and non-active fragments 40% of the dose. In the elderly, the apparent 
clearance of enoxaparin following multiple subcutaneous doses is similar to younger subjects. A 
linear relationship exists between activity and creatinine clearance.  
 
Standard dose enoxaparin for thromboprophylaxis in medical patients:  
In a double blind multicenter parallel group study, enoxaparin at 20mg or 40mg once a day for 
14 days was compared to placebo in medical patients with severely restricted mobility.[11] 
Patients were enrolled with the following diagnosis: congestive heart failure (NYHA class III or 
IV), acute respiratory failure or complicated chronic respiratory insufficiency, acute infection, or 
acute rheumatic disorder. A total of 1073 patients were treated on the study for a maximum of 14 
days (median 7 days). Enoxaparin administered at 40mg once daily was associated with a 
significant reduction in thromboembolic events compared with placebo (5.5 vs 14.9, P<.001). 
The lower (20mg) dose of enoxaparin was not associated with a reduction in thromboembolic 
events (12.2%). Enoxaparin (40mg) was well tolerated with 6 of 360 patients suffering a major 
hemorrhagic event compared with 4 of 362 treated with placebo. There were 8 cases of 
thrombocytopenia in the placebo group and 2 in the enoxaparin (40mg) treated group. There 
were no significant differences in the groups for any other adverse outcomes.    
 
Modified dose enoxaparin thromboprophylaxis in cancer patients.  
The pharmacokinetic profile of low molecular weight heparins are known to be dependent on 
body weight.[12] Compared with fixed dose enoxaparin at 40mg, weight adjusted dose of 
enoxaparin of 1mg/kg yields significantly greater peak anti-Xa activity, anti-IIa activity and 
inhibition of thrombin generation.[12, 13]   Notably, there is randomized trial data to support the 
safety and efficacy of enoxaparin at 1mg/kg daily for thromboprophylaxis in cancer patients. The 
CONKO-004 trial randomized over 300 patients with advanced pancreatic cancer to 
chemotherapy alone or chemotherapy with enoxaparin 1mg/kg daily for 3 months. At 3 months, 
they observed an approximate 85% risk reduction in the incidence of VTE in the arm 
randomized to intermediate dose enoxaparin (P=0.001) without an increase in major hemorrhage 
(P=1.0).[14] 
 
2.3 
Rationale 
 
Based on the available evidence, it is apparent that an accurate assessment of risk versus benefit 
for primary thromboprophylaxis of hospitalized cancer patients is not possible. It is also evident 
that hospitalized cancer patients commonly receive pharmacologic thromboprophylaxis without 
attention to the presence or absence of thrombotic risk factors. In highest risk cancer patients, 
current pharmacologic regimens are inadequate with as many as 20% patients suffering from 
thromboembolic events. The principle goals of this phase II clinical trial are to establish a more 
accurate point estimate of rate of VTE in high risk cancer patients receiving standard, fixed-dose 
low molecular weight heparin thromboprophylaxis and to develop a point estimate of 
hemorrhage using intermediate-dose enoxaparin prophylaxis in higher risk patients. 
 


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2.4 
Correlative Studies Background 
 
Evaluation of Padua, IMPROVE, and Khorana risk models in hospitalized cancer patients.  
Published risk models have been developed to identify a collective group of risk factors that 
identify patient populations considered to be at sufficiently high risk of thrombosis to warrant 
thromboprophylaxis. The IMPROVE scoring model was developed using a database of 15,000 
patients from 12 countries.  A multiple regression analysis identified independent risk factors for 
VTE in acutely ill hospitalized medical patients.[15] The incidence of thrombosis following 
hospitalization was 11% in patients with IMPROVE scores >5. The four independent risk factors 
at admission comprising the scoring model are: previous history of VTE (3 points), known 
thrombophilia (3 points), age>60 years (1 point), and cancer (1 point). The Khorana score was 
developed for cancer outpatients receiving chemotherapy. Abnormal pre-chemotherapy complete 
blood count indices (white blood cell > 11x109/L, hemoglobin < 10 g/dL, and/or platelet count > 
350x109/L) are independently associated with thrombosis in cancer outpatients and are elements 
of the Khorana risk score.[16-18] In order to evaluate the performance of the Khorana score in 
predicting thrombotic risk for hospitalized cancer patients, we will calculate the Khorana score 
utilizing laboratory data (e.g. blood counts) upon admission. The Khorana score will be 
calculated for all patients following completion of the study during the data analysis phase. As 
this scoring system was not specifically developed for cancer patients, we will explore whether 
improved specificity can be achieved while retaining sensitivity to identify patients at greatest 
risk for VTE.  
 
Microparticles and risk of thrombosis in cancer patients. 
Microparticles are vesicular structures measuring less than 1m in size and are derived from a 
number of cells within the vascular compartment including leukocytes, platelets, red blood cells, 
and endothelial cells.[19] Initial interest in exploring the association between tissue factor 
bearing microparticles and thrombosis was based on observations that tissue factor bearing 
microparticles bind to a developing thrombus and play a role in fibrin propagation in vivo.[20] 
Utilizing an impedance-based flow cytometer specifically modified for microparticle 
measurement, we observed that tissue factor bearing microparticles are elevated in cancer 
patients diagnosed with VTE (adjusted OR 3.72, P=0.01) and appear to be derived from the 
underlying tumor.[21] The association between tissue factor bearing microparticles and cancer 
associated thrombosis has now been reported by several groups, including in a mouse model of 
vascular injury.[22-25] A randomized, multi-center phase II clinical trial (MicroTEC Trial) 
substantiated the prognostic role of tissue factor bearing microparticles and VTE in cancer 
patients.[26] The cumulative incidence of VTE in cancer patients with elevated tissue factor 
bearing microparticles randomized to observation was 27% compared with 5%  in those 
receiving enoxaparin (Gray’s test P=0.06) while 7.2% of those cancer patients with low levels of 
tissue factor bearing microparticles were diagnosed with VTE without thromboprophylaxis. 
Notably, the cumulative incidence of VTE was 43% at 2 month in patients with both elevated 
levels of D-dimer and tissue factor bearing microparticles compared with 4.2% for all other 
study subjects (Gray’s test P value = 0.0001).[26] Planned correlative studies include the 
measurement of tissue factor bearing microparticles as well as the population of tissue factor 
bearing microparticles co-expressing P-selectin glycoprotein 1(PSGL-1).   
 


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3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Participants must have histologically or cytologically confirmed diagnosis of solid tumor 
malignancy, lymphoma, or multiple myeloma 
 
3.1.2 Cancer diagnosis or received treatment (chemotherapy or radiotherapy) for malignancy 
within the previous 6 months 
 
3.1.3 One or more Padua-based risk factor: 
 
History of previous venous thromboembolic event (excluding superficial vein 
thrombosis) 
 
Reduced mobility (ECOG performance status 3 or 4, see Appendix A) 
 
Established hereditary thrombophilia (e.g. Factor V Leiden, G20210 
prothrombin mutation, protein C or S deficiency, antithrombin deficiency). 
 
Recent surgery within the last 30 days 
 
Age > 70 years 
 Congestive heart failure (NYHA class III or IV) 
 Complicated respiratory insufficiency (defined as an increased requirement 
for supplementary oxygen of at least 2L) 
 
Acute myocardial infarction or ischemic stroke 
 
Obesity (BMI > 30) 
 
Receiving hormonal agents (e.g. tamoxifen, estrogen, testosterone) 
 
Acute infection (i.e. requiring antimicrobial therapy) 
 
3.1.4 Age > 18 years 
  
3.1.5 Life expectancy of greater than 30 days 
 
3.1.6 Platelet count > 100,000/mcL 
 
3.1.7 Creatinine < 1.5 mg/dL or estimated creatinine clearance > 50 mL/min/1.73 m2 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent document 
 
3.1.9 Weight between 50kg to 130 kg. 
 
 
3.2 
Exclusion Criteria 
 
 
3.2.1 History of allergic reactions attributed to heparin or low molecular weight heparin 
 


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3.2.2 Active bleeding or otherwise considered high risk for hemorrhage (e.g. known acute 
gastrointestinal ulcer) 
 
3.2.3 Any history of significant hemorrhage (requiring hospitalization or transfusion) within 
the last 6 months (excluding hemorrhage during operative procedure). 
 
3.2.4 History of heparin induced thrombocytopenia 
 
3.2.5 Presence of coagulopathy (PT or PTT> 1.2 x upper limit of normal) 
 
3.2.6 Known diagnosis of disseminated intravascular coagulation 
 
3.2.7 Currently receiving therapeutic anticoagulant therapy or dual antiplatelet therapy (eg. 
aspirin and clopidogrel) 
 
3.2.8 Uncontrolled arterial hypertension (systolic blood pressure > 200mmHg, diastolic 
>110mmHg) 
 
3.2.9 Active peptic ulcer disease 
 
3.2.10 Bacterial endocardititis 
 
3.2.11 Received any type of pharmacologic thromboprophylaxis (e.g. low molecular weight 
heparin or heparin) for >48 hours during current hospitalization 
 
3.2.12 Known brain metastases 
 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
 
4. REGISTRATION PROCEDURES 
 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. Registrations must occur prior to the 
initiation of protocol therapy. Any participant not registered to the protocol before protocol 
therapy begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
QACT protocol-specific eligibility checklist. 


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Following registration, QACT office will perform randomization to Arm A or Arm B of 
enoxaparin. Randomization arm will be communicated directly through QACT to the research 
pharmacy at Beth Israel Deaconess Medical Center. For participants enrolled at Cleveland 
Clinic, a representative from the BIDMC Research Pharmacy will forward the randomization 
assignment to the dedicated contact at the Cleveland Clinic Research Pharmacy. 
 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If a participant does not receive protocol therapy following registration, the 
participant’s registration on the study must be canceled. Notify the QACT Registrar of 
registration cancellations as soon as possible.  
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time.  
 
The registration procedures are as follows: 
 
 Obtain written informed consent from the participant prior to the performance of any 
protocol specific procedures or assessments.  
 
 Complete the QACT protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical record and/or research chart. To be 
eligible for registration to the protocol, the participant must meet all inclusion and 
exclusion criterion as described in the protocol and reflected on the eligibility 
checklist. 
 
 Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at xxx-
xxx-xxxx. For Phase I protocols, attach participant dose level assignment confirmation 
from the sponsor. 
 
 The QACT Registrar will (a) review the eligibility checklist, (b) register the participant 
on the protocol, and (c) randomize the participant when applicable. 
 
 An email confirmation of the registration and/or randomization will be sent to the Overall 
PI, research pharmacy, study coordinator(s) from the Lead Site, treating investigator and 
registering person immediately following the registration and/or randomization. 
 
4.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at Beth Israel Deaconess Medical Center 
by the Study Coordinator.   
 
Following registration, participants should begin protocol therapy within 24 hours. Issues that 
would cause treatment delays should be discussed with the Overall PI.  If a participant does not 


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receive protocol therapy following registration, the participant’s registration on the study must be 
canceled and they will be replaced.  The Study Coordinator should be notified of cancellations as 
soon as possible. 
 
4.4 
Registration Process for Other Investigative Sites 
 
To register a participant, the following documents should be completed by the research nurse or 
data manager and sent to:: 
 Copy of eligibility documentation 
 Signed eligibility and consent physician note 
 Signed participant consent form 
 HIPAA authorization form 
 Eligibility Checklist  
 
The research nurse or data manager at the participating site will then call xxx-xxx-xxxx or e-mail 
to verify eligibility.  To complete the registration process, the Coordinator will 
 register the participant on the protocol with the QACT 
 fax or e-mail the participant study number, and if applicable the dose treatment level 
to the participating site 
 call the research nurse or data manager at the participating site and verbally confirm 
registration 
 
NOTE: Registration and randomization with the QACT can only be conducted during the 
business hours of 8:00 AM and 5:00 PM Eastern Standard Time Monday through Friday. 
Same day treatment registrations will only be accepted with prior notice and discussion with the 
DF/HCC Lead Institution.  
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
Treatment Overview: 
 
Eligible participants will be randomized to standard dose enoxaparin at 40 mg once daily (Arm 
A) versus weight-based enoxaparin at 1 mg/kg once daily (Arm B). On study enoxaparin will be 
administered for up 14 days during hospitalization. Physicians and participants will be double-
blinded to enoxaparin dosing during hospitalization (or up to 14 days). After the day 14 
assessment, treatment arms will be un-blinded in order to appropriately schedule a bilateral lower 
extremity ultrasound for participants enrolled onto Arm A at day 17.  
 
Note that patients who are discharged and re-admitted prior to day 14 will resume study 
procedures and enoxaparin administration per initial randomization. 
 
 
 
Arm A: 


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Participants will receive enoxaparin 40 mg subcutaneously once daily.  
 
Arm B: 
Participants will receive enoxaparin at 1mg/kg subcutaneously once daily with maximum dose of 
100 mg daily. Participants who weigh more than 100kg will be capped at 100mg.  
 
Participants who receive at least one dose of treatment post-randomization will be considered 
evaluable for the study. 
 
5.2 
Pre-Treatment Criteria 
 
In order to proceed with day 1 administration of enoxaparin, platelet count must be > 50,000/l 
and CrCl must be >/= 50 ml/min. All other laboratory assessments performed within 48 hours of 
enrollment may be used to determine eligibility and do not need to be repeated.  
 
5.2.1 
Cycle 1, Day 1 
Enoxaparin syringe will be dispensed by research pharmacy. Baseline assessments for symptoms 
of VTE or hemorrhage will be recorded. All doses of enoxaparin will be recorded along with 
time of administration. 
 
5.2.2 
Day 7 + 1 days 
Enoxaparin will be ordered on a daily basis and study labs will be continued for those study 
subjects who remain hospitalized. Assessment for evidence of major hemorrhage or VTE will be 
recorded by study staff if the participant remains hospitalized. 
 
5.2.3 
Day 14 -4, + 7 days 
Enoxaparin should be continued until either hospital discharge or day 14. After receiving the 
final dose of enoxaparin no additional doses of enoxaparin on study will be administered.  
Assessment for evidence of major hemorrhage or VTE will be recorded. After the day 14 clinical 
assessment, study staff will become unblinded to treatment allocation in order to appropriately 
schedule a bilateral lower extremity ultrasound for study subjects on Arm A (see 5.3 below). For 
participants who remain hospitalized, study subjects should continue with standard 
pharmacologic thromboprophylaxis per the discretion of the treating physician. Day 14 symptom 
assessment can be performed by phone. 
 
   
5.3 
Off treatment procedures (unblinding) 
 
Following the completion of the day 14 assessment, study staff will contact a clinical research 
pharmacist at BIDMC. Criteria for off treatment will be reviewed and then the study staff will be 
informed as to whether the participant was previously assigned to Arm A (standard enoxaparin) 
versus Arm B (weight-based enoxaparin). For participants randomized to Arm A, a bilateral 
ultrasound will be scheduled (see study calendar) to evaluate for asymptomatic deep vein 
thrombosis.  
 
 


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5.4 
Agent Administration 
 
The concentration of enoxaparin is 100 mg/ml. All enoxaparin doses will be diluted to 1 ml final 
volume such that neither the healthcare providers nor the participant are readily able to identify 
dosage.  Subcutaneous enoxaparin administration may be alternated between the left and right 
anterolateral and left and right posterolateral abdominal wall once daily. 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
The use of growth factors will be recorded. Subject must be taken off protocol if requires 
therapeutic anticoagulation or dual antiplatelet agents (eg. aspirin and clopidrogel)  
 
5.6 
Criteria for Taking a Participant Off Protocol Therapy 
 
 
Cessation of enoxaparin and withdrawal from the study is mandated for the following reasons: 
 
 
Grade 3 or 4 hemorrhage and/or 
 
Symptomatic hemorrhage in a critical area or organ such as intracranial, 
intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or 
intramuscular with compartment syndrome, and/or hemorrhage causing an acute 
fall in hemoglobin > 2g/L or hemorrhage leading to a transfusion of > 2 units of 
packed red blood cells. 
 
 
Development of confirmed heparin induced thrombocytopenia 
 
 
Proximal deep vein thrombosis or pulmonary embolism 
 
 
Condition requiring therapeutic anticoagulation or dual antiplatelet therapy 
 
 
Renal failure (see section 6) 
 
 
Participant decides to withdraw from the protocol therapy 
 
 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the QACT website or obtained from the QACT 
registration staff. 
 


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15 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI:  
 
 
5.7 
Duration of Follow Up 
 
Participants will be followed until last scheduled protocol visit.  Participants removed from 
protocol therapy for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event. Participants who have ongoing related adverse events at the 
last visit will be followed until resolution of those adverse events. 
 
5.8 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
 Lost to follow-up 
 Withdrawal of consent for data submission 
 Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the QACT website or obtained from the QACT registration staff.  
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
 
 
Renal Failure 
 
CrCl (ml/min) 
Arm A (standard enoxaparin) 
Arm B (adjusted dose enoxaparin) 
>40 
No change 
No change 
30-40 
No change 
DECREASE to 40 mg daily 
<30 
HOLD 
HOLD 
 
 
Creatinine will be monitored at each study visit and as part of routine medical care. Enoxaparin 


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16 
will be held for acute renal failure (CrCl <30ml/min) diagnosed at any point during the study.  
 
Enoxaparin should be resumed when CrCl improves to > 40ml/min.  
 
The CrCl can be estimated by either the Modification of Diet in Renal Disease (MDRD) which 
can be found at http://www.kidney.org/professionals/KLS/gfr_calculator.cfm 
or Crockcroft-Gault equation (below) 
 
Men: 
(140 - age)  x  body weight [kg]  
CrCr (mL/min)    =    ————————— 
                                       Cr [mg/dL]  x  72 
 
Women: CrCl (mL/min) = CrCl (as above) * 0.85 
 
Thrombocytopenia 
 
Platelet Count 
Arm A (standard enoxaparin) 
Arm B (adjusted dose enoxaparin) 
 
<100,000/l and 
>50,000/l 
(CTCAE Grade 1 or 2) 
 
No change 
DECREASE to 40mg daily  
 
<50,000/l 
(CTCAE Grade 3 or 4) 
 
HOLD 
HOLD 
 
Platelet count will be monitored at least weekly and as part of routine medical care. At any point 
the platelet count is <50,000/l, then enoxaparin must be held. Enoxaparin should be resumed at 
when the platelet count is above 50,000/l. If heparin induced thrombocytopenia is diagnosed 
then enoxaparin is to be discontinued. 
 
Hemorrhage 
 
Hemorrhage 
Management/Next Dose for  
Arm A (standard enoxaparin) 
Management/Next Dose for  
Arm B (adjusted dose enoxaparin) 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold* until ≤ Grade 1.  Resume at 
same dose. 
Hold* until ≤ Grade 1.  Resume at 
same dose level. 
Grade 3 
Discontinue (off protocol therapy) 
Discontinue (off protocol therapy) 
Grade 4 
Discontinue (off protocol therapy) 
Discontinue (off protocol therapy) 
*Participants requiring a delay of >3 days should go off protocol therapy. 
 
 


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Planned Procedures 
 
Enoxaparin may be held for procedures and should be resumed at the discretion of treating 
physicians.  
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
 
7.1 Definitions 
 
Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition 
or experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is 
not considered to be related to the study. All related adverse events will be 
followed until resolution. 
 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
 Results in death 
 Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
 Prolongs inpatient hospitalization (i.e prolonged a hospitalization beyond 
the expected length of stay).  
 Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
 Is a congenital anomaly or birth defect; or 
 Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 


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18 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures elective or pre-planned 
treatment for a pre-existing condition that did not worsen. Emergency outpatient 
treatment for an event not fulfilling the serious criteria outlined above and not 
resulting in inpatient admission respite care. 
 
Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
Expected adverse event 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, an 
adverse event is considered expected when it appears in the current adverse event 
list or is included in the informed consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events associated with the 
study agent(s). 
Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected when it 
varies in nature, intensity or frequency from information provided in the current 
adverse event list or when it is not included in the informed consent document as 
a potential risk. 
   
7.2 
Expected Toxicities 
 
7.2.1 
Adverse Events List for enoxaparin 
 
Enoxaparin can be associated with an increased risk of hemorrhage including life 
threatening retroperitoneal, gastrointestinal, or intracranial hemorrhages. Cases of 
epidural or spinal hematomas have been reported with the associated use of 
enoxaparin and spinal/epidural anesthesia or spinal puncture resulting in long-term or 
permanent paralysis. The risk of these events is higher with the use of post-operative 
indwelling epidural catheters or by the concomitant use of additional drugs affecting 
hemostasis such as NSAIDs. The rate of major bleeding episodes following 
enoxaparin (40mg daily) in medical patients with severely restricted mobility during 


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acute illness was <1%.  
 
Thrombocytopenia can occur with the administration of enoxaparin. Moderate 
thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred 
at a rate of 1.3% in patients given enoxaparin, 1.2% in patients given heparin, and 
0.7% in patients given placebo in clinical trials. Platelet counts less than 50,000/mm3 
occurred at a rate of 0.1% in patients given enoxaparin, in 0.2% of patients given 
heparin, and 0.4% of patients given placebo in the same trials. Thrombocytopenia of 
any degree should be monitored closely. Cases of heparin-induced thrombocytopenia 
with thrombosis have also been observed in clinical practice. Some of these cases 
were complicated by organ infarction, limb ischemia, or death. 
 
Asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) 
aminotransferase levels greater than three times the upper limit of normal of the 
laboratory reference range have been reported in up to 6.1% and 5.9% of patients, 
respectively, during treatment with enoxaparin. Similar significant increases in 
aminotransferase levels have also been observed in patients and healthy volunteers 
treated with heparin and other low molecular weight heparins. Such elevations are 
fully reversible and are rarely associated with increases in bilirubin. 
 
Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow 
subcutaneous injection of enoxaparin. 
 
 
7.3 
Adverse Event Characteristics 
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 


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- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.4 
Expedited Adverse Event Reporting  
 
7.4.1 Investigators must report to the Overall PI any serious adverse event (SAE) attributed to 
heparin (definite, probable or possible) that occurs after the initial dose of study 
treatment, during treatment, or within 30 days of the last dose of treatment on the local 
institutional SAE form.  
 
7.4.2 For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting 
requirements set by the DF/HCC as defined below. This applies to any medical event 
equivalent to an unexpected grade 2 or 3 with a possible, probable or definite attribution, 
unexpected grade 4 toxicities, and grade 5 (death) regardless of study phase or 
attribution. 
 
7.4.3 
DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI 
Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
Other investigative sites will report SAEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional SAE form should be forwarded to the Overall PI within the timeframes 
detailed in the table below.  
 
 
 
 
 
Attribution 
DF/HCC Reportable AEs 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
Not required 
5 calendar daysb
24 hoursa 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hoursa 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
a For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 24 business hours of learning of the event. 
b Events that are due to underlying malignancy or its treatment do not need to be reported as SAE  
 
The Overall PI will submit SAE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events.  
 
 
7.5 
Reporting to NHLBI 
Adverse events and unanticipated problems will be reported by Dr. to NHLBI under the 


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following timelines: 
 
 Within 7 calendar days of initial receipt of information for fatal of life-
threatening unexpected, related serious adverse events.  
 Within 15 calendar days of initial receipt of information for non-life 
threatening unexpected, related SAE  
 Within 14 days of the investigator becoming aware of an unanticipated 
problem that is not an SAE 
 
7.6 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.7 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. Because of the established toxicity profile of enoxaparin, only 
attributable AE will need to be recorded. AEs reported through expedited processes (e.g., 
reported to the IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with enoxaparin administered in this 
study can be found in Section 7.1. 
 
 
8.1 
Enoxaparin 
 
8.1.1 
Description 
 
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester 
derived from porcine intestinal mucosa. Maximum anti-Factor Xa and anti-thrombin 
(anti-Factor Iia) activities occur 3 to 5 hours after subcutaneous injection. Mean absolute 
bioavailability of enoxaparin, after 1.5 mg/kg given subcutaneously, based on anti-Factor 
Xa activity is approximately 100% in healthy subjects. After repeated subcutaneous 
administration of 40 mg once daily, the steady state is reached on day 2 with an average 
exposure ratio about 15% higher than after a single dose. Steady-state enoxaparin activity 
levels are well predicted by single-dose pharmacokinetics. Following subcutaneous 
dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min of 
enoxaparin. Enoxaparin is primarily metabolized in the liver by desulfation and/or 
depolymerization to lower molecular weight species with much reduced biological 
potency. Total renal excretion of active and non-active fragments represents 40% of the 
dose. 
 


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8.1.2 
Form 
 
Enoxaparin is manufactured for subcutaneous injection. Enoxaparin in solution is 
supplied at varying volumes and concentrations, e.g. 100mg/ml. Enoxaparin is available 
through various manufacturers and suppliers.  
 
8.1.3 
Storage and Stability 
 
Recommended storage is 25oC (77oF); excursions permitted to 15-30oC (59-86oF).. 
 
8.1.4 
Compatibility – Normal saline  
 
8.1.5 
Handling 
Care should be taken when handling needles.  
 
8.1.6 
Availability 
Enoxaparin is available from various manufacturers and will be purchased and prepared 
by the research pharmacy. Enoxaparin will be covered by the grant and provided free of 
charge. 
 
8.1.7 
Preparation 
The QACT office will inform the research pharmacy of treatment allocation (Arm A or 
Arm B). The research pharmacy will not be blinded to treatment arm. Appropriate dose 
of enoxaparin will be aliquoted into syringes and diluted to 1 ml in normal saline. The 
syringe should not list the enoxaparin dosage.  
 
8.1.8 
Administration 
 
Participants should be lying down and enoxaparin administered by subcutaneous 
injection into the abdominal wall on a once daily basis.  
 
8.1.9 
Ordering 
An order will be written and signed by an authorized provider.  
 
8.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.1.11 Destruction and Return 
Any unused study drug will be destroyed on site per standard operating procedures.  
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 


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23 
9.1 
Biomarker Studies 
 
We previously demonstrated the predictive value of circulating tissue factor bearing 
microparticles in cancer outpatients. We will evaluate if the number of tissue factor bearing 
microparticles upon hospitalization predicts thrombotic risk. Microparticles will be isolated from 
plasma by differential centrifugation. We modified an impedance-based flow cytometry system 
(Beckman Coulter SC Quanta) in order to address the shortcomings of standard light scatter 
based flow cytometry in the measurement of small (<1 m) particles.[21] Using this 
methodology we observed a significant correlation between elevation in tissue factor bearing 
microparticles and the development of cancer-associated thrombosis.[21, 26]  
 
Based on animal models suggesting that tumor derived tissue factor bearing microparticles 
accumulate at the site of a developing thrombus through the binding of PSGL-1 with P-selectin, 
we will evaluate whether subpopulations of TF-bearing microparticles are associated with 
thrombosis in hospitalized cancer patients. By flow cytometry, we will determine the percentage 
of TF-bearing microparticles co-expressing the PSGL-1, MUC1, and/or CD14 antigens.  
 
D-dimer is a degradation product of cross-linked fibrin and is the most widely utilized sensitive 
biomarker to exclude venous thromboembolic events.[27, 28] Utility of D-dimer alone to predict 
thrombosis in cancer patients is limited due to poor specificity especially using standard cut-
offs.[29] D-dimer will be measured by using a commercially available immunoassay (Roche 
Diagnostics). We will analyze the association between thrombosis and elevated D-dimer values 
based on standard cutoff of >500ng/L, 75th percentile based on measurements using stored 
plasma from cancer patients[21, 29] or age adjusted-cutoff which was recently demonstrated to 
improve assay specificity in a large cohort of patients (including 429 patients with active 
malignancy).[28] In order not to confound study outcomes, D-Dimer measurements will be 
performed centrally at BIDMC after the completion of the trial and will not be recorded in the 
participant’s medical record. 
  
 
 
9.2 
Laboratory Correlative Studies 
 
9.2.1 Microparticles and D-dimer 
 
9.2.1.1 
Collection of Specimen:  
Blood will be obtained by a non-traumatic venopuncture from peripheral veins or 
from a central venous catheter draws up to 48 hours prior to the first dose of 
treatment. A total of 10 ml will be drawn into blue top tubes (3.2% citrate) in either 
two 5ml tubes or one 15ml tube.  
 


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9.2.1.2 
Handling of Specimens: First centrifugation should be performed within 1 hour of 
specimen collection. Plasma separated at 2100 x G for 20 minutes. The plasma layer 
will be centrifuged a second time at 2100 x G x 20 minutes in a single tube. The 
plasma supernatant will be transferred to a clean tube leaving the 1ml at the bottom of 
the tube undisturbed (to be discarded). The transferred plasma sample will be 
aliquoted (500l) into 1.5ml eppendorf tubes. 
  
Shipping of Specimens: Tubes can be stored locally at -80oC and batch sent on dry ice 
to: 
 
9.2.1.3 
Site Performing Correlative Studies: BIDMC 


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10. STUDY CALENDAR 
Baseline evaluations are to be conducted within 48 hours prior to start of protocol therapy.   
 
Event/Procedure 
Screening/ 
Pre-
treatment  
Day 1 
Days 2-6a 
Day 7a,c 
Days8-13a 
Day 14 
Day 
17 
Day Range 
-2 to 0 
 
 
+ 1 day 
 
-4, +7 days 
+ 5 
days 
Eligibility Assessments 
X 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
ECOG Performance 
Status Score 
X 
 
 
 
 
 
 
Concomitant 
medication review 
X 
 
 
X 
 
X 
 
Randomization 
X 
 
 
 
 
 
 
Administer enoxaparin 
 
X 
X 
X 
X 
X 
 
Clinical Assessments 
 
 
 
 
 
 
 
Physical examination 
including vital signs,  
and height 
X 
 
 
 
 
 
 
Clinical Prediction 
Score data collection  
X 
 
 
 
 
 
 
Weight 
X 
 
 
X 
 
 
 
Assessment of signs 
and symptoms of VTE 
and bleeding 
X 
 
 
X 
 
X 
 
Laboratory Tests 
 
 
 
 
 
 
 
Plasma storage for 
correlative studies 
X 
 
 
 
 
 
 
Complete blood count 
Xd 
X 
 
X 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
Creatinine 
X 
X 
 
X 
 
 
 
AST/ALT 
X 
 
 
 
 
 
 
Imaging 
 
 
 
 
 
 
 
Bilateral lower 
extremity ultrasound 
 
 
 
 
 
 
Xb 
a: Study subjects will only remain on treatment while hospitalized or until day 14, whichever comes first. 
b: Arm A ONLY (standard dose enoxaparin).  
c: Day 7 study visit not mandatory if participant is no longer hospitalized. 
d: Also record CBC from initial admission


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26 
 
11. MEASUREMENT OF EFFECT 
 
Venous Thromboembolism (VTE) 
 
Cumulative incidence of venous thromboembolic events is the primary endpoint for Arm A and a 
secondary endpoint for Arm B.  The composite endpoint includes objectively confirmed 
proximal or distal lower extremity DVT, subsegmental or larger pulmonary embolism; or fatal 
PE diagnosed by autopsy. All other venous or arterial events will be recorded and analyzed as 
secondary endpoints (including central line associated DVT). 
 
Participants presenting with symptoms compatible with DVT and/or PE will undergo 
radiographic imaging with compression ultrasound, VQ lung scan, or spiral CT. Confirmed 
episodes of VTE will be managed by the treating physician per standard of practice.  
 
Presence of any of the following will be considered diagnostic for a VTE: 
 New non-compressibility of lower extremity deep venous segments by compression 
ultrasound.  
 Intraluminal defects in two or more views on pulmonary angiography 
 Sudden contrast cut-off of one or more vessels greater than 2.5 mm in diameter on a 
pulmonary angiogram 
 A high probability VQ lung scan showing one or more segmental perfusion defects 
with corresponding normal ventilation (mismatch defect) 
 Abnormal spiral CT showing thrombus in pulmonary vessels (subsegmental or larger)  
 
Those VTE that do not qualify for the primary endpoint such as a central line-associated 
thrombus will be recorded and analyzed as secondary endpoints.  
 
Major Hemorrhage 
Adhering to published guidelines, the criteria of major hemorrhage in non-surgical participants 
is:[30] 
o Fatal bleeding, and/or 
o Symptomatic bleeding in a critical area or organ such as intracranial, 
intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or 
intramuscular with compartment syndrome, and/or 
o Bleeding causing a fall in hemoglobin level >2 g/L or 
o Bleeding leading to a transfusion of > 2 units of packed red blood cells.   
 
 
Response Review 
 
VTE: A blinded-centralized independent adjudication of VTE qualifying for the primary 
outcome will be performed at BIDMC. The review committee will be comprised of two 
independent radiologists who will review all lower extremity ultrasounds as well as any other 
imaging that identifies a new thromboembolism. Any disagreements will be settled by 
consensus.   


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27 
 
Major hemorrhage: 
An independent adjudication committee of three hematologists will review all details of 
hemorrhagic events in a blinded manner to determine whether event met criteria for major 
hemorrhage. Any disagreements will be settled by majority consensus.  
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
The QACT will collect, manage, and perform quality checks on the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the QACT according to the schedule set by the QACT. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study 
progress, toxicity, safety and other data from this study. The board is chaired by a medical 
oncologist from outside of DF/HCC and has external and internal representation. Information 
that raises any questions about participant safety or protocol performance will be addressed by 
the Overall PI, statistician and study team. Should any major concerns arise, the DSMB will 
offer recommendations regarding whether or not to suspend the study. 
 
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; adverse events and serious adverse events reported by category; 
summary of any deaths on study; audit results; and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  
 
12.3 
Multicenter Guidelines 
 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix B. 
 The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required. 


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28 
 
 Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
 
 Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 
 
 
12.4 
Collaborative Agreements Language:  
N/A 
 
13. STATISTICAL CONSIDERATIONS 
 
 
13.1 
Study Design/Endpoints 
 
The primary aim of randomized phase II trial is to estimate the cumulative incidence of VTE and 
major hemorrhage in hospitalized cancer patients receiving standard dose or weight adjusted 
enoxaparin.  
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
The documented incidence of VTE in cancer patients in randomized clinical trials ranges 
considerably (3-17%) on pharmacologic thromboprophylaxis at standard prophylactic dosing.[8] 
With the additional incorporation of tumor-specific thrombotic risk assessment, we anticipate the 
incidence of VTE for high risk cancer patients receiving fixed standard dose enoxaparin will be 
greater than 10%, especially with inclusion of protocol-mandated lower extremity ultrasounds.  
 
We plan to enroll a total of 50 high risk cancer patients between Beth Israel Deaconess Medical 
Center and Cleveland Clinic Foundation, of which 25 will be randomized to standard dose 
enoxaparin. Assuming a cumulative incidence of thrombosis at day 17 is 12% (90% binomial 
confidence interval 3.3to 28.2%),While we anticipate an increased risk of major hemorrhage 
observed in cancer patients compared to that of general medical patients, we expect these events 
to be rate. Point estimates of hemorrhage endpoints at Day 14 will be provided along with the 
90% exact binomial confidence intervals. The point estimate will serve to inform sample size 
calculations for a larger phase III clinical trial.  
 
 
The trial will only be open at BIDMC and Cleveland Clinic and we anticipate enrolling 3patients 
per month. 
 
Participants who receive at least one dose of treatment post-randomization will be considered 
evaluable for the study. 
 
 
 


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29 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
13 
+ 
12 
= 
25 
Not Hispanic or Latino 
12 
+ 
13 
= 
25 
Ethnic Category: Total of all subjects    25 (A1) 
+ 
25 
(B1) = 
50 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
 
+ 
 
= 
 
Asian 
3 
+ 
2 
= 
5 
Black or African American 
5 
+ 
6 
= 
11 
Native Hawaiian or other Pacific 
Islander 
 
+ 
 
= 
 
White 
17 
+ 
17 
= 
34 
Racial Category: Total of all subjects 
25 
(A2) + 
25 
(B2) = 
50 (C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
 
13.3 
Stratification Factors 
 
Randomization will be stratified for hospital (BIDMC and CCF) and risk of cancer based on 
Khorana model: very high risk (stomach, pancreatic), high risk (lung, lymphoma, gynecologic, 
bladder, testicular), and standard risk (all others).  
 
13.4 
Interim Monitoring Plan 
 
We plan an interim analysis for safety with the DSMBat any point the number of hemorrhages 
on Arm B is more than 2 greater than observed on Arm A.  (We note that the arms are unblinded 
on day 14, so this plan does not compromise the integrity of the study.)    If the true rate of 
hemorrhage on Arm B is 2%, the probability of observing 2 or more such events in 25 patients is 
0.09    In this setting, we will also provide the DSMB with the rates of hemorrhage on Arm A, as 
this study will provide the best available estimate of the rate of hemorrhage with standard dosing 
enoxaparin.  Efficacy data will also be provided, so that the DSMB can weigh benefit against 
risk. 
There is no plan to adjust the planned enrollment if the event rates are lower than anticipated. 
The reason being is that the primary goal is evaluate point estimates of VTE and hemorrhage in 
order to plan for a larger trial rather than adequately power for the direct comparison between 
fixed dose enoxaparin and intermediate-dose enoxaparin in the current study. 
 
13.5 
Analysis of Primary Endpoints 
 
Cumulative incidence of VTE at day 17 (in arm A) and major hemorrhage endpoints at day 14 
(both arms) will be calculated along with their 90% exact binomial confidence intervals. 
 


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13.6 
Analysis of Exploratory Objectives 
 
13.6.1 Efficacy analysis: Although the study is not formally powered to determine efficacy, we 
will perform a secondary analysis to preliminarily compare the cumulative incidence of 
symptomatic VTE (data collected prior to unblinding) for the standard dose(Arm A) 
versus intermediate dose enoxaparin (Arm B). Accordingly, assuming a VTE event rate 
of 25% which is towards the upper end of the binomial confidence interval in the 
standard enoxaparin arm compared with a 0% event rate in the intermediate dose 
enoxaparin arm, the power of the study is 0.74 with a one-sided  of 0.05.  The 
cumulative incidence rate of VTE at day 17 will be estimated using the competing risk 
method, where VTE is the primary event and death is considered the competing 
event.[31] 
 
13.6.2 Prediction models: For each of the three scoring systems (Padua, Khorana, IMPROVE), 
we plan to assess the 2 by 2 contingency table distributions while changing the score cut-
offs (such as a Padua score >6 or an IMPROVE scores >5 or a Khorana score >3) in 
order to evaluate whether the classification probabilities (particularly specificity and 
sensitivity) change based on the chosen cut-off. The goal is to see if we can determine a 
more stringent cut-off (compared to a Padua score>4) by considering the Padua scoring 
system and/or the other 2 scoring systems to further refine hospitalized cancer patients at 
high risk of VTE. We aim at maintaining 100% sensitivity, while improving the 
specificity of the refined risk model. We fully recognize that based on the limited number 
of patients enrolled that we will have limited power to determine definitively whether the 
additional risk models can reliably improve specificity without impacting sensitivity. 
Therefore, we do not plan on utilizing these data to refine the inclusion/exclusion criteria 
for the planned phase III trial, but rather will confirm the findings within the phase III 
trial through stratification at time of randomization.  
 


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31 
13.6.3 Biomarkers: The primary analysis of each of the biomarkers is to identify whether any of 
the pre-defined cutoff values are sensitive for VTE in the high risk cancer patients 
randomized to fixed-dose enoxaparin. Biomarkers such as tissue factor bearing 
microparticles and D-dimer have previously demonstrated low positive predictive values 
but high negative predictive values in cancer cohorts.[26, 28, 29] The combination of 
high tissue factor bearing microparticles (>3.5x104 microparticles/µl, the top tercile of 
tissue factor-bearing microparticle concentrations from the reference specimens) and 
elevated D-dimer further improved the sensitivity and specificity of the individual 
assays.[26] We will evaluate whether any of the individual biomarkers or combination of 
biomarkers are sensitive to identify all VTE diagnosed in the high risk cancer patients 
randomized to fixed-dose enoxaparin. We plan to assess the 2 by 2 contingency table 
distributions using the pre-defined cut-off values in order to evaluate the classification 
probabilities (particularly specificity and sensitivity) based on the chosen cut-off. The top 
tercile of tissue factor-bearing microparticle concentrations and D-dimer or the age-
adjusted D-dimer cut-off of the study cohorts will be also considered to evaluate the 
classification probabilities of the classification model. Fine and Gray univariate 
regression models will be used to assess the impact of each biomarker classification on 
the risk of developing VTE. In addition, using regression models we aim at assessing 
whether there is an association between the scores in the scoring systems and the 
biomarkers. As this is the initial exploratory evaluation of PSGL-1+ microparticles and 
thrombosis, additional validation in the phase III trial will be required.  
 
13.7 
Reporting and Exclusions 
 
13.7.1 Evaluation of Toxicity 
All participants will be evaluable for toxicity from the time of the first dose of enoxaparin.  
 
13.7.2 Evaluation of the Primary Efficacy Endpoint 
All participants will be assessed for primary endpoints as long as received at least 1 dose of 
enoxaparin following randomization.  
 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  


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32 
 
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Carrier M, Khorana AA, Moretto P, Le Gal G, Karp R, Zwicker JI. Lack of evidence 
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Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Frequency, risk 
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10 
Barbar S, Noventa F, Rossetto V, Ferrari A, Brandolin B, Perlati M, De Bon E, 
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12 
Bara L, Bloch MF, Zitoun D, Samama M, Collignon F, Frydman A, Uzan A, 
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Bendetowicz AV, Beguin S, Caplain H, Hemker HC. Pharmacokinetics and 
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Riess H, Pelzer U, Opitz M, Stauch M, Reitzig P, Hahnfeld S, Muller L, Sieler J, 
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15 
Spyropoulos AC, Anderson FA, Jr., Fitzgerald G, Decousus H, Pini M, Chong BH, 
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Nakamura M, Piovella F, Kakkar AK, Spencer FA. Predictive and associative models to identify 
hospitalized medical patients at risk for VTE. Chest. 2011; 140: 706-14. 
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Connolly GC, Khorana AA, Kuderer NM, Culakova E, Francis CW, Lyman GH. 
Leukocytosis, thrombosis and early mortality in cancer patients initiating chemotherapy. Thromb 
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17 
Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and 
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18 
Ay C, Dunkler D, Marosi C, Chiriac AL, Vormittag R, Simanek R, Quehenberger P, 
Zielinski C, Pabinger I. Prediction of venous thromboembolism in cancer patients. Blood. 2010; 
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Chou J, Mackman N, Merrill-Skoloff G, Pedersen B, Furie BC, Furie B. 
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21 
Zwicker JI, Liebman HA, Neuberg D, Lacroix R, Bauer KA, Furie BC, Furie B. 
Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic 
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22 
Manly DA, Wang J, Glover SL, Kasthuri R, Liebman HA, Key NS, Mackman N. 
Increased microparticle tissue factor activity in cancer patients with Venous Thromboembolism. 
Thromb Res. 2010; 125: 511-2. 
23 
Tesselaar ME, Romijn FP, Van Der Linden IK, Prins FA, Bertina RM, Osanto S. 
Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb 
Haemost. 2007; 5: 520-7. 
24 
Tesselaar ME, Romijn FP, van der Linden IK, Bertina RM, Osanto S. Microparticle-
associated tissue factor activity in cancer patients with and without thrombosis. J Thromb 
Haemost. 2009; 7: 1421-3. 
25 
Thomas GM, Panicot-Dubois L, Lacroix R, Dignat-George F, Lombardo D, Dubois 
C. Cancer cell-derived microparticles bearing P-selectin glycoprotein ligand 1 accelerate 
thrombus formation in vivo. J Exp Med. 2009; 206: 1913-27. 
26 
Zwicker JI, Liebman HA, Bauer KA, Caughey T, Campigotto F, Rosovsky R, Mantha 
S, Kessler CM, Eneman J, Raghavan V, Lenz HJ, Bullock A, Buchbinder E, Neuberg D, Furie B. 
Prediction and prevention of thromboembolic events with enoxaparin in cancer patients with 
elevated tissue factor-bearing microparticles: a randomized-controlled phase II trial (the 
Microtec study). Br J Haematol. 2013; 160: 530-7. 
27 
Bounameaux H, de Moerloose P, Perrier A, Reber G. Plasma measurement of D-


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dimer as diagnostic aid in suspected venous thromboembolism: an overview. Thromb Haemost. 
1994; 71: 1-6. 
28 
Righini M, Van Es J, Den Exter PL, Roy PM, Verschuren F, Ghuysen A, Rutschmann 
OT, Sanchez O, Jaffrelot M, Trinh-Duc A, Le Gall C, Moustafa F, Principe A, Van Houten AA, 
Ten Wolde M, Douma RA, Hazelaar G, Erkens PM, Van Kralingen KW, Grootenboers MJ, 
Durian MF, Cheung YW, Meyer G, Bounameaux H, Huisman MV, Kamphuisen PW, Le Gal G. 
Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. 
Jama. 2014; 311: 1117-24. 
29 
Ay C, Vormittag R, Dunkler D, Simanek R, Chiriac AL, Drach J, Quehenberger P, 
Wagner O, Zielinski C, Pabinger I. D-dimer and prothrombin fragment 1 + 2 predict venous 
thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis 
Study. J Clin Oncol. 2009; 27: 4124-9. 
30 
Schulman S, Kearon C. Definition of major bleeding in clinical investigations of 
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31 
Campigotto F, Neuberg D, Zwicker JI. Biased estimation of thrombosis rates in 
cancer studies using the method of Kaplan and Meier. J Thromb Haemost. 2012; 10: 1449-51. 
 


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15. APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16. APPENDIX B: SPECIMEN COLLECTION INSTRUCTION AND SHIPPING REPORT 
 
 
Instructions for Samples collection: 
 
1. Approximately 10ml of blood will be drawn into blue top tubes (3.2% citrate) in either 
two 5ml tubes or one 15ml tube. 
 
2. First spinning (centrifugation) should be done within 1 hour of specimen collection. 
Spin samples at 2100 x G for 20 minutes.  
 
3. Transfer plasma using transfer pipettes to 20cc tube (leave red cell layer undisturbed to 
be discarded).   
 
4. The plasma supernatant will be transferred to a clean single tube leaving the 1ml at the 
bottom of the tube undisturbed (to be discarded) and then the plasma layer has to be 
centrifuged a second time at 2100 x G x 20 minutes. 
 
5. The transferred plasma will be aliquoted into 4-6 cryotubes (up to 500l per tube) labeled 
screening visit. Leave the plasma at the bottom of the tube undisturbed (to be discarded). 
 
6. Label all cryotubes with the provided pre-filled labels  
 
7. Place tube in biohazard bag and inside an insulated shipper (cooler) with the appropriate 
quantity of dry ice. Ship sample along with the shipment report form. 
 
Tubes can be stored locally at -80oC and/or batch sent on dry ice to:  
Address: 
 
 
8. Please email study staff at XXX  to inform her that samples have been sent. 
 
 
 
 
 
 
 
 


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Specimen Shipment Report  
 
Medical Center: ______________________________ 
 
Study ID#: ____________ 
 
Collection Date: ____/___     / _____                                                                              
 
 
Time of draw:     :     AM/PM        Number Samples sent: _____________ 
Time of spin:       :     AM/PM        Number Samples store: _____________ 
                                                                      
 
Completed By: __________________________________________    
 
 
 
Comments:  
 
 
 
 
 
 
Contact Study Coordinator at Medical Center: _____________________ 
 
Phone:  _____________________       Email:   _____________________ 
 
 
 
This complete form and samples should be mailed to the below address.  
Please call or email study staff at BIDMC the day the shipment is sent out.   
Thank you!