Clinical trial NCT00952380
Conditions: Venous Thromboembolism
Keywords: VTE
Sponsor: Pfizer
Start date: 2009-08-01; Completion date: 2018-03-01
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Three month treatment of acute VTE with Fragmin in pediatric cancer patients

Detailed description:
Primary study objectives include are to determine the pharmacodynamic (PD) profiles for treatment doses of dalteparin in pediatric subjects of different ages with cancer and venous thromboembolism (VTE), using anti-Xa (Xa) levels and a population PD analysis methodology, and to determine the median dose required to achieve therapeutic anti- Xa levels (0.5 to 1.0 International Units \[IU\]/mL) based on subject age and weight.

Arms: arm 1: Single arm open-label
Interventions: intervention 1: dalteparin
Intervention descriptions: intervention 1: dalteparin subcutaneous injection

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL
A THREE MONTH PROSPECTIVE OPEN LABEL STUDY OF THERAPY WITH 
FRAGMIN® (DALTEPARIN SODIUM INJECTION) IN CHILDREN WITH VENOUS
THROMBOEMBOLISM WITH OR WITHOUT MALIGNANCIES
Compound:
PN180524
Compound Name :
Dalteparin Sodium Injection (Fragmin®)
United States (US) Investigational New 
Drug (IND) Number:
IND 79,617
European Clinical Trials Database
(EudraCT) #:
2016-000394-21
Protocol Number:
FRAG-A001-201 (A6301094)
Phase:
II
Version #:
Amendment 9 – 18 October 2016
Pfizer Inc
235 East 42nd Street
New York, NY 10017


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Document History
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.
Document
Date
Summary of Changes and 
Rationale
Original Protocol
June 23, 2008
Legacy Eisai Inc Protocol
Protocol Amendment 1
September 04, 2008
Legacy Eisai Inc Protocol
Correction to Amendment 1
January 05, 2009
Legacy Eisai Inc Protocol
Protocol Amendment 2
February 20, 2009
Legacy Eisai Inc Protocol
Protocol Amendment 3
September 15, 2010
Legacy Eisai Inc Protocol
Protocol Amendment 4
September 01, 2011
Legacy Eisai Inc Protocol
Protocol Amendment 5
April 21, 2015
Administrative changes per 
transition of study to Pfizer Inc from 
Eisai; Updating of Safety Section 
per Pfizer safety reporting processes 
and procedures, and other relevant 
sections per Pfizer Inc processes and 
procedures.
Protocol Amendment 6
09 September 2015
This version was never finalized or 
submitted and was replaced by 
Amendment 7.
Protocol Amendment 7
18 November 2015
Includes protocol modifications 
endorsed by FDA in a Type C 
Meeting conducted on 05 November 
2015, including updating age cohort 
groups, inclusion of all patients with 
VTE and removal of the central 
imaging reader and Adjudication 
Committee.
Protocol Amendment 8
24 March 2016
Includes various minor text 
clarification modifications per 
Quality Gate 1 findings and other 
noted discrepancies and discussion 
during US Investigator Meeting that 
took place on March 11-12, 2016 to 


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add clarity regarding procedures, 
inclusion/exclusion, clinical supply 
and other sections.
Protocol Amendment 9
18 October 2016
Incorporation of administrative 
changes from Protocol 
Administrative Change Letters; 
Inclusion of Schwartz Method and 
Revised Schwartz Method for 
Creatinine Clearance calculations; 
other minor changes


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PROTOCOL SYNOPSIS
Study Number:
FRAG-A001-201 (A6301094)
Study Title:
A THREE MONTH PROSPECTIVE OPEN LABEL STUDY OF 
THERAPY WITH FRAGMIN® (DALTEPARIN SODIUM
INJECTION) IN CHILDREN WITH VENOUS 
THROMBOEMBOLISM WITH OR WITHOUT MALIGNANCIES
Primary
Objectives:

To determine the pharmacodynamic (PD) profiles for treatment 
doses of dalteparin in pediatric subjects of different ages with 
venous thromboembolism (VTE), and with or without cancer,
using anti-Xa (Xa) levels and a population PD analysis
methodology;

To determine the median dose (IU/kg) required to achieve
therapeutic anti-Xa levels (0.5 to 1.0 International Units [IU]/mL) 
based on subject age and weight.
Secondary
Objectives:

To assess the proportion of major bleeding events during 
dalteparin treatment.

To assess the proportion of minor bleeding events during 
dalteparin treatment;

To explore the proportion of objectively documented new or 
progressive symptomatic VTE during dalteparin treatment;

To explore the relationships of recurrent VTE and major bleeding 
events with anti-Xa levels if data permits;

To explore the proportions of subjects with progression, 
regression, resolution or no change in the qualifying VTE during 
dalteparin treatment;

To describe the overall safety profile of dalteparin in pediatric 
subjects of different ages with or without cancer and VTE;

To assess proportion of subjects achieving an anti Xa therapeutic 
range of 0.5 to 1.0 IU/mL during the Dose Adjustment Phase.
Study Phase:
II
Study Design:
A prospective, multicenter, open-label cohort study in North 
America and Europe Divided into three phases: Dose Adjustment
Phase, PD Phase and Follow- up Phase.
Number of Centers: Approximately 40 sites in North America and Europe.
Sample Size:
Subjects will be enrolled into the following five age groups:


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
0 to < 8 Weeks;

≥8 Weeks to < 2 Years;

≥2 Years to < 8 Years;

≥8 Years to < 12 Years;

≥12 Years to < 19 Years.
The target enrollment is 50 subjects who have PD profiles after 
treatment doses of dalteparin.
Inclusion Criteria:
Subjects meet inclusion if all of the following are true:
1. Have been objectively diagnosed with a venous thrombotic event 
documented using one of the following acceptable imaging
modalities within 4 days of the Screening Visit:

Compression ultrasound with Doppler [CUD];

Computed tomography with/without venography
[CT/CTV];

Magnetic resonance imaging with/without venography
[MRI/MRV];

Conventional venography [CV];

Ventilation-perfusion scan [V/Q] (for pulmonary artery);

Spiral CT angiography [SCTA];

Conventional pulmonary angiogram [CPA].
2. Are judged clinically to require anticoagulation therapy.
3. Are in the age range of ≥36 weeks gestation and <19 years at the 
Screening Visit.
4. Have given signed informed consent (and assent, as appropriate) 
to participate prior to the Screening Visit.
5. For cancer patients, a diagnosis of active malignancy (currently 
under treatment), other than basal cell or squamous cell carcinoma 
of the skin.
6. Male subjects able to father children and female subjects of 
childbearing potential and at risk for pregnancy must agree to use 
a highly effective method of contraception throughout the study 
and for at least 28 days after the last dose of assigned treatment. 
7. Willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
8. Female subjects of non-childbearing potential must meet at least 


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1 of the following criteria:  
a.  Achieved post-menopausal status, defined as follows:  
cessation of regular menses for at least 12 consecutive months 
with no alternative pathological or psychiological cause; [status 
may be confirmed with/and have] a serum follicle-stimulating 
hormone (FSH) level confirming the post-menopausal state; 
b.  Have undergone a documented hysterectomy and/or bilateral 
oophorectomy; 
c. Have medically confirmed ovarian failure.
9.
All other female subjects (including female subjects with tubal 
ligations) are considered to be of child bearing potential.
Exclusion Criteria:
Subjects are excluded if any one of the following apply:
1. Weight ≤3.0 kg or >100 kg at the Screening Visit.
2. Platelet count ≤ 50,000/mm3 (despite appropriate medical
measures to support platelet count).
3. Received oral anticoagulant (OAC) therapy within 3 days of the 
Screening Visit.
4. History of administration of therapeutic doses of Low Molecular
Weight Heparin (LMWH) or unfractionated heparin for a period
of > 4 days (or >8 doses of LMWH) for the qualifying VTE.
5. Received unfractionated heparin within 3 hours, or LMWH
within 12 hours, of the first dose of dalteparin.
6. Acute VTE intervention which includes thrombolytic therapy.
7. Subjects with major bleeding or bleeding disorders such as 
Platelet Dysfunction, Protein Deficiency, Disseminated 
Intravascular coagulation (DIC), Factor Deficiency, Hemophilia, 
Idiopathic Thrombocytopenic Purpura (ITP) or Von Willebrand 
Disease at the time of the Screening Visit or an unacceptably
high risk of bleeding, at the discretion of the investigator, should 
not be considered candidates..
8. Activated partial thromboplastin time (aPTT) 5 seconds above
upper limit of normal (ULN), and that corrects to within normal
limits upon 1:1 mixing with normal plasma.
9. Prothrombin time (PT) 2 seconds above ULN, and that corrects
to within normal limits upon 1:1 mixing with normal plasma.
10. Creatinine clearance <60 mL/min/1.73m2 in subjects >1 month
of age.
11. Uncontrolled hypertension characterized by a sustained systolic 
pressure or diastolic pressure >99th percentile of age- and height-


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related norms.
12. History of heparin-induced thrombocytopenia (HIT).
13. Any condition in which the investigator feels the subject is
unsafe or inappropriate for study participation.
14. Participation in other clinical studies involving investigational 
drug(s) within the past 30 days.
15. Insufficient subcutaneous tissue to facilitate subcutaneous drug 
administration.
16. Pregnant female subjects; breastfeeding female subjects; male 
subjects able to father children and female subjects of childbearing 
potential who are unwilling or unable to use a highly effective 
method of contraception as outlined in this protocol for the 
duration of the study and for at least 28 days after the last dose of 
assigned treatment.
17. Unable or unwilling to comply with scheduled follow-up visits.
(See Section 6.2 for complete listing of Inclusion Criteria and
Exclusion criteria).
Study Drug/Dosing: Dalteparin sodium (Fragmin®) will be provided in:

Multiple dose vials of 25,000 IU/1 mL (3.8mL for US or 4mL for 
ROW) containing preservative benzyl alcohol;

Preservative-free single dose vials of 2,500 IU/1 mL (4mL) [where 
available];

Preservative-free 10,000 IU / 1 mL single-dose graduated syringe 
(can be diluted as needed per the IP Manual).
Dosing administration is subcutaneous, twice daily.  Study medication 
can only be administered to a subject by a healthcare professional (ie,
study nurse) or trained parent/caregiver.  Hospital nurses that may 
administer study medication to in-patient subjects do not require GCP 
training.  However, they must receive study medication administration 
training from the site staff and the training should be documented.
Subject’s aged 0 to less than 8 weeks will receive an initial dose of
125 IU/kg twice daily. Subjects aged greater than or equal to 8 weeks
to less than 2 years will receive an initial dose of 150 IU/kg twice 
daily. Subjects aged greater than or equal to 2 years to less than
8 years or greater than or equal to 8 years to less than 12 years will
receive an initial dose of 125 IU/kg twice daily. Subjects aged
greater than or equal to 12 years to less than 19 years will receive an
initial dose of 100 IU/kg twice daily. All subjects will have dose
adjustments in the Dose Adjustment Phase in 25 IU/kg 
increments/decrements based upon an anti-Xa therapeutic goal


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range of 0.5 to 1.0 IU/mL.  
Study Procedures:
In the Dose Adjustment Phase, all eligible subjects will receive
dalteparin sodium subcutaneously every 12 hours ±1 hour (no less 
than 8 hours between doses) for up to 7 days. However, if a dose is 
not able to be delivered every 12 hours ±1 hour, administer the dose 
(no less than 8 hours between doses) and record the actual dosing 
time. 
The first anti-Xa level after initial study medication treatment may 
be taken 4 hours ±1 hour after the first, second or third dose per 
Investigator judgment .  All plasma samples should be drawn within 
the assigned window at each visit, however, if this is not possible, 
record the actual time the sample is drawn. Plasma samples drawn 
during the Dose-Adjustment phase that deviate outside the 4 ± 1 hr 
window cannot use the anti-Xa reference range, 0.5-1.0 IU/ml, and 
should be repeated the next day for both central lab and local lab. The 
actual dosing time prior to the repeat plasma sample draw and the 
actual time of the repeat sample draw must be recorded.  Subsequent 
anti-Xa levels will be measured to determine if the anti-Xa level is 
within the target therapeutic range of 0.5 to 1.0 IU/mL.  If the 
therapeutic range is not achieved, the dalteparin dose must be adjusted 
per protocol.  After any dose adjustment, anti-Xa should be re-drawn 
after the first, second or third dose per Investigator judgment.  If the 
target range is not achieved within the 7 day period, the subject’s 
study participation will be terminated.
In the PD Phase, subjects completing the Dose Adjustment Phase will 
receive their maintenance therapeutic dose of dalteparin sodium (last 
dose from Dose Adjustment Phase) subcutaneously every 12 hours 
±1 hour (no less than 8 hours between doses). However, if a dose is 
not able to be delivered every 12 hours ±1 hour, administer the dose 
(no less than 8 hours between doses) and record the actual dosing 
time.  Subjects from each age group will be randomized to two 
different plasma sampling windows (1 to 3 h and 5 to 8 h or 3 to 5 h
and 8 to 12 h) for the anti-Xa plasma samples for the central lab, only.  
A total of two plasma samples will be drawn for each subject per their 
randomization schedule during the PD Phase.  The plasma sampling 
times can be spread over the duration of the PD phase (up to 7 days) if 
necessary. All plasma samples should be drawn within the assigned 
window at each visit, however, if this is not possible, record the actual 
time the sample is drawn.  The sample should be repeated if possible 
at the correct time point.
In the Follow-Up Phase (Visits 5, 6, 7), subjects will continue to 
receive their maintenance therapeutic dose of dalteparin sodium
subcutaneously every 12 hours ±1 hour (no less than 8 hours between 
doses) through Visit 7. However, if a dose is not able to be delivered 


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every 12 hours ±1 hour, administer the dose (no less than 8 hours 
between doses) and record the actual dosing time. Anti-Xa levels and 
safety/efficacy assessments will be conducted at Visits 5, 6 and 7. 
Anti-Xa plasma samples will be collected at 4 hours ± 1 hour 
post-dose at each Follow-Up Visit to check if anti-Xa levels remain 
within the target therapeutic range. All plasma samples should be 
drawn within the assigned window at each visit, however, if this is not 
possible, record the actual time the sample is drawn. Plasma samples 
drawn during the Follow-Up Phase that deviate outside the 4 ± 1 hr 
window cannot use the anti-Xa reference range, 0.5-1.0 IU/ml, and 
should be repeated the next day.  The actual dosing time prior to the 
repeat plasma sample draw and the actual time of the repeat sample 
draw must be recorded. The Principal Investigator or designee will 
follow up weekly with a telephone interview to all subjects or 
parents/guardians after discharge from hospital to assess study
compliance and general well-being. At the end of the study or on
the presentation of a recurrent or progressive VTE, evaluation of
thrombus regression or resolution will be performed using the same
imaging technique as for VTE diagnosis at study entry. If an image
has been captured prior to the end of study (EOS) and it demonstrates 
complete resolution of the qualifying VTE, then a repeat image does
not need to be done at EOS. For purposes of the study, the complete 
resolution image will be considered as part of the EOS evaluation.
Study Duration:
Study duration is 90 days of open-label treatment with dalteparin
sodium (Fragmin®) for cancer patients and treatment of non-cancer 
patients should be aligned with the 2012 American College of Chest 
Physicians (ACCP) Guidelines15 which suggest a total duration of 
anticoagulation treatment of between 6 weeks and 3 months rather 
than shorter or longer durations (Grade 2C), following completion of 
the PD Phase. Non-cancer patients will be required to remain in the 
study, however for the full 3 months to complete all remaining study 
visits, regardless of dalteparin treatment duration. For non-cancer 
patients who stop dalteparin treatment prior to 3 months, Anti-Xa and 
Anti-IIa plasma sampling will not be required after study medication 
discontinuation
Pharmacodynamic 
Endpoints
Pharmacodynamic Evaluation:
Primary Endpoints:

Determine the median dose of dalteparin (IU/kg) associated with 
the achievement of the therapeutic anti-Xa level (0.5-1.0 IU/mL) 
among subjects that achieved their therapeutic anti-Xa level during 
the dose adjustment phase, for each age cohort group;

Anti-Xa activity versus time profile following dalteparin treatment 
will be explored using a population PD analysis methodology.  
Population PD parameters such as clearance, volume of 


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distribution, absorption rate constant will be estimated based on 
anti-Xa levels collected during dose adjustment phase, PD phase 
and follow-up phase. Age and other relevant covariates will be 
explored in the population PD analysis.
Efficacy Endpoints
(all are secondary):

Proportion of subjects achieving an anti Xa therapeutic range of 
0.5 to 1.0 IU/mL during the Dose Adjustment Phase;

Proportion of subjects with objectively documented new or 
progressive symptomatic VTE during dalteparin treatment;

Proportions of subjects with progression, regression, resolution, or 
no change in the qualifying VTE during dalteparin treatment;

Time to first episode of recurrent VTE during dalteparin treatment.
Safety Endpoints
(all are secondary):

Proportion of subjects with major bleeding during dalteparin 
treatment;

Proportion of subjects with minor bleeding during dalteparin 
treatment;

Relationship between major bleeding event and the Anti-Xa level 
during dalteparin treatment if data permits;

Description of subjects' adverse events (AE) throughout the study 
period;

Summary of chemistry, hematology, vital signs and physical 
examinations;

Time to first major bleeding events during dalteparin treatment.
Statistical Methods: Sample Size:
A sample size of 50 subjects is sufficient to estimate anti-Xa total
body clearance of the drug (CL) and volume of distribution (Vd) of
dalteparin. Enrollment will continue until 50 subjects have provided 
viable PD Phase anti-Xa data.
Sample size determination.
Based on historical data and a population pharmacokinetic (PK)/PD 
model, evaluated the effect of sample scheme and sample size per age 
stratum on the bias and precision of key PK/PD parameters.

Evaluated total N of 10, 20, 30, 40 and 50 (2, 4, 6, 8, and
10 per age stratum, as available);

Evaluated single and 2-point sample densities and impact of 
randomization across stratum.

100 trial simulations per design examined.
Sampling Density.


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
Single-point sampling designs yielded unacceptable bias in CL 
and/or Vd; confounding of effects if blocked within strata;

Compared double sampling at 2, 6 and 4, 10 hours post-dose
versus 3, 8 and 5, 12 hours post-dose.  Randomized 
two-sample designs with sampling at 3, 8 and 5, 12 hours 
post-dose performs more efficiently.
Analysis Populations:
There will be two analysis populations defined in the study. The
Safety Population will include subjects who receive at least one
treatment of dalteparin.  The safety analysis will be based on this
population.  The PD Population will include subjects in the Safety
Population who achieve therapeutic range of anti-Xa during the Dose
Adjustment Phase. This population will be the primary analysis
population for the PD and efficacy analysis. 
Pharmacodynamic Analysis:

Pharmacodynamic response of dalteparin will be evaluated by
using a population PD analysis methodology based on anti-Xa
levels;

The median dose (IU/kg) required per age group to
demonstrate an anti-Xa of 0.5 to 1.0 IU/mL at 4 hours ± 1 hour 
post-dose during the Dose Adjustment Phase;

Proportion of subjects who achieve the therapeutic range of
0.5 to 1.0 IU/mL at 4 hours ± 1 hour post-dose of dalteparin 
treatment will be summarized.
Efficacy Analysis:
Proportion of subjects with objectively documented new or 
progressive symptomatic VTE will be summarized overall and by age 
group.  Proportion of subjects with any VTE by age group and 
proportion of subjects with progression, regression, resolution and no 
change to the qualifying VTE during dalteparin treatment, and 
relationships of new or progressive VTE with anti-Xa levels will be 
summarized.  Time to the first recurrent VTE and time to first major 
bleeding events will be evaluated by Kaplan-Meier method and the 
Cox regression model will be used to assess the recurrent VTE with 
prognostic factors of age group and baseline tumor type.  Exploratory 
analyses will include a logistic regression model to assess if subjects 
achieved an anti-Xa therapeutic range during the Dose Adjustment 
Phase using the odds ratio of prognostic factors of age, gender, 
chemotherapy status and dose of dalteparin.
Safety Analysis:
Proportion of subjects with any major bleeding events will be 


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summarized overall and by age group during dalteparin treatment, as 
well as monthly. Proportion of subjects with any bleeding and fatal 
bleeding will also be summarized.  Time to the first major bleeding 
events will be evaluated by the Kaplan-Meier method and the Cox 
regression model with prognostic factors (eg, baseline anti-Xa level, 
age group, baseline tumor type, and chemotherapy status in the model. 
All other AEs will be described. All laboratory data will be 
summarized as well as vital signs and physical examinations.


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PROTOCOL FLOWCHART
Table 1.
Protocol Flowchart
Follow-up Phase12
Unscheduled13
Assessments
Screen
Visit 1
Baseline3
Visit 2
Dose 
Adjustment 
Phase12
Visit 3
PD4
Visit 4
Telephone Contact6
Visit 5
Visit 6
Visit 7
Event
Visit
Day(s)- (Days may vary 
according to number of days 
required for Dose Adjustment 
Phase. Total treatment period is 
90 days.)
-3 to -1
1
1 to 7
2/3 to 14
out-patient period
Days 15-44 Days 45-74
ET
Days 75-104
Informed Consent
x
Medical History1,2
x
x
Physical Exam3
x
x
x
x
x
x
x
x
x
Imaging
x
x
x7
x7,8
Vital Signs
x
x
x
x
x
x
x
x
x
Clinical Laboratory:

Hematology/Coagulation
x5
x
x
x
x
x
x9
x9

Antithrombin Activity
x5
x5
x
x
x
x
x
x9
x9

Clinical Chemistries14
X
x
x
x
x
x
x9
x9
Pregnancy test, (serum or urine) if 
applicable
x
x
x
x
x
x
x
x
x
Evaluate Contraception if 
applicable
x
x
x
x
x
x
x
x
x
Anti-Xa level5
L, C
L, C
C
L, C
L, C
L, C
L9
L9
Anti-IIa level5
C
C
C
C
C
C
Dispense Study Drug11
x
x
x
x10
x
x
x
Return Study Drug
x
x
x
x
x
x
x
Concomitant Medication
x
x
x
x
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
Medication Compliance
x
x
x
x
x
x
x
Abbreviations: L- Local Lab, C- Central Lab
1.
Any change in medical history after the first dose of study medication is administered will be considered an AE.
2.
All subjects at high risk for bleeding or who have bleeding disorders such as Platelet Dysfunction, Protein Deficiency, DIC, Factor Deficiency, Hemophilia, ITP or Von
Willebrand disease should not be considered candidates.


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3.
Physical Exam including weight and height will be assessed at the end of the Dose Adjustment Phase (ie, Screening, Baseline, end of Dose Adjustment Phase, The PD 
Phase, and during the Follow-Up Phase at Visits 5, 6 and 7 per protocol) to determine any change resulting in an AE. Medical History, Physical Exam (including weight 
and height), Pregnancy test, Imaging and Clinical Labs (Chemistry, Antithrombin, and Hematology) are only required once (at Screening or Baseline visit if Screening is
within 48 hours of the Baseline visit).
Repeated evaluations at Baseline are at the investigator’s discretion.  Antithrombin activity is evaluated only once during the Dose 
Adjustment and PD Phases.
4.
The PD phase will last for up to 7 days in order to complete two PD samples (anti-Xa). Subjects will be randomized through a randomization scheme as assigned by the 
electronic system, IMPALA, into two different sampling windows: 1 to 3 h and 5 to 8 h or 3 to 5 h and 8 to 12 h until at least 50 subjects provide viable PD Phase anti-Xa 
values. The plasma sampling times can be spread over the duration of the PD Phase if necessary to avoid blood volume shifts. Lab samples for anti-Xa and anti-IIa levels
will be sent to Central (C) lab only. All plasma samples should be drawn within the assigned window at each visit, however, if this is not possible, record the actual time the 
sample is drawn and repeat it when appropriate at the correct time, if possible. Plasma samples drawn during the dose-adjustment phase and follow up phase that deviate 
outside the 4 ± 1 hr window cannot use the anti-Xa reference range, 0.5-1.0 IU/mL, and should be repeated the next day for both central and local labs. The actual dosing 
time prior to the repeat plasma sample draw and the actual time of the repeat sample draw must be recorded. NOTES: 1) Plasma samples drawn for anti-Xa and anti-IIa must 
not be hemolyzed.  All precautions must be made to ensure that the plasma samples are not hemolyzed.  2) For non-cancer patients, if study medication is stopped prior to 
3 months of treatment per the ACCP Guidelines, no further anti-Xa or anti-IIa sampling is required while study medication is not taken.
5.
For subjects whose platelet counts unexpectedly fall below 50,000/mm3, HIT antibody will be assessed. If the HIT antibody is positive, the subject must be discontinued.  
Antithrombin levels are to be performed once within 1 week post-diagnosis of VTE and at each study visit when anti-Xa samples are drawn.  Anti-Xa levels will be measured
at 4 hours post-dose (±1 hour) daily for up to 7 days (Days 1-7) during Dose Adjustment Phase. The first anti-Xa level may be drawn after the first, second or third doseper 
Investigator judgment during Dose Adjustment Phase.  After any dose adjustment, anti Xa should be re drawn after the first, second or third dose or per institutional standard.  
If the target range is not achieved within the 7 day period, the subject’s study participation will be terminated. These assessments are mandatory at Visits 5, 6 and 7 during 
follow-up Phase. The Anti-Xa samples will also be collected at 4 hours post-dose (±1 hour) at each visit during follow-up Phase.  All plasma samples should be drawn within 
the assigned window at each visit, however, if this is not possible, record the actual time the sample is drawn). . Indications for monthly anti-Xa checks include but are not
limited to a new compromising event change in renal function, significant weight change and suspected lack of treatment adherence. Lab samples collected for anti-Xa 
level during Dose Adjustment Phase and Follow-up Phase will be sent to both Local (L) and Central (C) labs. In addition, central lab samples for anti-Xa levels will also 
be used for anti-IIa measurement.  See item 4 above for anti-Xa samples to be drawn in the PD Phase.
6.
Telephone contacts are weekly following discharge from the hospital through the end of the study except weeks with clinical visits, ie, Visits 5, 6 and 7 per protocol).
7.
The same imaging modality should be performed from the Screening/Baseline visit as the EOS Visit or at an Unscheduled Event visit for recurrent or new VTEs. Note: The 
EOS visit (per protocol) imaging is not required if a previous visit imaging has demonstrated resolution of a clot.
8.
Imaging must be performed at an unscheduled visit if there is suspicion of a recurrent or new VTE; otherwise images are not required but can be performed at the discretion
of the investigator as per standard of care.
9.
Clinical laboratory testing should be performed per the investigator’s discretion.
10. Study drug exposure to be assessed during telephone contacts.


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11. Study drug will be dispensed to subjects according to their dosing requirements. Cancer patients will be dispensed study drug for the entire 3 months, whereas non-cancer 
patients will be dispensed study drug for the appropriate treatment period for them according the ACCP Guidelines of 6 weeks to 3 months. Non-cancer patients will, 
however, be required to complete all remaining study visits, but no anti-Xa or anti-IIa plasma samples will be required once the non-cancer patients stop study drug.
12. During the Dose Adjustment Phase and Follow-Up Phase, if a plasma sample for anti-Xa is drawn outside the 4 hour (+/- 1 hour) window, the plasma sample for anti-Xa must 
be re-drawn the next day within the correct window and sent to the Local Lab and Central Lab.  If this occurs, an Unscheduled Visit must be conducted to redraw the anti-Xa 
plasma samples.  The actual dosing time prior to the repeat plasma sample draw and the actual time of the repeat sample draw must be recorded in the CRF.
13. Unscheduled Events are bleeding or VTE events that require an Unscheduled Event visit.  Unscheduled visits are conducted for any other reason.
14. Urine collection for creatinine to be conducted if applicable, per institutional standards


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................19
LIST OF FIGURES .................................................................................................................20
APPENDICES .........................................................................................................................20
1. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .........................................21
2. INVESTIGATORS AND STUDY PERSONNEL...............................................................23
3. INTRODUCTION ...............................................................................................................23
3.1. Background .............................................................................................................23
3.2. Rationale..................................................................................................................23
4. STUDY OBJECTIVES AND ENDPOINTS .......................................................................25
5. INVESTIGATIONAL PLAN ..............................................................................................26
5.1. Overall Study Design and Plan – Description.........................................................26
5.2. Discussion of Study Design, Including the Choice of Subjects..............................27
5.3. Definition of End of Study and Early Discontinuation...........................................28
5.4. Sponsor’s Qualified Medical Personnel..................................................................29
6. SELECTION OF STUDY POPULATION..........................................................................29
6.1. Number of Subjects.................................................................................................29
6.2. Inclusion Criteria.....................................................................................................29
6.3. Exclusion Criteria....................................................................................................30
6.3.1. Unscheduled Termination from the Study...................................................32
6.3.1.1. Subject Removal from the Study...............................................33
6.3.2. Subject Replacement Policy .......................................................................33
7. TREATMENTS...................................................................................................................33
7.1. Dose Modification...................................................................................................35
7.1.1. Thrombocytopenia......................................................................................35
7.1.2. Renal Dysfunction ......................................................................................35
7.2. Use of Other Anticoagulants...................................................................................36
7.3. Identity of Investigational Product(s)......................................................................36
7.4. Labeling and Packaging of Treatments...................................................................37
7.4.1. Storage........................................................................................................37
7.4.2. Drug Supplies .............................................................................................38
7.4.3. IP Accountability Log.................................................................................38
8. ADMINISTRATION OF TREATMENTS .........................................................................39


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8.1. Dosing Groups:........................................................................................................39
8.2. Dosing Scheme: Three Phases.................................................................................41
8.3. Method of Assigning Subjects to Treatment Groups..............................................43
8.4. Selection of Doses in Study ....................................................................................43
8.5. Blinding...................................................................................................................43
8.6. Prior and Concomitant Therapy..............................................................................43
9. ASSESSMENTS AND ENDPOINT DEFINTIONS...........................................................43
9.1. Endpoint Definitions ...............................................................................................43
9.1.1. VTE Endpoints ...........................................................................................43
9.1.2. Bleeding/Safety Events...............................................................................45
9.1.3. Medical History ..........................................................................................45
9.1.4. Physical Examination .................................................................................46
9.1.5. Pregnancy Test............................................................................................46
9.1.6. Imaging.......................................................................................................47
9.1.7. Vital Signs ..................................................................................................47
9.1.8. Clinical Laboratory Assessments ...............................................................48
9.1.9. Telephone Follow-Up.................................................................................51
9.1.10. VTE Assessment and VTE Definitions ....................................................52
9.2. Screening Schedule .................................................................................................52
9.3. Treatment Period.....................................................................................................52
9.3.1. Screening/Baseline (Visit 1/Visit 2)...........................................................52
9.3.2. Dose Adjustment Phase (Visit 3)................................................................53
9.3.3. Pharmacodynamic Phase.............................................................................54
9.3.4. Follow-up Phase (For Out-Patients only)...................................................54
9.3.5. Final Visit/Early Termination (ET) .............................................................55
9.3.6. Unscheduled Event (In-Clinic Visit, if Required) ......................................55
9.3.7. Unscheduled Visit (In-Clinic visit, if required)...........................................56
10. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND REPORTING..................56
10.1. Adverse Events......................................................................................................56
10.1.1. Reporting Period.......................................................................................57
10.1.2. Definition of an Adverse Event ................................................................57
10.2. Medication Errors..................................................................................................58
10.3. Abnormal Test Findings........................................................................................58


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10.4. Serious Adverse Events.........................................................................................58
10.4.1. Protocol-Specified Serious Adverse Events.............................................59
10.4.2. Potential Cases of Drug-Induced Liver Injury..........................................60
10.5. Hospitalization ......................................................................................................61
10.6. Severity Assessment..............................................................................................62
10.7. Causality Assessment............................................................................................62
10.8. Exposure During Pregnancy..................................................................................62
10.9. Occupational Exposure .........................................................................................64
10.10. Withdrawal Due to Adverse Events....................................................................64
10.11. Eliciting Adverse Event Information ..................................................................64
10.12. Reporting Requirements......................................................................................64
10.12.1. Serious Adverse Event Reporting Requirements ...................................64
10.12.2. Nonserious Adverse Event Reporting Requirements .............................65
10.12.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............65
10.13. Breaking the Blind ..............................................................................................65
11. GUIDANCE TO THE INVESTIGATOR..........................................................................65
12. STATISTICAL METHODS...............................................................................................65
12.1. Determination of Sample Size...............................................................................65
12.2. PD Phase Plasma Sampling Randomization Plan.................................................66
12.3. Statistical Plan.......................................................................................................66
12.3.1. Statistical Methodology............................................................................66
12.3.2. Definition of Study Populations for Analysis ...........................................66
12.3.3. Analysis of Baseline and Demographic Variables ....................................67
12.3.4. Analysis of Pharmacodynamic Variables .................................................67
12.3.5. Analysis of Efficacy Variables..................................................................67
12.3.6. Analysis of Safety Variables.....................................................................68
12.3.7. Some Statistical Considerations................................................................69
13. DATA MONITORING COMMITTEE.............................................................................69
13.1. Institutional Review Board/Ethics Committee......................................................69
13.2. Ethical Conduct of the Study ................................................................................70
13.3. Subject Information and Consent..........................................................................70
13.4. Subject Recruitment ..............................................................................................71


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13.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................71
14. TREATMENT COMPLIANCE.........................................................................................71
14.1. Drug Accountability Procedures ...........................................................................71
14.2. Receipt of Study Drug...........................................................................................72
14.3. Handling of Study Drug ........................................................................................72
14.4. Records of Study Drug..........................................................................................72
15. STUDY MANAGEMENT AND ADMINISTRATION...................................................72
15.1. Monitoring.............................................................................................................72
15.2. Audit and Inspection .............................................................................................73
15.3. Quality Control and Quality Assurance ................................................................73
16. DATA HANDLING AND RECORD KEEPING .............................................................73
16.1. Case Report Forms/Electronic Data Record .........................................................73
16.1.1. Record Retention ......................................................................................74
16.2. Investigator Site File .............................................................................................74
16.3. Sponsor Discontinuation Criteria..........................................................................75
16.4. Publication of Study Results .................................................................................75
16.4.1. Communication of Results by Pfizer........................................................75
16.4.2. Publications by Investigators....................................................................76
16.5. Clinical Study Report............................................................................................76
16.6. Subject Insurance and Indemnity..........................................................................77
16.7. Amendments to the Protocol.................................................................................77
16.8. Disclosure of Information and Results..................................................................77
16.9. Publication and Presentation Policy......................................................................77
16.10. Archiving and Data Retention.............................................................................77
16.11. Data Protection....................................................................................................78
17. REFERENCES ..................................................................................................................79
18. APPENDICES ...................................................................................................................80
LIST OF TABLES
Table 1.
Protocol Flowchart................................................................................................13


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LIST OF FIGURES
Figure 1.
Chemical Structure of Dalteparin Sodium............................................................23
Figure 2.
Schematic Trial Design.........................................................................................26
APPENDICES
Appendix 1. World Medical Association Declaration Helsinki ..............................................80
Appendix 2. Study Drug (dalteparin sodium) Dosing Calculation Examples (Additional 
dosing administration instructions can be found in the Investigational 
Product (IP) Manual) ............................................................................................84
Appendix 3. Dalteparin Simulation Strategy...........................................................................85


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1. LIST OFABBREVIATIONS AND DEFINITION OF TERMS
ACCP
American College of Chest Physicians
AE
Adverse Event
Anti-Xa
Anti-Factor Xa
Anti-IIa
Anti-Factor IIa
aPTT
Activated Partial Thromboplastin Time
C
Celsius
CAT
Cancer-Associated Thrombosis
CCG
CRF Completion Guideline
CFR
Code of Federal Regulations
CL
Total body clearance of the drug
CPA
Conventional Pulmonary Angiogram
CRF
Case Report Form
CSA
Clinical Study Agreement
CT
Computed Tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTV
Computed Tomography Venography
CU
Compression Ultrasound
CUD
Compression Ultrasound with Doppler
CV
Conventional Venography
DIC
Disseminated Intravascular Coagulation
DVT
Deep Vein Thrombosis
EC
EDP                                    
Ethics Committee
Exposure During Pregnancy
EOS
End of Study
ET
Early Termination
EU
EudraCT
European Union
European Clinical Trials Database
FDA
Food and Drug Administration
FSH
Follicle-Stimulating Hormone
GAG
Glycosaminoglycan
GCP
Good Clinical Practice
HIT
Heparin-Induced Thrombocytopenia
ICH
ID
International Conference on Harmonization
Identification
IEC
Independent Ethics Committee
IIP
Investigator Initiation Package
IND
Investigational New Drug
INR
IP
International Normalized Ratio
Investigational Product
IRB
Institutional Review Board
ITP
Idiopathic Thrombocytopenic Purpura
IU
International Units
IUD
Intra-Uterine Device
IV
Intravenous
LFT
Liver Function Test
LMWH
Low Molecular Weight Heparin
IWRS
Interactive Web Response System
MRV
Magnetic Resonance Venography


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MRI
Magnetic Resonance Imaging
NCI
National Cancer Institute
OAC
PD
Oral Anticoagulant
Pharmacodynamic(s)
PE
Pulmonary Embolism
PI
Principal Investigator
PK
Pharmacokinetic
PT
Prothrombin Time
SAE
Serious Adverse Event
SC
Subcutaneous
SCTA
SOP
SRSD
Spiral Computed Tomography Angiography
Standard Operating Procedure
Single Reference Safety Document
TB
Tuberculin
Vd
Volume of Distribution
VTE
Venous Thromboembolism
V/Q 
Ventilation-Perfusion Scan
tPA
Tissue Plasminogen Activator
US
United States
Xa
Factor Xa


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2. INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified Investigators under the sponsorship of Pfizer 
Inc at approximately 40 investigational site(s) in North America and Europe.
3. INTRODUCTION
3.1. Background
This protocol implements a post-approval clinical commitment originally with Eisai Inc and 
now between Pfizer Inc., and the Food and Drug Administration (FDA) relating to the
dalteparin s NDA 20-287/S-035, “for the extended treatment of symptomatic venous 
thromboembolism [VTE (proximal deep vein thrombosis [DVT] and/or pulmonary
embolism [PE])] to reduce recurrent VTE in subjects with cancer”, hereafter referred to
as the “CLOT indication”.1 The Agency indicated that a post-approval study to
investigate the safety and efficacy of dalteparin in a pediatric cancer population requiring
anticoagulation was warranted. Following a Type C Meeting with FDA on October 5, 2015, 
this study now includes both pediatric patients with and without cancer.
This phase II pharmacodynamic (PD) study is intended to provide information to guide the 
conditions under which dalteparin may be used for the acute treatment and secondary 
prophylaxis of recurrent VTE in children with or without cancer. Pharmacodynamics of
dalteparin is being measured only using the Anti-Factor Xa (Xa) activity and not the drug
level in the body. In this study, the PD effect (anti-Xa level) is used as a surrogate for the
time course of drug exposure because 1) analytical difficulty in measuring the drug in plasma
and 2) the instantaneous drug effect on anti-Xa level. Hence, the study is only
characterizing the PD of dalteparin in pediatric subjects with and without cancer.
Figure 1.
Chemical Structure of Dalteparin Sodium
3.2. Rationale
Dalteparin sodium (Fragmin®) is a low molecular weight heparin (LMWH), produced by 
degradation of heparin, a member of the glycosaminoglycan (GAG) family of biological 
entities found in the intestinal mucosa. Dalteparin was first approved in the US in
December 1994 for primary prophylaxis of DVT in subjects undergoing abdominal surgery. 
This was followed by approvals for primary prophylaxis of DVT in subjects undergoing
hip surgery and in medical subjects with severely restricted mobility during acute illness. 
Dalteparin sodium is also indicated for the prophylaxis of ischemic complications in
unstable angina and non-Q-wave myocardial infarction, when concurrently administered 
with aspirin therapy.


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Daltaperin was approved in 2006 for the extended treatment of VTE in adult patients (age
18 years) with cancer. For these indications, dalteparin has an acceptable safety profile. 
Further information regarding dosage, safety profile, etc., can be found in the current US
Package Insert or local Summary of Product Characteristics, which will serve as the
Investigators’ Brochure for this study.
Multiple retrospective studies have shown that cancer-associated thrombosis (CAT) is a 
significant entity previously under recognized and under treated.2-9  When compared to
subjects without cancer, cancer subjects are far more prone to develop VTE; in fact, VTE
may represent the initial presenting finding for an otherwise occult cancer.10 When
compared to cancer-free subjects with symptomatic VTE, cancer subjects with VTE are
more prone to recurrence and to treatment-related bleeding complications.
The CLOT study [“Randomized Comparison of Low Molecular Weight Heparin
(Dalteparin, Fragmin®) versus Oral Anticoagulant Therapy for Long Term Anticoagulation in
Cancer Subjects with Venous Thromboembolism”] was the first multinational prospective
randomized clinical trial in a general cancer population to show the superiority of
LMWH therapy for secondary prophylaxis compared to standard of care therapy using
vitamin K antagonists (oral anticoagulants [OAC]) in cancer subjects with confirmed
symptomatic lower extremity DVT, PE, or both.1 However, the CLOT study did not include
pediatric subjects and there is limited information in the literature regarding the proper
dosing of dalteparin for treatment of VTE in pediatric subjects with cancer.
The use of LMWHs has been evaluated in several published pediatric studies. In a
1996 report, Massicote et al.,11 described their evaluation of enoxaparin in 25 pediatric
subjects in Canada either with VTE or at risk of VTE, and deemed by their physicians to be
at risk of bleeding with unfractionated heparin.  It was observed that an inverse relationship
existed between the subject’s age (correlated with body weight) and dosing required to
achieve effective anti-Xa inhibition, with “newborns” requiring a greater than 50% increased
dose per kg (perhaps due to a larger volume of distribution [Vd]).
Likewise, in a 1999 report by Nohe et al.,12 doses of dalteparin in 48 children were shown to
be effective (129±43 anti-Xa International Units (IU)/kg, q24h for treatment; 92±52 anti-Xa
IU/kg, q24h for prophylaxis as recommended in the 7th ACCP Guidelines15), with higher
dosing required for younger children to achieve the same target anti-Xa level. Risk factors
for thrombosis in this cohort included the presence of carcinoma in some of the children.
Dosing with enoxaparin in 173 pediatric thrombosis subjects was also evaluated by Dix et al.
and reported in 2000.13 The authors concluded again, as above, that the use of LMWH in
children was “…a safe and effective form of anticoagulation”.
The combination of the published data and recognition that for more than 10 years children 
worldwide have been treated with LMWH for VTE, outside of the approved indication,
supports the safety of the recommended doses of LMWH in children.


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4. STUDY OBJECTIVES AND ENDPOINTS
The primary objective of this study is to:

To determine the PD profiles for treatment doses of dalteparin in pediatric
subjects of different ages with or without cancer and VTE, using Anti-Xa levels and
a population PD analysis methodology;

To determine the median dose (IU/kg) required to achieve therapeutic Anti-Xa levels
(0.5-1.0 IU/mL) based on subject age and weight.
Secondary objectives will be:

To assess the proportion of major bleeding events during dalteparin treatment;

To assess the proportion of minor bleeding events during dalteparin treatment;

To explore the proportion of objectively documented new or progressive
symptomatic VTE during dalteparin treatment;

To explore the relationships of recurrent VTE and major bleeding events with anti-Xa
levels, if data permits;

To explore the proportions of subjects with progression, regression, resolution or no
change in the qualifying VTE during dalteparin treatment;

To describe the overall safety profile of dalteparin in pediatric subjects of different
ages with or without cancer and VTE.

To assess the proportion of subjects achieving an anti-Xa therapeutic range of 0.5 to 
1.0 IU/mL during the Dose Adjustment Phase.
Primary Endpoints:

Determine the median dose of dalteparin (IU/kg) associated with the achievement of 
the therapeutic Anti-Xa level (0.5-1.0 IU/mL) among subjects that achieved their 
therapeutic Anti-Xa level during the dose adjustment phase, for each age cohort 
group;

Anti-Xa activity versus time profile following dalteparin treatment will be explored 
using a population PD analysis methodology. Population PD parameters such as 
clearance, volume of distribution, absorption rate constant will be estimated based on 
Anti-Xa levels collected during dose adjustment phase, PD phase and follow-up 
phase. Age and other relevant covariates will be explored in the population 
PD analysis.
Secondary Endpoints:

Proportion of subjects achieving an Anti-Xa therapeutic range of 0.5 to 1.0 IU/mL 
during the Dose Adjustment Phase (up to 7 days);

Proportion of subjects with objectively documented, new or progressive symptomatic 
VTE during dalteparin treatment utilizing the same objective technique performed at 
Baseline;

Time to first episode of symptomatic recurrent VTE during dalteparin treatment;


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
Proportions of subjects with progression, regression, resolution and no change (in 
comparison to qualifying VTE) during dalteparin treatment;

Proportion of subjects with major bleeding during dalteparin treatment;

Proportion of subjects with minor bleeding during dalteparin treatment;

Relationship between major bleeding event and the Anti Xa level during dalteparin 
treatment if data permits;Description of subjects' adverse events (AEs) throughout the 
study period;

Summary of chemistry, hematology, vital signs and physical examinations.

Time to first major bleeding events during dalteparin treatment.
5. INVESTIGATIONAL PLAN
5.1. Overall Study Design and Plan – Description
The study is a 3-month prospective, multicenter, open-label cohort study in North
America and Europe to determine twice daily dosing recommendations of dalteparin as a
function of age in order to achieve Anti-Xa levels of 0.5 to 1.0 IU/mL at 4 hour
(± 1 hour) post-dose in children with or without various cancers and requiring
anticoagulation for the treatment and secondary prophylaxis of VTE. The study is divided
into 3 phases: 1) Dose Adjustment Phase of up to 7 days; 2) PD Phase; and 3) Follow-Up 
Phase, to complete up to 90 days of treatment for cancer patients and treatment of non-cancer 
patients should be aligned with the 2012 ACCP Guidelines15 which suggest a total duration 
of anticoagulation treatment of between 6 weeks and 3 months rather than shorter or longer 
durations (Grade 2C), following completion of the PD Phase. Non-cancer patients will be 
required to remain in the study, however, for the full 3 months to complete all remaining 
study visits, regardless of dalteparin treatment duration. For non-cancer patients who stop 
dalteparin treatment prior to 3 months, Anti-Xa and Anti-IIa plasma sampling will not be 
required after study medication discontinuation. 
Figure 2.
Schematic Trial Design
Visit 1
Visit 2
Visit 3
Visit 4
Visits 5, 6 & 7/End of
Treatment/ET
Screening
(Day -3         
to -1)
Baseline
 ( Day 1)
Dose 
Adjustment
(Day 1 up
    to 7)
PD Phase
   (Day 2 or 3
         to 14)
Follow-up
(Days 15- 104)


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5.2. Discussion of Study Design, Including the Choice of Subjects
This is a multi-center open-label study with no control group. This Phase II PD study is
intended to provide information to guide the conditions under which dalteparin may be used
for the treatment of acute and secondary prophylaxis of VTE in children with or without 
cancer. Subjects will be enrolled into the following five age groups:

0 to < 8 Weeks;

≥8 Weeks to < 2 Years;

≥2 Years to < 8 Years;

≥8 Years to < 12 Years;

≥12 Years to < 19 Years.
The target enrollment is a total of 50 subjects who have viable PD profiles after treatment 
doses of dalteparin.
Dose Adjustment Phase:
The Dose Adjustment Phase will begin following the first dose and continue for up to
7 days. During the Dose Adjustment Phase, doses are adjusted according to Anti-Xa levels. 
The starting doses for the five age groups are as follows: 

0 to <8 weeks – 125 IU/kg;

≥8 weeks to < 2 years– 150 IU/kg;

≥2 years to <8 years – 125 IU/kg;

≥8 years to <12 years – 125 IU/kg and

≥12 years to <19 years – 100 IU/kg.
The first Anti-Xa plasma sample drawn after the initial dose of study drug treatment should 
be conducted 4 hours ±1 hour after the first, second or third dose of study medication per 
Investigator judgment. Subsequent Anti-Xa plasma samples conducted following dose 
adjustments will also be drawn at 4 hours ±1 hour post-dose, after the first, second or third 
dose of study medication per Investigator judgment. Doses will be adjusted in increments or 
decrements of 25 IU/kg in order to achieve target anti-Xa levels (0.5-1.0 IU/mL). All plasma 
samples should be drawn within the assigned window at each visit, however, if this is not 
possible, record the actual time the sample is drawn. Plasma samples drawn during the 
Dose-Adjustment Phase and Follow-Up Phase that deviate outside the 4 ± 1 hr window 
cannot use the anti-Xa reference range, 0.5-1.0 IU/mL, and should be repeated the next day
for both central and local labs. The actual dosing time prior to the repeat plasma sample 
draw and the actual time of the repeat sample draw must be recorded.
PD Phase:
Subjects completing the Dose Adjustment Phase will enter into the PD Phase. Dalteparin 
sodium will be administered subcutaneously every 12 hours ±1 hour (no less than 8 hours 
between doses) with the maintenance therapeutic dose from the Dose Adjustment Phase.  


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However, if a dose is not able to be delivered every 12 hours ±1 hour, administer the dose 
(no less than 8 hours between doses) and record the actual dosing time.  The PD Phase will
last for 1 to 7 days in order to complete two PD samples for each subject (for the central lab, 
only).
Subjects from each age group will be randomized according to a randomization 
scheme provided by the electronic system, IMPALA, into two different plasma sampling
windows: 1 to 3 h and 5 to 8 h or 3 to 5 h and 8 to 12 h until at least 50 subjects provide 
viable PD Phase Anti-Xa values.  All plasma samples should be drawn within the assigned 
window at each visit, however, if this is not possible, record the actual time the plasma 
sample is drawn in the Case Report Form (CRF) and repeat it when appropriate at the correct 
time, if possible.
The plasma sampling times can be spread over the duration of the PD Phase (up to
7 days) to avoid blood volume shifts if necessary. The assignment of the time points to
the subjects within each age group will be centrally randomized.
Follow-up Phase:
After subjects successfully complete the PD Phase, they will enter the Follow-up Phase.
During this phase, dalteparin sodium will be administered subcutaneously every 
12 hours ±1 hour (no less than 8 hours between doses) with the maintenance therapeutic dose 
at Visits 5, 6 and 7. However, if a dose is not able to be delivered every 12 hours ±1 hour, 
administer the dose (no less than 8 hours between doses) and record the actual dosing. One 
Anti-Xa plasma sample will be collected at 4 hours ±1 hour post-dose at each visit to check if 
the Anti-Xa level remains within the target therapeutic range. If not, a dose adjustment may 
be required, per Investigator judgment.  All plasma samples should be drawn within the 
assigned window at each visit, however, if this is not possible, record the actual time the 
sample is drawn. Plasma samples drawn during the follow up phase that deviate outside the 
4 ± 1 hr window cannot use the Anti-Xa reference range, 0.5-1.0, and should be repeated the 
next day for both central and local labs. The actual dosing time prior to the repeat plasma 
sample draw and the actual time of the repeat sample draw must be recorded.
For non-cancer patients who stop dalteparin treatment prior to 3 months according to the 
ACCP Guidelines, Anti-Xa and Anti-IIa plasma sampling will not be required after study 
medication discontinuation.
Throughout the 3 month study period, the actual times of dosing and anti-Xa blood draw 
times will be captured on the patient Case Report Form (CRF).
The use of intravenous or intra-arterial cannulas for blood sample collection is not permitted.
5.3. Definition of End of Study and Early Discontinuation
End of study (EOS) is defined as Day 90 (± 14 days) after study Baseline. Early
Discontinuation from Study Drug: Early discontinuation from study drug treatment will be 
defined as less than 90 days of study treatment for cancer patients. For non-cancer 
patients, between 6 weeks and 3 months, rather than shorter or longer durations (Grade 2C), 
following completion of the PD Phase (2012 ACCP Guidelines15) due to: 1) new or
recurrent VTE; 2) bleeding necessitating permanent discontinuation of anticoagulant
therapy; 3) unexpected permanent discontinuation of anticoagulant therapy; 4) AEs
necessitating discontinuation of study drug; 5) withdrawal of consent to participate in the


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trial, or 6) inability to achieve therapeutic range during Dose Adjustment Phase.  
Non-cancer patients will be required to remain in the study, however, for the full 3 months, 
regardless of dalteparin treatment duration.
5.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the team SharePoint site.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact center phone number can also be used by 
investigational staff if they are seeking advice on medical questions or problems; however, it 
should only be used in the event that the established communication pathways between the 
investigational site and the study team are not available. It is therefore intended to augment, 
but not replace, the established communication pathways between the investigational site and 
the study team for advice on medical questions or problems that may arise during the study. 
The contact number is not intended for use by the subject directly, and if a subject calls that 
number, he or she will be directed back to the investigational site.
6. SELECTION OF STUDY POPULATION
6.1. Number of Subjects
Subjects, from approximately 40 centers in North America and Europe, will be enrolled
into the following five age groups:

0 to < 8 Weeks;

≥ 8 Weeks to < 2 Years;

≥ 2 Years to < 8 Years;

≥ 8 Years to < 12 Years;

≥ 12 Years to < 19 Years.
The target enrollment is 50 subjects. Enrollment will continue until 50 subjects have viable 
PD profiles after treatment doses of dalteparin. 
6.2. Inclusion Criteria
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be
eligible for entry into the study.
Subjects meet inclusion if all of the following are true:


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1. Have been objectively diagnosed with a venous thrombotic event documented using one
of the following acceptable imaging modalities within 4 days of the Screening Visit:

Compression ultrasound with Doppler [CUD];

Computed tomography with/without venography [CT/CTV];

Magnetic resonance imaging with/without venography [MRI/MRV];

Conventional venography [CV]);

Ventilation-perfusion scan [V/Q] (for pulmonary artery);

Spiral CT angiography [SCTA];

Conventional pulmonary angiogram [CPA].
2. Are judged clinically to require anticoagulation therapy.
3. Are in the age range of ≥36 weeks gestation and <19 years at the Screening Visit.
4. Have given signed informed consent (and assent, as appropriate) to participate prior to 
the Screening Visit.
5. For cancer patients only, a diagnosis of active malignancy (currently under treatment), 
other than basal cell or squamous cell carcinoma of the skin.
6. Male subjects able to father children and female subjects of childbearing potential and at 
risk for pregnancy must agree to use a highly effective method of contraception 
throughout the study and for at least 28 days after the last dose of assigned treatment. 
7. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.
8. Female subjects of non-childbearing potential must meet at least 1 of the following 
criteria:  
a.
Achieved post-menopausal status, defined as follows:  cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or psychiological 
cause; (status may be confirmed with/and have) (select one as appropriate) a serum 
follicle-stimulating hormone (FSH) level confirming the post-menopausal state; 
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c.
Have medically confirmed ovarian failure.
6.3. Exclusion Criteria
Subjects are excluded if any one of the following apply:
1. Weight ≤3.0 kg or >100 kg at the Screening Visit.


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2. Platelet count ≤50,000/mm3 (despite appropriate medical measures to support platelet 
count).
3. Received OAC therapy within 3 days of the Screening Visit .
4. History of administration of therapeutic doses of LMWH or unfractionated heparin for a 
period of > 4 days (or >8 doses of LMWH) for the qualifying VTE.
5. Received unfractionated heparin within 3 hours, or LMWH within 12 hours, of the first 
dose of dalteparin.
6. Acute VTE intervention which includes thrombolytic therapy.
7. Subjects with Mmajor bleeding or bleeding disorders such as Platelet Dysfunction, 
Protein Deficiency, Disseminated Intravascular coagulation (DIC), Factor Deficiency, 
Hemophilia, Idiopathic Thrombocytopenic Purpura (ITP) or Von Willebrand Disease at 
the time of the Screening Visit or an unacceptably high risk of bleeding, at the discretion 
of the investigator, should not be considered candidates.
8. Major bleeding at the time of the Screening Visit or an unacceptably high risk of bleeding
at the discretion of the investigator.
9. Activated partial thromboplastin time (aPTT) 5 seconds above upper limit of normal 
(ULN), which does not correct to within normal limits upon 1:1 mixing with normal 
plasma.
10. Prothrombin time (PT) 2 seconds above ULN, and that corrects to within normal limits 
upon 1:1 mixing with normal plasma.
11. Creatinine clearance <60 mL/min/1.73m2 in subjects >1 month of age.
12. Uncontrolled hypertension characterized by a sustained systolic pressure or diastolic 
pressure >99th percentile of age- and height-related norms.
13. History of heparin-induced thrombocytopenia (HIT).
14. Any condition in which the investigator feels the subject is unsafe or inappropriate for 
study participation.
15. Participation in other clinical studies involving investigational drug(s) within the past 
30 days.
16. Insufficient subcutaneous tissue to facilitate subcutaneous drug administration.
17. Pregnant female subjects; breastfeeding female subjects; male subjects able to father 
children and female subjects of childbearing potential who are unwilling or unable to use 
a highly effective method of contraception as outlined in this protocol for the duration of 
the study and for at least 28 days after the last dose of assigned treatment.


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18. Unable or unwilling to comply with scheduled follow-up visits.
6.3.1. Unscheduled Termination from the Study
Withdrawal of consent: Subjects or parents/guardians who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures.  The only exception to this is when a subject or parents/guardians
specifically withdraws consent for any further contact with him or her or persons previously 
authorized by the subject or parents/guardians to provide this information. Subjects or 
parents/guardians should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. 
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is only from further receipt of investigational 
product or also from study procedures and/or post-treatment study follow-up, and entered on 
the appropriate CRF page.  In the event that vital status (whether the subject is alive or dead) 
is being measured, publicly available information should be used to determine vital status 
only as appropriately directed in accordance with local law.
Lost to follow-up: All reasonable efforts must be made to locate subjects to determine and 
report their ongoing status. 
This includes follow-up with persons authorized by the subject or parents/guardians as noted 
above.  Lost to follow-up is defined by the inability to reach the subject after a minimum of 
2 documented phone calls, faxes, or e-mails as well as lack of response by the subject or 
parents/guardians to 1 registered mail letter.  All attempts should be documented in the 
subject’s medical records.  If it is determined that the subject has died, the site will use 
permissible local methods to obtain the date and cause of death.  If the investigator’s use of a 
third-party representative to assist in the follow-up portion of the study has been included in 
the subject’s informed consent, then the investigator may use a sponsor-retained third-party 
representative to assist site staff with obtaining the subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study.  The site 
staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.  If, after all attempts, 
the subject remains lost to follow-up, then the last-known-alive date as determined by the 
investigator should be reported and documented in the subject’s medical records.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject or parents/guardians and information received 
during contact attempts must be documented in the subject’s medical record.  In any 
circumstance, every effort should be made to document subject outcome, if possible.  The 
investigator should inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a final visit, if 
applicable, and follow up with the subject regarding any unresolved adverse events (AEs).


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If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
6.3.1.1. Subject Removal from the Study
When subjects are removed from the study the following information will be obtained:
a.
The date of the last administration and dose of study medication and all observations 
collected up to the time of termination will be recorded on the subject’s CRF along with
the reason for termination.
b. An examination of the subject will be conducted, if possible.  All assessments that 
would be conducted at Visit 7 (EOS) should be performed.
6.3.2. Subject Replacement Policy
All subjects who prematurely discontinue from the study and do not complete the PD Phase
will be replaced until 50 subjects have viable PD Phase Anti-Xa data. 
7. TREATMENTS
Dalteparin sodium (Fragmin®) will be provided in:

Multiple dose vials of 25,000 IU/1 mL (3.8mL for US or 4mL for ROW) containing 
preservative benzyl alcohol;

Preservative-free single dose vials of 2,500 IU/1 mL (4mL) [where available];

Preservative-free 10,000 IU / 1 mL single-dose graduated syringe (can be diluted as 
needed per the IP Manual).
Dosing administration is subcutaneous, twice daily.  Study medication can only be 
administered to patient by a healthcare professional (ie, study nurse) or trained 
parent/caregiver.  Hospital nurses that may administer study medication to in-patient subjects 
do not require GCP training.  However, they must receive study medication administration 
training from the site staff and the training should be documented.
The use of cannulas to administer study medication is not permitted.
Subjects, aged 0 to less than 8 weeks will receive twice daily dose of 125 IU/kg.  
Subjects, aged greater than or equal to 8 weeks to less than 2 years will receive twice
daily dose of 150 IU/kg. Subjects aged greater than or equal to 2 years to less than
8 years and subjects aged greater than and equal to 8 years to less than 12 years will
receive twice daily dose of 125 IU/kg. Subjects aged 12 years to less than 19 years will
receive twice daily dose of 100 IU/kg. 
All subjects will have dose adjustments in 25 IU/kg increments or decrements based upon
Anti-Xa therapeutic goal range of 0.5 to 1.0 IU/mL. Dalteparin sodium will be 
administered subcutaneously every 12 hours ±1 hour (no less than 8 hours between doses).
However, if a dose is not able to be delivered every 12 hours ±1 hour, administer the dose 
(no less than 8 hours between doses) and record the actual dosing time.


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
Dose Adjustment Phase (Baseline/Day 1 up to Day 7):
Anti-Xa levels will be measured at 4 hours post-dose (±1 hour) daily for up to 7 days to 
determine if the anti-Xa level is within the target therapeutic range of 0.5 to1.0 IU/mL. 
However, the first Anti-Xa level may be taken after the first, second or third dose per 
Investigator judgment.  The next dalteparin dose will be adjusted if the target therapeutic
range is not achieved. If the therapeutic range is not achieved, the dalteparin dose must be
adjusted per protocol.  All plasma samples should be drawn within the assigned window at 
each visit, however, if this is not possible, record the actual time the sample is drawn).  
Plasma samples drawn during the Dose-Adjustment Phase and Follow-Up Phase that deviate 
outside the 4 ± 1 hr window cannot use the anti-Xa reference range, 0.5-1.0 IU/mL, and 
should be repeated the next day for both central and local labs. The actual dosing time prior 
to the repeat plasma sample draw and the actual time of the repeat sample draw must be 
recorded.
After dose adjustment, Anti-Xa levels should be re-measured after the first, second or third
dose per Investigator judgment. Dosage can be adjusted a maximum of up to 6 times (up to
Day 7) to achieve Anti-Xa therapeutic range. If the target range is not achieved within the
7 day period, the subject is withdrawn from the study. 
The dose at which a therapeutic Anti-Xa level is achieved is then maintained as the
therapeutic dose in subsequent phases of the study unless dose adjustment is necessary.

Pharmacodynamic Phase (Following completion of Dose Adjustment Phase) 
Day 2 or 3 up to Day 14 [up to 7 days]): Subjects completing the Dose Adjustment
Phase will enter into the PD Phase and continue daily dosing every 12 hours ±1 hour
of dalteparin sodium with the final maintenance therapeutic dose from the Dose
Adjustment Phase (no less than 8 hours between doses). However, if a dose is not 
able to be delivered every 12 hours ±1 hour, administer the dose (no less than 8 hours 
between doses) and record the actual dosing time.  The plasma sample should be 
re-drawn, if possible, at the correct time point.

Follow-up Phase (Visits 5, 6 and 7, following completion of Pharmacodynamic 
Phase): Dalteparin sodium will be administered subcutaneously every 12 hours ±1 hour
(no less than 8 hours between doses) during Visits 5, 6 and 7. However, if a dose is 
not able to be delivered every 12 hours ±1 hour, administer the dose (no less than 
8 hours between doses) and record the actual dosing time.

No other systemic anticoagulants are allowed during the study with the exception of
allowance of hospital specific Intra Venous (IV) (including central venous catheter
line patency protocols which could include tissue Plasminogen Activator (tPA) and
3 IU/kg stat dose of unfractionated heparin, if the subject is unable to be treated with 
study drug due to an unanticipated hospital admission or a clinical event.


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For non-cancer patients who stop dalteparin treatment prior to 3 months according to the 
ACCP Guidelines, Anti-Xa and Anti-IIa plasma sampling will not be required after study 
medication discontinuation.  Treatment will be continued until any of the following occurs:

New or progressive VTE (whether symptomatic or asymptomatic);

Bleeding necessitating permanent discontinuation of anticoagulant therapy;

Unexpected thrombocytopenia;

Other AE necessitating discontinuation of study drug, withdrawal of consent or, 
scheduled study termination completion;

Unexpected permanent discontinuation of anticoagulation therapy.
7.1. Dose Modification
In the event of medical procedures that may be required during the study, study medication 
can be held according to the institutional standard of care.
7.1.1. Thrombocytopenia
Platelet count will be evaluated at Screening, Baseline, the last day of the dose adjustment
and PD Phases, as well as the clinical visits during the Follow-up Phase. For subjects
whose platelet counts unexpectedly fall below 50,000/mm3, HIT antibody testing will
be performed. If the HIT antibody is positive, the subject must be discontinued. If, 
during the study, the platelet count falls to below 50,000/mm3in a manner that is deemed to
be expected by the treating oncologist (ie, consistent with chemotherapeutic effect on 
hematopoiesis), the administration of dalteparin should be temporarily stopped. After
medical measures have been taken to increase the platelet count to a level 50,000/mm3,
administration of dalteparin can be restarted.  If the platelet count does not increase to a level 
of 50,000/mm3 within 2 days in spite of medical measures, discontinuation of dalteparin
should be considered. 
Withdrawal of the subject from the study should be considered if platelet count does not
increase to a level of 50,000/mm3 after 5 days following discontinuation of dalteparin.
7.1.2. Renal Dysfunction
For subjects who may experience impaired renal function during the course of the study,
whose CrCl declines to <30 mL/min/1.73m2, dalteparin sodium may need to be adjusted
and Anti-Xa levels should be monitored to maintain appropriate levels (ie, trough Anti-Xa
levels of <0.4 IU/mL) and the medical monitor should be notified.  Subjects with major
bleeding or bleeding disorders such as Platelet Dysfunction, Protein Deficiency,
Disseminated Intravascular coagulation (DIC), Factor Deficiency, Hemophilia, Idiopathic 
Thrombocytopenic Purpura (ITP) or Von Willebrand Disease at the time of the Screening
Visit or an unacceptably high risk of bleeding, at the discretion of the investigator, should not 
be considered candidates.


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
To assess for bioaccumulation of dalteparin sodium, trough Anti-Xa levels should be
checked prior to the next dose. The trough Anti-Xa levels should be <0.4 IU/mL;

If the Anti-Xa level is above 0.4 IU/mL, the dose of dalteparin sodium should be
reduced by either holding one dose or reducing by 25 IU/kg, or by doing both;

The Anti-Xa measurement should be repeated after the next dose. The actual dosing 
time prior to the repeat plasma sample draw and the actual time of the repeat sample 
draw must be recorded.
7.2. Use of Other Anticoagulants
No other systemic anticoagulants are allowed during the study with the exception of
allowance of hospital specific IV line patency protocols which could include tPA and
3 IU/kg dose of unfractionated heparin or transient use of another LMWH or un-fractionated
heparin for no longer than 48 hours, if the subject is unable to be treated with study drug
due to an unanticipated hospital admission or a clinical event.
Subjects are excluded if they received unfractionated heparin within 3 hours, or LMWH 
within 12 hours, of the first dose of dalteparin.
7.3. Identity of Investigational Product(s)
The medication used in this study will be dalteparin sodium (Fragmin®), supplied in
open-label format as the following:

Multiple dose vials of 25,000 IU/1 mL (3.8mL for US or 4mL for ROW) containing 
preservative benzyl alcohol;

Preservative-free single dose vials of 2,500 IU/1 mL (4mL) [where available];

Preservative-free 10,000 IU /1 mL single-dose graduated syringe (can be diluted as 
needed per the IP Manual).
The multidose vials utilized in this study include a preservative. The single-dose pre-filled
syringe and single-dose vial are preservative-free.
Only study subjects that are hospital in-patients can receive the 10,000 IU/1mL dosage form, 
diluted to 2,500 IU/mL. If a study subject is an out-patient and will be administered study 
drug at home by a caregiver, they must use either the 2,500 IU / 1 mL preservative-free 4 mL 
vial to prepare the prescribed dose or the 10,000 IU / 1 mL preservative-free syringe 
undiluted to prepare the prescribed dose.  The 10,000 IU / 1 mL preservative-free syringe 
must not be further diluted when prepared at the study subject’s home.
Each of the above three study medication presentations can be dispensed to subjects when 
they are out-patients, however, not if they require dilution.


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7.4. Labeling and Packaging of Treatments
The study medication, dalteparin sodium (Fragmin®), will be manufactured by Pfizer Inc.
and packaged and distributed by a designated vendor in accordance with instructions
provided by Pfizer Inc. Pfizer Inc will also provide the 0.5 mL and 1.0 mL Tuberculin
(TB) latex-free, micro-dosing syringes as well as sterile empty vials for evacuation.
Each carton will contain a clinical label including text to meet the country regulatory
requirements and include but not limited to the following information: sponsor name,
protocol number, storage conditions, contents and directions for use. 
Cartons with multidose and single-dose vials will contain 1 vial per carton. Cartons with
pre-filled syringes will contain 36 syringes per carton.
Refer to the tables in Appendix2 for guidance on subjects dosing requirements.
Dosing of the 10,000 IU/1 mL pre-filled syringe formulation should not be administered 
directly via the original pre-filled syringe unless the intended patient dose is exactly 
10,000 IU/1 mL. All other doses using the 10,000 IU/1 mL pre-filled syringe presentation 
should be evacuated into a sterile vial and administered via a separate syringe to ensure 
accurate patient dosing. For full preparation and administration information on all three 
investigational product presentations refer to the Investigational Product Manual. 
7.4.1. Storage
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products (including any comparator and/or marketed products) are stored in a 
secured area with controlled access under required storage conditions and in accordance with 
applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
See the Investigational Product (IP) manual or package insert for storage conditions of the 
product once diluted.
Any storage conditions stated in the single reference safety document (SRSD) will be 
superseded by the storage conditions stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 


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Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
7.4.2. Drug Supplies
For full Investigational product details, please refer to the Investigational Product Manual.
Drug supply will be provided to sites after the site’s Investigator Initiation Package (IIP) 
documents are received and approved All drug supplies for this study must be stored 
according to labeled storage conditions.  If any excursion from the recommended storage (per 
study drug label) occurs, the study monitor or other sponsor study team member must be 
consulted before using the study drug.
Two different size syringes (1 mL TB syringe and 0.5 mL TB syringe) will be available to all 
sites. Investigators will use their clinical judgment regarding which size syringe is most 
applicable for administration of each subject’s individual study drug dose level. 
7.4.3. IP Accountability Log
The Investigator or delegated personnel on the study site must maintain records of the
receipt of study drug to the study site, the inventory at the site, the amount dispensed to each
subject, and the return of the unused study medication by the subject to the Investigator. 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer and all destruction must be adequately documented.
All used syringes will be disposed as per local biohazard requirements.
The IP Accountability Log must be available for monitoring, auditing or inspection. 
Details of the accountability of clinical supplies will be recorded.


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8. ADMINISTRATION OF TREATMENTS
All subjects will be dosed based on age, weight, and anti-Xa levels.  After the Baseline 
evaluations have been completed, subjects will receive their first dose of study medication
by subcutaneous injection according to the following dosing administration instructions 
below:

Patients should be sitting or lying down for FRAGMINdeep subcutaneous 
administration injection.  Based on experience in adults, dalteparin sodium 
(Fragmin) should be injected in a U-shape area around the navel, the upper outer side 
of the thigh or the upper outer quadrangle of the buttock.  However, other sites may 
be more suitable for pediatric patients.  Using the thumb and forefinger, you must lift 
up a fold of skin while giving the injection.  The entire length of the needle should be 
inserted at a 45 to 90 degree angle.  The injection site should be varied daily;

If a subject receives a partial dose due to a dosing error, a second dose should not be 
given to supplement the initial partial dose. This should be stressed to parents and 
caregivers if administering study drug to subjects who are out-patients and to hospital 
staff that will dose the study subjects who are in-patients;

Clinical supply that is unused by one subject and returned to the site cannot be 
redispensed for another visit for the same subject or be redispensed to a different 
subject.
8.1. Dosing Groups:
1. Subjects ages 0 (greater than or equal to 36 weeks gestation) to less than 8 weeks
will receive an initial dose of 125 IU/kg twice daily by subcutaneous injection of 
preservative-free solution ONLY supplied in single-dose prefilled graduated
syringes, containing 10,000 IU/1 mL or preservative-free 4 mL single-dose vials 
containing 2,500 IU/1 mL if available. If the 2,500 IU/1 mL vials are not available, 
the 10,000 IU/1 mL dosage form can be diluted in the hospital pharmacy to 
2,500 IU/1 mL by a trained pharmacist or pharmacy technician as needed, according 
to the suggested dilution process outlined in the IP Manual. 
2. Subjects aged greater than equal to 8 weeks to less than 2 years will receive an 
initial dose of 150 IU/kg twice daily by subcutaneous injection of 
preservative-free solution ONLY supplied in single-dose prefilled graduated 
syringes, containing 10,000 IU/1 mL, or preservative-free 4 mL single-dose vials 
containing 2,500 IU/1 mL if available. If the 2,500 IU/mL vials are not 
available, the 10,000 IU/1 mL dosage form can be diluted in the hospital 
pharmacy to 2,500 IU/1 mL by a trained pharmacist or pharmacy technician as 
needed, according to the suggested dilution process outlined in the IP Manual. 
3. Subjects aged greater than or equal to 2 years to less than 8 years and subjects ages
greater than or equal to 8 years to less than 12 years will receive an initial dose of
125 IU/kg by subcutaneous injection of preservative-free solution supplied in
prefilled syringes containing 10,000 IU/1 mL, or preservative-containing
95,000 IU/3.8 mL (US) or 100,000/4mL (Europe) (25,000 IU/1 mL) multidose vials.
For smaller doses, preservative-free 4 mL single dose vials containing 2,500 IU/1 mL 


FRAG-A001-201 (A6301094)
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Page 40
may be used for dose preparation if available.  If the 2,500 IU/1 mL vials are not 
available, the 10,000 IU/1 mL dosage form can be diluted in the hospital pharmacy to 
2,500 IU/1 mL by a trained pharmacist or pharmacy technician as needed, according 
to the suggested dilution process outlined in the IP Manual.
4. Subjects aged greater than or equal to 12 years to less than 19 years will receive an 
initial dose of 100 IU/kg by subcutaneous injection of preservative-containing 
solution supplied in either preservative-free pre-filled syringes prefilled syringes 
containing 10,000 IU/1 mL or preservative containing 95,000 IU/3.8 mL 
(25,000 IU/1 mL) multidose vials.

If hospitalized during the Dose Adjustment and PD Phases, all doses will be prepared
daily by the trained hospital staff. After hospital discharge, study drug will be
dispensed to the parents/guardians who will be trained in the handling and storage of
the study drug. If a subject receives a partial dose due to a dosing error, a second 
dose should not be given to supplement the initial partial dose.  This should be 
stressed to parents and caregivers if administering study drug to subjects who are 
out-patients and to hospital staff that will dose the study subjects who are in-patients.
While subjects are in-patients at the hospital, study drug administration will be conducted by 
the delegated, trained investigative site staff, or, delegated other hospital personnel who are 
trained by the Investigator regarding correct study drug administration.  When subjects are 
released from the hospital, the designated parents/guardians will be trained by the 
Investigator regarding correct study drug dosing and administration.  The trained 
parents/guardians will dose and administer study drug to the subjects at home.
If parents/guardians are not deemed capable or are not willing to administer study drug to the 
subjects when they are released from the hospital, a visiting nurse,  may be trained and made
available by the Principle Investigator (PI) or designee, to prepare and administer a daily
dose for subjects as needed, if this service is available through the investigative site..
To calculate dosing volumes refer to the protocol dosing directions below. Subjects
weighing greater than 3 kg and less than or equal to 100.1 kg are allowed in the study.  
For age- and weight-based dosing calculations, see Appendix 2.

For subjects 0 (≥36 weeks gestation) to <2 year of age, weighing ≥3.0 kg:
Preservative-free dosing solutions must be used in these subjects.  The final dose is to 
be prepared by drawing up the appropriate dose of drug solution into the appropriate
syringe supplied;

For subjects ≥2 years to <12 years: Withdraw dosing volume needed (obtained from
dosing charts) from the 95,000 IU/3.8 mL (25,000 IU/1 mL) multidose vial using a
1.0 mL micro-dosing syringe or per Investigator’s judgment, the 2,500 IU/1mL single 
dose vial or, utilize the prefilled syringes containing 10,000 IU/1 mL labeled 
Fragmin(dalteparin sodium), for the required dose.  Note that if the required dose is 
exactly 10,000 IU/mL, the dose can be administered directly from the pre-filled 
syringe. 

For subjects ≥12 years to < 19 years of age: Withdraw dosing volume needed
(obtained from dosing charts) from 95,000 IU/3.8 mL (25,000 IU/1 mL) multidose
vial labeled Fragmin® (dalteparin sodium) using a 1.0 mL micro-dosing syringe, or 


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per the Investigator’s judgment or utilize the prefilled syringes containing
10,000 IU/1 mL labeled Fragmin® (dalteparin sodium).  Note that if the required 
dose is exactly 10,000 IU/mL, the dose can be administered directly from the 
pre-filled syringe.
8.2. Dosing Scheme: Three Phases
1. Dose Adjustment Phase:
All subjects will receive daily dosing every 12 hours ±1 hour with dalteparin sodium
with the final dose from the Dose Adjustment Phase (no less than 8 hours between 
doses). However, if a dose is not able to be delivered every 12 hours ±1 hour, 
administer the dose (no less than 8 hours between doses) and record the actual dosing 
time. The first Anti-Xa plasma sample drawn after the initial dose of study drug 
treatment should be conducted 4 hours ±1 hour after the first, second or third dose of 
study medication per Investigator judgment.  Subsequent Anti-Xa plasma samples
conducted following dose adjustments will also be drawn at 4 hours ±1 hour
post-dose, after the first, second or third dose of study medication per Investigator 
judgment. .  If the Anti-Xa level is not within the target therapeutic range of 
0.5-1.0 IU/mL, the dose must be adjusted in increments or decrements of 25 IU/kg
in order to achieve target Anti-Xa levels (0.5 to 1.0 IU/mL). After dose
adjustment, Anti-Xa levels should be measured also after the first, second or third 
dose per Investigator judgment. If the therapeutic range is not achieved after a
maximum of 6 adjustments (up to Day 7), the subject will be withdrawn from the
study.
2. Pharmacodynamic Phase:
Subjects completing the Dose Adjustment Phase will enter into the PD Phase and
will continue with daily dosing every 12 hours ±1 hour with dalteparin sodium with
the final dose from the Dose Adjustment Phase (no less than 8 hours between doses).
However, if a dose is not able to be delivered every 12 hours ±1 hour, administer the 
dose (no less than 8 hours between doses) and record the actual dosing time. Subjects
will be randomized to two different plasma sampling windows (1 to 3 h and 5 to
8 h or 3 to 5 h and 8 to 12 h) for anti-Xa plasma samples (for the central lab, only) via 
the Pfizer Interactive Web Response System (IWRS) system, IMPALA (see below). 
IMPALA will only provide the subject Screening ID number and randomized plasma 
sampling group assignment (and respective Randomization Number) during the study
(it will not manage drug supply inventory). The plasma sampling times can take
place over the duration of the PD Phase to avoid blood volume shifts if necessary.  If 
a plasma sample is not drawn during the correct assigned time point, it should be 
repeated if possible, at the correct time point when appropriate.
The assignment of the plasma sampling time points to the subjects within each age group 
will be centrally randomized via the IMPALA system (note that only plasma sampling 
groups will be randomized, not study medication.  This is an open-label treatment study).
The two plasma samples will be collected from each subject during the PD Phase based on 
the subject’s assigned plasma sampling randomization group:

Randomization Schedule A:


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
One sample at 1 to 3 hours post-dose;

One sample at 5 to 8 hours post-dose.

Randomization Schedule B:

One sample at 3 to 5 hours post-dose;

One sample at 8 to 12 hours post-dose.
3. Follow-up Phase:
In the Follow-Up Phase, subjects will continue daily dosing every 12 hours ±1 hour 
with dalteparin sodium with the final dose from the Dose Adjustment Phase (no less 
than 8 hours between doses) until EOS or ET. However, if a dose is not able to be 
delivered every 12 hours ±1 hour, administer the dose (no less than 8 hours between 
doses) and record the actual dosing time. In-clinic visits will occur on Visits 5, 6 and 
7 for safety, and efficacy assessments, and Anti-Xa plasma samples.  Dose 
adjustments can be made during these visits if necessary.  The Principal Investigator or 
designee will follow-up weekly during a telephone interview with subjects and/or 
caregivers after discharge from the hospital to assess study compliance and general 
well-being.  Subjects will have repeat imaging (using the same imaging method used 
at Screening) at the EOS visit or Early Termination (ET) visit to measure clot 
resolution.
For non-cancer patients who stop dalteparin treatment prior to 3 months according to the 
ACCP Guidelines, Anti-Xa and Anti-IIa plasma sampling will not be required after study 
medication discontinuation.
Treatment will continue until any of the following occurs:

New or progressive VTE (whether symptomatic or asymptomatic);

Bleeding necessitating permanent discontinuation of anticoagulant therapy;

Unexpected thrombocytopenia;

Other AEs necessitating discontinuation of study drug, withdrawal of consent, or 
scheduled study termination completion;

Unexpected permanent discontinuation of anticoagulation therapy.
For procedures that require interruption of study treatment, it is recommended to follow
the ACCP guidelines.1 The guidelines state that it may be advisable to omit two doses of
LMWH before procedures being performed and resume 12 to 24 hours after the procedures.


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8.3. Method of Assigning Subjects to Treatment Groups
This is an open label study. All 50 subjects will receive dalteparin sodium (Fragmin®). 
During the PD Phase, subjects will be centrally randomized to one of two different plasma 
sampling windows (1 to 3 h and 5 to 8 h or 3 to 5 h and 8 to 12 h) via the Pfizer IWRS
system, IMPALA.
8.4. Selection of Doses in Study
Dosing in the study was based upon published literature describing the dosing previously
used in this subject population with (Fragmin®).  Nohe et al have shown that the Anti-Xa
levels in these subjects have fallen within the target range of Anti-Xa levels (0.5 to
1.0 IU/mL) using similar dosing.12
8.5. Blinding
This is an open-label trial.
8.6. Prior and Concomitant Therapy
No other systemic anticoagulants are allowed during the study with the exception of
allowance of hospital specific IV line patency protocols which could include tPA and
3 IU/kg stat dose of unfractionated heparin, if the subject is unable to be treated with study 
drug due to an unanticipated hospital admission or a clinical event.  Subjects are excluded 
from the study if they received unfractionated heparin within 3 hours, or LMWH within
12 hours, of the first dose of dalteparin.  Use of oral, inserted, injected, implanted or 
transdermal hormonal methods of contraception is not allowed due to risks of VTE.
9. ASSESSMENTS AND ENDPOINT DEFINTIONS
9.1. Endpoint Definitions
9.1.1. VTE Endpoints
A suspected new or progressive symptomatic VTE, in the same anatomical region, should
be documented with the same imaging method used at Screening/ Baseline. Suspected
new or progressive VTE in a different anatomical region should be documented utilizing
institutional standards. These images should be collected and be included in the primary 
source records. Thrombus resolution of the qualifying event will be measured by repeat
imaging at the EOS visit (using the same modality as that which was used to diagnosis the
thrombosis prior to enrollment). If an image has been captured prior to the EOS and it
demonstrates complete resolution of the qualifying VTE, then a repeat image does not 
need to be done again at day 90. For purposes of the study, the complete resolution image
will be the “EOS” image for the index event.
In the assessment of a new or progressive symptomatic thrombus, the following general 
definitions will be utilized;
Symptomatic New VTE: Symptomatic VTE confirmed by at least one radiographic test.  
Asymptomatic VTE within a venous segment noted to be patent on a prior imaging study.  
Symptomatic will be defined as: New or progressive signs and symptoms as judged by the 
investigator including but not limited to:


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
Objective swelling;

Pain or tenderness;

Pitting edema;

Erythema or cyanosis.
All New VTE: All VTE confirmed by at least one radiographic test.
Stable VTE: Follow-up study demonstrating stable clot burden utilizing the same imaging 
modality as the Screening Visit.
Regression of VTE: Follow-up study demonstrating regressed clot burden utilizing the
same imaging modality as the Screening Visit.
Progression of VTE: Progression of clot burden on a follow-up study in terms of
severity of occlusion, or involvement of new venous segments at any time after the initial
diagnosis.
In the assessment of a new or recurrent PE, the following general definitions will be utilized;
New PE: Symptomatic PE confirmed by presence of an intraluminal filling defect of the 
pulmonary artery on CT angiography and/or a mismatched defect on a nuclear V/Q scan. All
new PE’s will be considered to be a symptomatic event.
Stable PE: Follow-up study demonstrating stable clot burden utilizing the same imaging 
modality as the Screening Visit.
Regression of PE: Follow-up study demonstrating regressed clot burden utilizing the
same imaging modality as at the Screening Visit.
Progression of PE: Progression of clot burden on a follow-up study in terms of
involvement of new pulmonary arterial segments within 14 days after the initial diagnosis or 
PE.
Determination of the above definitions will be made utilizing set criteria based on clot
location and imaging modality utilized.
DVT and PE specific definitions;
To meet the criteria for new or progressive DVT one of the following criteria must be met:
1. A new intraluminal filling defect in two or more projections on venography (New
VTE).
2. 5 cm or more extension or an intraluminal filling defect previously seen on ultrasound
or venography (progression of VTE).
3. Presence of intraluminal thrombus.
PE Specific Definition:
To meet the criteria for new or progressive PE one of the following criteria must be met:
1. A new intraluminal filling defect or a sudden cut-off of vessels more than 2.5 mm in
diameter on a pulmonary angiogram.


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2. An intraluminal filling defect on CT angiography involving the main pulmonary 
artery, or proximal generations of the branch pulmonary arteries that are reliably 
evaluated by CT.
3. High probability V/Q scans.
9.1.2. Bleeding/Safety Events
Safety assessments: (as described in the Protocol Flow Chart) will include the following:
medical history, physical examination, vital signs, and study drug exposure/compliance, 
review of AEs and concomitant medications, and laboratory evaluations.
Bleeding events will be classified as follows:
MAJOR BLEEDING (Composite of the following)
a.
Fatal bleeding.
b. Clinically overt bleeding associated with a decrease in Hgb of at least 2 g/dL in
24 hours.
c.
Overt bleeding deemed by the attending physician to be unrelated to the subject’s 
underlying condition and accompanied by blood product administration.
d. Overt bleeding which is retroperitoneal, intracranial, intraspinal, intraocular, or intra 
articular.
e.
Overt bleeding deemed by the attending physician to necessitate permanent 
discontinuation of trial medication.
CLINICALLY RELEVANT NON MAJOR BLEEDING

Bleeding resulting in any medical or surgical interventions but which did not meet
the criteria for major bleeding.
MINOR BLEEDING

Bleeding that does not meet the criteria for Major or clinically relevant non
major bleeding.

Screening evaluations may be used as the baseline assessments.
Antithrombin levels are to be performed once within 1 week post-diagnosis of VTE and
at each study visit when Anti-Xa samples are drawn.
9.1.3. Medical History
A complete medical history will be obtained at Screening from the subject and/or guardian. 
All body systems, conditions and diagnoses will be reviewed noting onset and end dates. 
Any clinically significant changes and/or exacerbations of condition from following the first 
dose of study medication will be considered an AE.


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9.1.4. Physical Examination
A complete physical examination will be performed at Screening and/or Baseline visit per 
Investigator judgment, the end of the Dose Adjustment Phase, the PD Phase, and during the 
Follow-Up Phase at Visits 5, 6, and 7. This exam will include evaluation of the head, eyes,
ears, nose, throat, neck, circulatory system, heart, chest, lungs, abdomen, extremities, skin,
neurological status and weight measurements, as well as any other physical condition of 
note.
9.1.5. Pregnancy Test
For female subjects of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 IU/mL, will be performed at screening, before investigational 
product administration at the Baseline visit, unless the Baseline visit is conducted within 
2 days of the Screening Visit, and at all other study visits.  During the Dose Adjustment 
Phase, if multiple study visits are conducted, the pregnancy test will only be required once in 
the 7-day Dose Adjustment Phase.  A negative pregnancy result is required before the subject 
may receive the investigational product.  Pregnancy tests will also be done whenever 
1 menstrual cycle is missed during the active treatment period (or when potential pregnancy 
is otherwise suspected), and repeated at follow-up visits and at the end of the study to 
confirm the subject has not become pregnant during the study.  Pregnancy tests may also be 
repeated as per request of institutional review boards (IRBs)/ethics committees (ECs) or if 
required by local regulations.
In the case of a positive confirmed pregnancy, the subject will be withdrawn from 
administration of investigational product and from the study.
All male subjects who are able to father children and female subjects who are of childbearing 
potential and are sexually active and at risk for pregnancy must agree to use a highly 
effective method of contraception consistently and correctly for the duration of the active 
treatment period and for at least 28 days after the last dose of investigational product.  The 
investigator or his or her designee, in consultation with the subject, will confirm that the 
subject has selected an appropriate method of contraception for the individual subject and his 
or her partner from the permitted list of contraception methods (see below) and instruct the 
subject in its consistent and correct use.  Subjects need to affirm that they meet the criteria 
for correct use of at least 1 of the selected methods of contraception.  The investigator or 
his/her designee will discuss with the subject the need to use highly effective contraception 
consistently and correctly according to the schedule of activities and document such 
conversation in the subject’s chart.  In addition, the investigator or his or her designee will 
instruct the subject to call immediately if the selected contraception method is discontinued 
or if pregnancy is known or suspected in the subject or the subject’s partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Correctly placed copper -containing intrauterine device (IUD). 


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2. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate (See Appendix 4 regarding countries where this method of birth 
control is not considered highly effective).
3. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
4. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject. 
The use of oral, inserted, injected, implanted or transdermal hormonal methods of 
contraception are not allowed due to risks of VTE.  If a subject was using a hormonal based 
contraceptive prior to study entry, it should be discontinued prior to study entry.  There is no 
required wash-out period required for recently discontinued hormonal based contraception.
9.1.6. Imaging
Documentation of an objectively diagnosed venous thrombotic event will be diagnosed using 
the following acceptable imaging at Screening:

Compression ultrasound with Doppler [CUD];

Computed tomography with/without venography [CT/CTV];

Magnetic resonance imaging with/without venography [MRI/MRV];

Conventional venography [CV]);

Ventilation-perfusion scan [V/Q] (for pulmonary artery);

Spiral CT angiography [SCTA];

Conventional pulmonary angiogram [CPA].
The investigator will make every effort to have a repeat imaging performed using the same 
method at the end of study (EOS) (Visit 7) at ET or due to progression of a VTE. The Visit 
7 EOS visit imaging is not required if a previous visit imaging has demonstrated resolution
of clot.
A copy of all images should be kept with the source documents.
9.1.7. Vital Signs
Vital signs will be measured at each visit. Evaluations will include the following
measurements, a resting supine or sitting position for 2 minutes:

Blood Pressure;


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
Temperature (recorded in Celsius);

Heart Rate;

Respiratory Rate;

Height and Weight.
For the weighing of infants and newborns, clothing should be removed leaving only a clean, 
dry diaper and be positioned in the center of the scale tray, which should be placed on a 
stable, flat surface. For older children, a scale with appropriate range and resolution should
be used. Shoes, bulky layers of clothing and jackets must be removed prior to weight 
measurement so that only light clothing remains. The contents of pockets should be emptied.  
Subjects should remain still during the measurement of weight.
9.1.8. Clinical Laboratory Assessments
Anti-Xa assessments will be conducted at both the local and central laboratories at each 
visit, except during the PD Phase, when the Anti-Xa assessment will be conducted at only the 
central laboratory.  Additionally, the Anti- IIa assessments will be conducted only at the
central laboratoryat each visit.
Anti-Xa levels will be measured at 4 hours (±1 hour)
post-dose daily for up to 7 days during the Dose Adjustment Phase. The first Anti-Xa level
after initial study medication dosing may be drawn after the first, second or third dose or per
Investigator judgment and sent to both the central and local laboratories until a target 
therapeutic range of 0.5 to 1.0 IU/mL is obtained. Plasma samples may be drawn after the 
morning or evening dose.  After any dose adjustments, the Anti-Xa samples may also be 
drawn after the first, second or third dose, per Investigator judgment.
During the PD Phase, subjects will be randomized to 1 of 2 different plasma sampling
windows. The Anti-Xa plasma samples (2 samples per subject) will be obtained at either
1 to 3 hours and 5 to 8 hours or 3 to 5 hours and 8 to12 hours (for central lab, only). This
plasma sampling can occur over a 7-day time frame. Once in the Follow-up Phase,
subjects will then have Anti-Xa plasma samples drawn at Visits 5, 6 and 7 post-dose and sent
to both the local and central laboratories.
The use of cannulas for blood collection are not permitted.
NOTE: Plasma samples drawn for Anti-Xa and Anti-IIa must not be hemolyzed. All 
precautions must be made to ensure that the plasma samples are not hemolyzed. 
Throughout the 3 month study period, the actual times of dosing and Anti-Xa blood draw
times will be captured on the patient CRF.
Pharmacodynamic Measurements
Blood volumes for PD measurements (Anti Xa and Anti IIa) will be as follows for the 
Central Lab blood sample collection:


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
Newborn and Infant Cohort Groups: One 2.0 mL Blue Topped Tube filled to the top 
with 1.8 mL of blood (tube provided by Central Lab) for processing the plasma 
samples (contains 0.2 mL of sodium citrate anticoagulant)

Pre School, School Age and Teen Cohort Groups: One 3.0 mL Blue Topped Tube, 
filled to the top with 2.7 mL of blood (tube provided by Central Lab) for processing 
the plasma samples (contains 0.3mL of sodium citrate anticoagulant).
The 2.0 mL tubes will be provided to the site in a bulk shipment, whereas the 3.0 mL tubes 
will be provided in kits per visit.
Instructions for collection, processing, and shipment of samples for anti Xa and anti IIa 
analysis by the central lab will be provided in the Laboratory Manual.  Please refer to the 
Laboratory Manual for all details regarding the drawing and processing of the anti Xa and 
anti IIa plasma samples.
Unfractionated heparin contamination is a major concern when blood samples are taken from 
a port when testing for low molecular weight heparin (Fragmin®).  The following procedure 
will help eliminate the interference of unfractionated heparin in the anti Xa PD samples:

Access the port according to the institutional protocol.

Prior to plasma sampling, flush the port with 5 ml of heparin free normal saline.  For 
subjects 0 1 years of age, follow the institutional protocol for flush and discard.

For children <7 kg body weight use 3ml discard.  Draw 5 ml of whole blood for 
discard for children > 7kg body weight.  The institutional protocol takes precedent 
over the above procedure for saline flush and discard volumes.
Subjects will be randomized to two different plasma sampling windows (1 to 3 h and 5 to 8 h 
or 3 to 5 h and 8 to 12 h), so each subject will have two blood draws during the PD Phase for 
the central lab, only.  The plasma sampling times can be spread over the duration of the PD 
Phase (up to 7 days) to avoid blood volume shifts if necessary.  All plasma samples should be 
drawn within the assigned window at each visit, however, if this is not possible, record the 
actual time the sample is drawn.  If the PD Phase sample is drawn outside the required 
randomization assigned time period, it should be repeated if possible. 
Plasma samples drawn during the Dose Adjustment Phase and Follow Up Phase that deviate 
outside the 4 ± 1 hr window cannot use the Anti Xa reference range, 0.5 1.0 IU/mL, and 
should be repeated the next day.  The actual dosing time prior to the repeat plasma sample 
draw and the actual time of the repeat sample draw must be.
In this study, the PD effect (Anti Xa level) is used as a surrogate (PK of dalteparin) for the 
time course of drug exposure because 1) analytical difficulty in measuring the dalteparin 
levels in plasma and 2) the instantaneous drug effect quantitated by Anti Xa level.  Hence, 
the study is only characterizing the PD of dalteparin
The safety lab tests below will be conducted at the institutional local lab.


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
Hematology/Coagulation: red blood cells (RBC), Hemoglobin, Hematocrit, Total 
White Blood Cell Count with differential, Platelet Count, PT, aPTT, International 
Normalized Ratio (INR);

Antithrombin level at every visit that anti-Xa levels are drawn, and as per 
investigator’s discretion at the Unscheduled Visit;

Clinical Chemistry: Albumin, Alkaline Phosphatase, Alanine Aminotransferase 
(ALT), Aspartate Aminotransferase (AST), Calcium, Phosphorus, Total Protein, 
Magnesium, lactate dehydrogenase (LDH), Creatinine, Glucose, Total Bilirubin, 
Sodium, Potassium, Chloride, Carbon Dioxide, and Blood Urea Nitrogen (BUN), 
Creatinine Clearance:

Pregnancy: Serum beta Human Chorionic Gonadotropin (β hCG) assessments or 
urine pregnancy tests will be performed for post-menarchal females at Screening or 
Baseline and all other study visits;

Contact the sponsor if a subject is <1 month old. 

For any study sites that also require urine specimen collection in addition to blood 
draw for Creatinine Clearance reporting, according to local standards, urine collection 
will be conducted as required per local standards and Creatinine Clearance results 
will be provided in the CRF accordingly.

If any study site’s institutional laboratory does not conduct Creatinine Clearance tests,  
or if the Creatinine Clearance test is deemed not feasible or reliable by the 
Investigator given the study participant’s clinical circumstances the Investigator can 
calculate the estimated Creatinine Clearance value via the Schwartz Method Formula 
or the Revised Schwartz Method Formula below.  It is preferable, for the Creatinine 
Clearance value to be provided by the laboratory, if possible.  If the estimated 
Creatinine Clearance is used, the estimated Creatinine Clearance results must be 
noted in the subject’s primary source records indicating which of the above formulas 
was used and the results must also be entered in the CRF accordingly. 

If the Creatinine Clearance is estimated, the same Schwartz/Revised Schwartz 
method formula should be used throughout the study for each subject for consistency

Creatinine Clearance values are not to be used from any electronic creatinine 
clearance calculators. These are not validated methods and do not meet Pfizer 
standards.


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
Schwartz Method Formula:  
Child Age
k
Infant (Low Body Weight < 1 year)
0.33
Infant (Term < 1 year)
0.45
Child or Adolescent Girl 
0.55
Adolescent Boy
0.70
__________________________________________________________________________

Revised Schwartz Method Formula:
GFR = 0.413 * Height
              CR 
Serum
–
Height is measured in cm
–
Serum creatinine is measured in mg/dl
9.1.9. Telephone Follow-Up
The Principal Investigator or designee will be responsible, after hospitalization, for weekly 
follow-up telephone interviews to all subjects or parents/guardians.
The following
information will be documented, from the subject and/or caregiver/visiting nurse, (where 
applicable) a provided service, as needed:

General health; changes in medications or cancer treatment(s);

Signs and symptoms of bruising or bleeding episodes;

Local injection site reactions;

Medication Exposure;

Concomitant medications;

Adverse experiences;

Study medication compliance.


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9.1.10. VTE Assessment and VTE Definitions
For the qualifying event, the diagnostic technique used at Screening should be repeated at
EOS or early termination. If an image has been captured prior to the EOS and it
demonstrates resolution of the qualifying VTE, then a repeat image does not need to be done
on the index event. Full images should be captured of the qualifying event at
Screening/Baseline and at EOS. For new and recurrent VTEs, the institution’s diagnostic
standard shall be utilized. 
For these events, full images should be captured of the new or recurrent event. For
instructions, please refer to Section 9.1.1. A copy of all images should be kept with the
source documents.
9.2. Screening Schedule
The nature and purpose of the investigation must be explained to the subjects and 
parents/guardians and written informed consent/assent obtained from both parties, where 
applicable, prior to initiating any screening activities.
Under certain circumstances, rescreening of a subject may be conducted one time, only if 
approved by the Study Clinician. If you wish to rescreen a subject, contact the Study 
Clinician prior to rescreening the subject to discuss the specifics and to receive approval.  
Documentation of rescreening approval must be included in the primary source records of the 
subject.
9.3. Treatment Period
This Baseline assessment can be conducted within 4 days of the Screening visit. If the 
Screening visit is conducted within 48 hours of the Baseline visit, the Medical History, 
Physical Exam (including weight and height), Pregnancy Test, Imaging and Clinical Labs 
(Chemistry, Antithrombin and Hematology) do not need to be repeated at the Baseline 
visit. 
Baseline- Day 1 –The first study drug dose is administered.  The subject could potentially 
have their first dose adjustment conducted on Day 1 if the Investigator deems it appropriate. 
The following procedures will be conducted:
9.3.1. Screening/Baseline (Visit 1/Visit 2)

Informed Consent/Assent where applicable;

Medical History;

Imaging of qualifying VTE;

Vital Signs including height and weight;

Physical Exam;

Anti-Xa level (Baseline only: local and central laboratories) and Anti-IIa (central lab 
only);


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
Antithrombin level;

Clinical Laboratory (hematology/coagulation/clinical chemistry);

Serum or urine pregnancy tests (on post-menarche females) (only to be conducted once 
during the Dose Adjustment Phase, if there are multiple site visits during this phase);;

Prior and Concomitant Medications/Treatments;

AEs;

Dispense Study Drug;

Study Drug Administration at Baseline;

Contraception check;

Clinical lab for urine creatinine if applicable
9.3.2. Dose Adjustment Phase (Visit 3) 
If first dose adjustment is on conducted on Day 1, the first Dose Adjustment Phase Visit date 
would be the same as the Baseline Visit date.  If first dose adjustment is conducted on Day 2, 
that would be the first Dose Adjustment Visit.

(CRF pages to be completed when optimal dose is achieved)

Physical Exam (at the end of the Dose Adjustment Phase);

Vital Signs including weight and height (at the end of the Dose Adjustment Phase);

Anti-Xa level (local and central laboratories) and Anti-IIa (central Lab only).  Plasma 
samples drawn during the Dose-Adjustment Phase that deviate outside the 4 hour 
(± 1 hour) window cannot not use the Anti-Xa reference range of 0.5-1.0 IU/mL and 
should be repeated the next day for both central and local laboratories;

Antithrombin level (once at the end of the Dose Adjustment Phase);

Serum or urine pregnancy tests (on post-menarche females) (only to be conducted 
once during the Dose Adjustment Phase, if there are multiple site visits during this 
phase);

Dosing and administration compliance;

Concomitant Medications/Treatments;

AEs;

Dispense Study Drug;

Return Study Drug;

Contraception check;

Clinical lab for urine creatinine if applicable.


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9.3.3. Pharmacodynamic Phase

(CRF pages to be completed when both of the two plasma samples have been drawn)

Physical Exam (at the end of the PD Phase if it is >1 day);

Vital Signs including weight and height (at the end of the PD Phase if it is
>1 day);

Clinical Laboratory (hematology/coagulation/clinical chemistry at the end of this 
phase);

Serum or urine pregnancy tests (on post-menarche females);

Anti-Xa level and Anti-IIa (central laboratory, only);

Antithrombin level (once at the end of the PD Phase);

Dosing and administration compliance;

Concomitant Medications/Treatments;

AEs;

Dispense Study Drug

Return Study Drug;

Contraception check;

Clinical lab for urine creatinine if applicable.
9.3.4. Follow-up Phase (For Out-Patients only)
NOTE: For non-cancer patients who stop dalteparin treatment prior to 3 months according to 
the ACCP Guidelines, Anti-Xa and Anti-IIa plasma sampling will not be required after study 
medication discontinuation.

Telephone Interview (Weekly, through EOS, except weeks with clinical visits, ie,
Visits 5, 6 and 7;

Physical Exam;

Vital Signs including weight and height;

Dosing and administration compliance;

Clinical Laboratory (hematology/coagulation/clinical chemistry);

Serum or urine pregnancy tests (on post-menarche females);

Anti-Xa level (local and central laboratories) and Anti-IIa (central Lab only).  Plasma 
samples drawn during the Follow-Up Phase that deviate outside the 4 hour (± 1 hour) 
window cannot not use the anti-Xa reference range of 0.5-1.0 IU/mL and should be 
repeated the next day for both central and local laboratories;

Antithrombin level;

Concomitant Medications/Treatments;


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
Adverse Events;

Dispense Study Drug, if applicable;

Return Study Drug

Contraception check;

Clinical lab for urine creatinine if applicable.
9.3.5. Final Visit/Early Termination (ET)
NOTE: For non-cancer patients who stop dalteparin treatment prior to 3 months according to 
the ACCP Guidelines, Anti-Xa and Anti-IIa plasma sampling will not be required after study 
medication discontinuation.

In-clinic visit (Visit 7 or ET);

Physical Exam;

Vital Signs including weight and height;

Clinical Laboratory (hematology/coagulation/clinical chemistry);

Serum or urine pregnancy tests (on post-menarche females);

Imaging (same imaging modality at Screening). Note: Visit 7/EOS visit imaging
is not required if a previous visit imaging has demonstrated resolution of a clot;

Dosing and administration compliance;

Anti-Xa level (local and central laboratory) and Anti-IIa (central Lab only);

Antithrombin level;

Concomitant Medications/Treatments;

Adverse Events;

Return Study Drug.
9.3.6. Unscheduled Event (In-Clinic Visit, if Required)
Unscheduled Events are conducted if the subject experiences a bleeding event or VTE.  
NOTE: For non-cancer patients who stop dalteparin treatment prior to 3 months according to 
the ACCP Guidelines, Anti-Xa and Anti-IIa plasma sampling will not be required after study 
medication discontinuation.

Physical Exam;

Vital Signs including height and weight;

Clinical Laboratory (hematology/coagulation/clinical chemistry);

Serum or urine pregnancy tests (on post-menarche females);

Imaging (same imaging modality at Screening);

Antithrombin level;


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
Dosing and administration compliance;

Anti-Xa level (local laboratory, if required);

Concomitant Medications/Treatments;

Adverse Events;

Dispense Study Drug, if applicable;

Return Study Drug.
9.3.7. Unscheduled Visit (In-Clinic visit, if required)
Unscheduled visits are conducted for any other reason, aside from bleeding events or VTE 
concerns, per the above Unscheduled Event (In-Clinic Visit, if Required) section. 
NOTE: For non-cancer patients who stop dalteparin treatment prior to 3 months according to 
the ACCP Guidelines, Anti-Xa and Anti-IIa plasma sampling will not be required after study 
medication discontinuation.

Physical Exam including height and weight;

Vital Signs including height and weight;

Clinical Laboratory (hematology/coagulation/clinical chemistry);

Serum or urine pregnancy tests (on post-menarche females);

Antithrombin level;

Dosing and administration compliance;

Anti-Xa level (local laboratory, if required;

Concomitant Medications/Treatments;

Adverse Events;

Dispense Study Drug, if applicable;

Return Study Drug.
10. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND REPORTING
10.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.


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As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
10.1.1. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the subject has taken at least 1 dose of investigational product through the subject’s last 
visit. 
10.1.2. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;


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
Medication error;

Occupational exposure.

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
10.2. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
10.3. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
10.4. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;


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
Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 5 (see the section on Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
Medical device complaints may meet the SAE reporting requirement criteria (see the section 
on Sponsor’s Reporting Requirements to Regulatory Authorities).  An incident is any 
malfunction (ie, the failure of a device to meet its performance specifications or to perform as 
intended; performance specifications include all claims made in the labeling for the device) 
that, directly or indirectly, might lead to or might have led to the death of a subject, or user, 
or of other persons, or to a serious deterioration in their state of health. 

A life-threatening illness, even if temporary in nature;

A permanent impairment of a body function or permanent damage to a body 
structure; 

A condition necessitating medical or surgical intervention to prevent the above 
2 bulleted items;

Any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use;

Fetal distress, fetal death, or any congenital abnormality or birth defects.
10.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements). 


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10.4.2. Potential Cases of Drug-Induced Liver Injury
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal 
range who subsequently present with AST or ALT values 3 times the upper limit 
of normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no 
evidence of hemolysis and an alkaline phosphatase value 2 × ULN or not 
available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 × ULN, or 
8 × ULN (whichever is smaller).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 × ULN or
if the value reaches ≥3 × ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  For oncology studies, the 
possibility of hepatic neoplasia (primary or secondary) should be considered.
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug, and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted. All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for Liver Function Test (LFT) abnormalities identified at 
the time, should be considered potential Hy’s law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs.


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10.5. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, 
for workup of persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the 
study protocol);

Optional admission not associated with a precipitating clinical AE (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the 
baseline documentation for the entire protocol and/or for the individual subject;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.


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10.6. Severity Assessment
GRADE
Clinical Description of Severity
0
No change from normal or reference (This grade is not included in the Version 
4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
10.7. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
10.8. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; 


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a.
An example of environmental exposure would be a case involving direct 
contact with a Pfizer product in a pregnant woman (eg, a nurse reports that she 
is pregnant and has been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
subject reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs.  In addition, infant deaths after 1 month should be 
reported as SAEs when the investigator assesses the infant death as related or 
possibly related to exposure to the investigational product. 
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study subject with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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10.9. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
10.10. Withdrawal Due to Adverse Events
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
10.11. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject/parent(s)/legal guardian/legally acceptable representative.  In addition, each 
study subject/parent(s)/legal guardian/legally acceptable representative will be questioned 
about AEs.
10.12. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
10.12.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event. 
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 


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on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. 
Information on other possible causes of the event, such as concomitant medications, 
vaccines, and/or illnesses, must be provided.  In the case of a subject death, a summary of 
available autopsy findings must be submitted as soon as possible to Pfizer or its designated 
representative. 
10.12.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
10.12.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
10.13. Breaking the Blind 
This is an open-label study and breaking the blind is not applicable.
11. GUIDANCE TO THE INVESTIGATOR
Risk/Benefit Statement FRAGMIN (dalteparin sodium) was first approved for marketed
use in 1985 and there has been extensive post-marketing and clinical trial exposure. 
However, the safety and effectiveness of FRAGMIN in the pediatric population has not been 
established. This is primarily a study of the safety and pharmacodynamics of FRAGMIN
in children with or without cancer and venous thromboembolism. As with any
medication, it must be emphasized that serious adverse events, previously identified or not,
may occur.  Subjects participating in this study cannot be guaranteed a clinical benefit
from the administration of the test drug. Thus, for each subject, the possibility of a positive
therapeutic effect and their contribution to the scientific understanding of the long term
safety of FRAGMIN are the only possible benefits.
12. STATISTICAL METHODS
12.1. Determination of Sample Size
Subjects, with or without a diagnosis of various cancers within 6 months of the Screening 
Visit and requiring anticoagulation for the treatment and secondary prophylaxis of VTE,
will be enrolled into the following five age groups:

0 to < 8 Weeks;

≥ 8 Weeks to < 2 Years;

≥ 2 Years to < 8 Years;

≥ 8 Years to < 12 Years;


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
≥12 Years to < 19 Years.
Target enrollment is 50 subjects. A sample size of 50 subjects is sufficient to estimate
Anti-Xa clearance and Vd of dalteparin. Enrollment will continue until 50 subjects have
viable PD profiles after treatment doses of dalteparin.
The sample size was determined based on historical data and a population pharmacokinetic 
(PK)/PD model, evaluation of the effect of sample scheme and sample size per age stratum
on the bias and precision of key PK/PD parameters, after evaluation of total N of 10, 20, 30,
40 and 50 (2, 4, 6, 8, 10 per age stratum as available) and evaluation of single and
2-point sample densities and impact of randomization across strata with 100 trial
simulations per design examined.  In addition, blood sampling density was also considered 
after the subject sample size was determined. Single-point sampling designs yielded
unacceptable bias in total body clearance of the drug (CL) and/or Vd; confounding of effects
if blocked within stratum. Double sampling at 3, 8 and 5, 12 hours post-dose performs more 
efficiently.
Therefore, randomized two-sample design per each subject was also determined.
See Appendix3 for additional information regarding the trial simulation strategy.
12.2. PD Phase Plasma Sampling Randomization Plan
Enrolled subjects who achieve the target therapeutic Anti-Xa level in the Dose Adjustment
Phase will advance to the PD Phase. Subjects will be randomized (at Baseline) to two
different plasma sampling schemes (1 to 3 h and 5 to 8 h, or 3 to 5 h and 8 to 12 h) in the 
PD Phase with a ratio of 1:1 in each age group and the randomization will be blocked and
stratified by age group via the electronic system, IMPALA. Randomization will continue
until 50 subjects have viable PD Phase profiles.
12.3. Statistical Plan
12.3.1. Statistical Methodology
All statistical analyses will be performed using SAS® (Version 9.1 or higher), and will
be assessed at the two-sided 0.05 level.  Mean, standard deviation, median, minimum and
maximum will be summarized for continuous variables. Frequency and percentage will be
summarized for categorical variables. Ninety-five percent (95%) confidence intervals
will be provided for primary and selected secondary safety endpoints. Paired t-tests will
be performed for the changes from baseline for selected continuous variables. Time to
event will be described by using the Kaplan-Meier method. In addition, the Cox
Proportional Hazard Regression model will be employed to assess the hazard ratio of the
event with prognostic factors.
12.3.2. Definition of Study Populations for Analysis
There will be two analysis populations defined in the study.

Safety Population: Subjects who receive at least one treatment of dalteparin.  
All safety analysis will be based on this population;

Pharmacodynamic Population: Subjects in the Safety Population who achieve 
therapeutic range of anti-Xa during Dose Adjustment Phase. This population
will be the primary analysis population for PD and efficacy analysis.


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12.3.3. Analysis of Baseline and Demographic Variables
Demographic and pretreatment characteristics for the safety population will be summarized
for all subjects and by age group using descriptive statistics including number of subjects,
mean, standard deviation, median and range for continuous variables; and the frequency and
percent for categorical variables.
12.3.4. Analysis of Pharmacodynamic Variables
All PD variables will be analyzed within the PD population.
The primary study analysis will be a PD evaluation of dalteparin based on Anti-Xa levels
using a population PD analysis methodology. Due to the sparse plasma sampling strategy,
population PD analyses will be explored. The PD effect (Anti-Xa level) is used as a 
surrogate PK of dalteparin for the time course of drug exposure.  The population PD analysis 
may also be named as a population PK analysis.  Details of the Population PD analysis will 
be described in a separate population PD modeling analysis plan document and results will 
be presented in a separate population PD report.
The secondary PD analyses will include the proportion of children achieving an Anti-Xa 
therapeutic range of 0.5 to 1.0 IU/mL at 4 hours ± 1 hour post-dose during the Dose
Adjustment Phase (up to 7 days) and the proportion of subjects who remain within
therapeutic range over the Follow-Up Phase (Visits 5, 6 and 7).
These analyses will be
descriptively summarized for all subjects and by age groups.
The final dose of dalteparin given to a subject during the Dose Adjustment Phase of the
study will be considered the maintenance therapeutic dose (ie, the dose achieving an
Anti-Xa level of 0.5 to 1.0 IU/mL at 4 hours ± 1 hour post-dose). The time to achieve the
target range is defined as the number of days from the first dose to the final dose that
achieves the target Anti-Xa level.
The maintenance dose, time to achieve the target range, 
and number of dose adjustments during the Dose Adjustment Phase will be summarized by 
age group using summary statistics.
Aggregate PD profiles (curves of Anti-Xa level versus hours after dosing time) and
summary measures will be calculated using combined data for all subjects within a given age
group.
Additionally, for each age group, the percentage of Anti-Xa levels measured 4 hours 
post-dose ± 1 hour post-dose that are outside the target range will be calculated during the
Follow-up Phase of the study.
12.3.5. Analysis of Efficacy Variables
All efficacy variables will be analyzed within the PD population.
Efficacy variables include:


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
Proportion of subjects with objectively documented new or progressive symptomatic 
VTE will be summarized overall and by age groups during dalteparin treatment; the 
proportions will be accompanied by an exact 95% confidence interval;

Proportions of subjects with progression, regression, resolution, or no change in the 
qualifying VTE will be summarized overall and by age groups during dalteparin 
treatment; the proportions will be accompanied by an exact 95% confidence interval;

Time to first episode of recurrent VTE will be analyzed using Cox regression model 
to assess recurrent VTE during dalteparin treatment, with prognostic factors (eg, age 
group, baseline tumor type).  Kaplan Meier estimates of time will also produced.
Exploratory analyses:

Logistic regression model assessing if subjects achieve an Anti-Xa therapeutic
range during the Dose Adjustment Phase, using the Odds Ratio of prognostic
factors of age, gender, chemotherapy status, and dose of dalteparin.
12.3.6. Analysis of Safety Variables
All safety variables will be summarized within the safety population.
Safety analysis will focus on bleeding, AEs, laboratory tests, physical exam, vital signs, 
treatment exposure, study drug compliance, and subject disposition during dalteparin 
treatment.
The investigators’ assessments for bleeding events will be collected and used as secondary 
analyses.
1. The safety analysis will include the following:

Proportion of subjects with any major bleeding events will be summarized overall 
and by age group during dalteparin treatment; the proportion will be accompanied 
by an exact 95% confidence interval; 

Proportion of subjects with any bleeding events (major and minor) will be 
summarized overall and by age group during dalteparin treatment; the proportion 
will be accompanied by an exact 95% confidence interval;

Proportion of subjects with any minor bleeding events will be summarized overall 
and by age group during dalteparin treatment; the proportion will be accompanied 
by an exact 95% confidence interval;

Time to first major bleeding events will be analyzed using Cox Proportional 
Hazard Regression model to assess the major bleeding events during dalteparin 
treatment with prognostic factors (eg, age group, baseline tumor type, baseline 
chemotherapy status) in the model.  Kaplan Meier estimates of time will also be 
produced. 

Relationship between major bleeding event and the Anti-Xa level during 
dalteparin treatment will be analyzed using logistic regression for major bleeding 
event assessed on prognostic factors (eg, baseline Anti-Xa level [observed at the 
end of dose adjustment], age).


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2. AE and SAEs will be summarized for the number of subjects with
treatment-emergent AEs by System Organ Class and Preferred Term (MedDRA 
coded) overall, by Severity (NCI CTC version 3.0), by Relationship to study drug, by
Seriousness, by if leading to dose change and by if leading to subject’s
discontinuation of the study.
3. Subject disposition, PE, Vital Signs and Labs will be descriptively summarized. 
Change from baseline for continuous variable will be analyzed using paired-T test.
4. Treatment Exposure: Treatment duration, summary of daily dose, number of subjects 
with any dose change and number of changes per each subject, frequency of missed
or interrupted study drug and the duration per each interruption or missed, and
reasons for study drug interruption or missed will be descriptively summarized.
5. Study Compliance:

Study Compliance is defined based on the number of daily doses of study
medication administered divided by the intended days of treatment;

80% in this variable will indicate that the subject was compliant. The proportion 
of subjects that were compliant will be presented.
12.3.7. Some Statistical Considerations
Censoring Criteria for Time to Events:
When there is no occurrence of the event, time to event will be censored to the date of last
event assessment (last visit, death, or date of ET).
13. DATA MONITORING COMMITTEE
This study will not use a data monitoring committee.
It should be emphasized that the subject, the subject’s parent and/or legal representative are
at liberty to withdraw their consent to participate at any time, without penalty or loss of
benefits to which the subject is otherwise entitled. Subjects, their parents and/or legal
representatives, who refuse to give, or withdraw, written informed consent may not be
included or continued in this study, but this will not impact their subsequent care.
13.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/assent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.


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13.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practice (GCP), International Conference on 
Harmonisation (ICH 6), and the Declaration of Helsinki (World Medical Association 
(1996 & 2008).
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
13.3. Subject Information and Consent
Protection and safety of vulnerable subjects (including illiterate subjects) will be ensured to 
uphold the subjects’ well-being, rights, and confidentiality and the integrity of their data will 
be safeguarded.  This includes both consent procedures and methods to ensure the veracity of 
study assessments.
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study subjects.  The study site 
will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent/assent documents must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent/assent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study subject or his or her legally acceptable 
representative, or parent(s) or legal guardian if a minor, is fully informed about the nature 
and objectives of the study and possible risks associated with participation. 
Whenever consent is obtained from a subject’s legally acceptable representative/parent(s) or 
legal guardian, the subject’s assent (affirmative agreement) must subsequently be obtained 
when the subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a subject’s decisional capacity is so limited he/she cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the subject’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study subject does not provide 
his or her own consent, the source documents must record why the subject did not provide 
consent (eg, minor, decisionally impaired adult), how the investigator determined that the 
person signing the consent was the subject’s legally acceptable representative, the consent 


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signer’s relationship to the study subject (eg, parent, spouse), and that the subject’s assent 
was obtained, or waived.  If assent is obtained verbally it must be documented in the source 
documents.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must re-consent as adults to remain in the study.  If the 
enrollment of ‘emancipated minors’ is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative, parent(s) or legal 
guardian and the subject’s assent, when applicable, before any study-specific activity is 
performed, unless a waiver of informed consent has been granted by an IRB/EC.  The 
investigator will retain the original of each subject's signed consent/assent document.
13.4. Subject Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.  Pfizer will have an opportunity to review and approve the content of 
any study recruitment materials directed to potential study subjects before such materials are 
used.
13.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
14. TREATMENT COMPLIANCE
14.1. Drug Accountability Procedures
An Investigational Product Accountability Log must be kept current and available for
inspection by the clinical trial monitor, and should contain the following information:

Initial Inventory upon receipt of study drug and clinical supplies at the clinical
study site;

The identification number of each subject to whom study drug was administered;

The date(s), quantities, lot numbers, and the dispenser’s initials for all study
drug administered;

Running and final inventory (upon completion of the clinical study).
This inventory must be available for inspection by the clinical trial monitor.


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Following the closeout of the study, all unused clinical supplies are to be destroyed on site 
or shipped by the monitor to Pfizer Inc’s designated drug destruction site.
14.2. Receipt of Study Drug
The Investigator (or Pharmacist, as appropriate) must maintain records of the delivery of
the study medication to the study site, the inventory at the site, the use for each subject,
and the return to a delegate of Pfizer Inc.
14.3. Handling of Study Drug
All drug supplies for this study must be stored according to labeled storage conditions. If 
any excursion from the recommended storage (per study drug label) occurs, the study 
monitor or other sponsor study team member must be consulted before using the study drug.
14.4. Records of Study Drug
Study Drug will be dispensed at Baseline, Dose Adjustment Phase, PD Phase, Follow-Up and 
Unscheduled Visits as appropriate, and returned at Dose Adjustment Phase, PD Phase, 
Follow-Up and Unscheduled Visits as appropriate and End of Study. All drug dispensation 
and return will be documented on the IP Accountability Log.  The Drug Dispensing Log must
be available for monitoring, auditing, and inspection.
15. STUDY MANAGEMENT AND ADMINISTRATION
15.1. Monitoring
Pfizer Inc, or designee, will perform all monitoring functions. Monitors will work in
accordance with Pfizer monitoring Standard Operating Procedures (SOPs) or the SOPs of
the contract research organization, as designated in the contract.  Monitors will be 
responsible for establishing and maintaining regular contact between the Investigators and 
the Sponsor. Monitors will also control adherence to the protocol at the Investigative sites.
Monitors will evaluate the competence of each study site. Monitors will inform Pfizer Inc
regarding problems relating to facilities, technical equipment, or medical staff. Monitors
will arrange for the supply of study drug and ensure appropriate storage conditions are
maintained. Monitors will ensure that written informed consent/assent has been correctly 
obtained from all subjects/responsible party prior to administration of any study procedures
or drug administration and during the study will ensure that data are recorded correctly and
completely in the CRF.
Monitoring visits will be made to each center approximately every 6 to 8 weeks and may need
to occur more or less frequently if deemed necessary by Pfizer Inc. In addition, the
Monitor will maintain regular contact with the site to follow study progress including
subject disposition and occurrence of SAEs. The Monitor will make written reports to
Pfizer Inc on each visit made to the Investigative site.
During monitoring visits, original source documents will be compared to entries in the CRF. 
For all subjects, monitoring of source data documentation will occur at 100%. The Monitor
should have access to laboratory test reports and other subject records needed to verify the
entries on the CRF. The Investigators (or his/her designee) agree to cooperate with the
Monitor to ensure that any problems detected in the course of these monitoring visits are
resolved.


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15.2. Audit and Inspection
Investigator sites, the study database, and the study documentation may be subject to
quality assurance audits during the course of the study either by Pfizer Inc, or their
appointed representatives. In addition, regulatory bodies at their discretion may conduct
inspections.
15.3. Quality Control and Quality Assurance
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
16. DATA HANDLING AND RECORD KEEPING
16.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 


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data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital’s or the physician's subject chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
16.1.1. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent/assent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
16.2. Investigator Site File
At the beginning of the study, an investigator’s study file will be established at the study
center.  The investigator/institution is responsible for maintaining the study documents as
specified in the guideline for ICH GCP and as required by the applicable regulatory 
requirement(s).  The investigator/institution must take measures to prevent accidental or
premature destruction of these documents.
The following guidelines, instructions and certifications are regarded as relevant
supplements and will be provided for the investigator's study file at each center:

World Medical Association Declaration of Helsinki (See Appendix 1);

Package Insert to serve as the Investigator’s Brochure;

Sample shipment details.


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16.3. Sponsor Discontinuation Criteria
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer. 
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within a time set by Pfizer Inc.  As directed by Pfizer, 
all study materials must be collected and all CRFs completed to the greatest extent possible.
16.4. Publication of Study Results
16.4.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date for 
studies in adult populations or within 6 months of the primary completion date for studies in 
pediatric populations.
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the primary completion date for studies in adult populations or 
within 6 months of the primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.


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16.4.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.
16.5. Clinical Study Report
A final integrated clinical/statistical report will be prepared that is compliant with the ICH 
Harmonized Tripartite Guideline.


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16.6. Subject Insurance and Indemnity
Pfizer Inc will provide the insurance in accordance with local guidelines and requirements as
a minimum for the subjects participating in this study. The terms of insurance will be kept
in the study files.
16.7. Amendments to the Protocol
Modifications of the signed protocol are only possible by approved protocol amendments
and with the agreement of all responsible persons.  The procedure for approval of a protocol 
amendment is identical to that for approval of the protocol. The ethics committee must be 
informed of all protocol amendments and should be asked for its opinion as to whether a
full reevaluation of the ethical aspects of the study is necessary by the committee. This
should be fully documented.
The investigator must not implement any deviation from or change to the protocol, without 
discussion with, and, agreement by Pfizer Inc and prior review and documented
approval/favorable opinion of the amendment from the relevant ethics committee, except
where it is necessary to eliminate an immediate hazard to study subjects, or where the
change(s) involves only logistical or administrative aspects of the study (eg, change in
monitor(s), change of telephone number(s)).  Protocol amendments will be submitted to the
appropriate authority (ies) as required by the applicable regulatory requirement(s).
16.8. Disclosure of Information and Results
In signing the final protocol, every participating investigator agrees to keep all information
and results concerning the study and the investigational product confidential.  The
confidentiality obligation applies to all personnel involved at the investigational site.
16.9. Publication and Presentation Policy
The results of this study will be published and/or presented at scientific meetings in a
timely manner. Any formal publication of study results will be a collaborative effort between
Pfizer Inc and the investigator(s).
All manuscripts or abstracts will be reviewed and 
approved in writing by Pfizer Inc prior to submission.
16.10. Archiving and Data Retention
All study documents should be retained until at least 2 years after the last approval of
a marketing application in an ICH region and until there are no pending or contemplated
marketing applications in an ICH region or at least 2 years have elapsed since the formal
discontinuation of clinical development of the investigational product, in accordance with
21 CFR (Code of Federal Regulations) 312.62. These documents should be retained for a 
longer period however, if required by regulatory requirements or by agreement with the
Sponsor. It is the responsibility of the Sponsor to inform the Investigator/Institution as to
when these documents no longer need to be retained.
The final database will be archived by Pfizer Inc, according to regulatory requirements.


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16.11. Data Protection
Personal and sensitive personal data will be treated as confidential. The results of the study
will be made available for review by authorized representatives of Pfizer Inc and/or
submitted to one or more sponsor offices worldwide, the ethics committee and regulatory
authorities.
For this purpose the data may be transferred within Europe or to countries outside the
European Union, where the laws about the protection of personal/sensitive data may not be
as strict as in Europe. The data collected from this study is considered as
personal/sensitive data as defined under the European Union Directive 95/45/EC. The data
controller of Pfizer Inc will take steps to ensure that data are protected.
Prior to the subject’s Screening Visit in the study, the subject’s consent is required for the data to
be used for these purposes and to gain direct access to their medical records for data
verification purposes.
The subject must be assured that their identity will be protected.  To facilitate this, a
unique identification code will be assigned by the investigator to each study subject. This
will be used instead of the subject’s name and cross-referenced with the subject’s date of
birth when reporting AEs and /or other study-related data.


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17. REFERENCES
1.
Lee AY, et al. Low-molecular-weight heparin versus a coumadin for the prevention of 
recurrent venous thromboembolism in subjects with cancer. N Engl J Med. 2003;
349(2):146-53.
2.
Agnelli G, and Verso M. Thrombosis and cancer: clinical relevance of a dangerous 
liaison.
Haematologica 2005; 90(2):155-6.
3.
Bauer KA. Venous thromboembolismin malignancy. J. Clin Oncol 2000; 18(17):3065-7.
4.
Falanga A. Thrombosis and malignancy: an underestimated problem.
Haematologica
2003; 88(6):607-10.
5.
Rickles FR. Thrombosis and lung cancer. Am Rev Respir Dis 1989; 140(3):573-5.
6.
Bick RL. Cancer-associated thrombosis. N Engl J Med 2003; 349(2):109-11.
7.
Bick RL Straus JF, and Frenkel EP.  Thrombosis and hemorrhage in oncology 
subjects. Hematol Oncol Clin North Am 1996; 10(4):875-907.
8.
Bick RL. Coagulation abnormalities in malignancy: a review.  Semin Thromb Hemost
1992; 18(4); 353-72.
9.
Falanga A, and Zacharski L. Deep vein thrombosis in cancer: the scale of the 
problem and approaches to management. Ann Oncol 2005; 16(5):696-701.
10.
Ageno W, Squizzato A, Garcia D, and Imberti D. Epidemiology and risk factors of 
venous thromboembolism.
Semin Thromb Hemost 2006; 32:651-658.
11.
Massicotte P, et al. Low-molecular-weight heparin in pediatric subjects with 
thrombotic disease: a dose finding study.
J Pediatric 1996; 128(3):313-8.
12.
Nohe N, et al. The low molecular weight heparin dalteparin for prophylaxis and 
therapy of thrombosis in childhood: a report on 48 cases. Eur J Pkediatr 1999; 158
Suppl 3:S134-9.
13.
Dix D, et al. The use of low molecular weight heparin in pediatric subjects: a 
prospective cohort study.
J Pediatr; 2000:136(4):439-45.


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18. APPENDICES
Appendix 1. World Medical Association Declaration Helsinki
Recommendations guiding physicians in biomedical research involving human subjects.

Adopted by the 18th World Medical Assembly Helsinki, Finland, June 1964.

29th World Medical Assembly, Tokyo, Japan, October 1975.

35th World Medical Assembly, Venice, Italy, October 1983.

41st World Medical Assembly, Hong Kong, September 1989.

48th General Assembly, Somerset West, Republic of South Africa, October 1996.

52nd WMA General Assembly Edinburgh, Scotland October 2000.
Note of Clarification:
Paragraph 29 added by the WMA General Assembly, Washington 2002. 
Paragraph 30 added by the WMA General Assembly, Tokyo 2004. 
INTRODUCTION
It is the mission of the physician to safeguard the health of the people.
His or her
knowledge and conscience are dedicated to the fulfillment of this mission.
The Declaration of Geneva of the World Medical Association binds the physician with
the words, "The Health of my subject will be my first consideration," and the International
Code of Medical Ethics declares that, "A physician shall act only in the subject's interest
when providing medical care which might have the effect of weakening the physical and
mental condition of the subject."
The purpose of biomedical research involving human subjects must be to improve
diagnostic, therapeutic and prophylactic procedures and the understanding of the etiology
and pathogenesis of disease.
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve 
hazards.
This applies especially to biomedical research.
Medical progress is based on research, which ultimately must rest in part on
experimentation involving human subjects.
In the field of biomedical research a fundamental distinction must be recognized between 
medical research in which the aim is essentially diagnostic or therapeutic for a subject, and 
medical research, the essential object of which is purely scientific and without implying
direct diagnostic or therapeutic value to the person subjected to the research.
Special caution must be exercised in the conduct of research, which may affect the
environment, and the welfare of animals used for research must be respected.
Because it is essential that the results of laboratory experiments be applied to human beings
to further scientific knowledge and to help suffering humanity, the World Medical
Association has prepared the following recommendations as a guide to every physician in
biomedical research involving human subjects. They should be kept under review in the


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future. It must be stressed that the standards as drafted are only a guide to physicians all
over the world. Physicians are not relieved from criminal, civil and ethical responsibilities
under the laws of their own countries.
I. BASIC PRINCIPLES
1. Biomedical research involving human subjects must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and animal 
experimentation and on a thorough knowledge of the scientific literature.
2. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol which should be transmitted for 
consideration, comment and guidance to a specially appointed committee independent of 
the investigator and the sponsor provided that this independent committee is in 
conformity with the laws and regulations of the country in which the research experiment 
is performed.
3. Biomedical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  
The responsibility for the human subject must always rest with a medically qualified 
person and never rest on the subject of the research, even though the subject has given his 
or her consent.
4. Biomedical research involving human subjects cannot legitimately be carried out unless 
the importance of the objective is in proportion to the inherent risk to the subject.
5. Every biomedical research project involving human subjects should be preceded by 
careful assessment of predictable risks in comparison with foreseeable benefits to the 
subject or to others. Concern for the interests of the subject must always prevail over the 
interests of science and society.
6. The right of the research subject to safeguard his or her integrity must always be 
respected. Every precaution should be taken to respect the privacy of the subject and to 
minimize the impact of the study on the subject's physical and mental integrity and on the 
personality of the subject.
7. Physicians should abstain from engaging in research projects involving human subjects 
unless they are satisfied that the hazards involved are believed to be predictable.  
Physicians should cease any investigation if the hazards are found to outweigh the 
potential benefits.
8. In publication of the results of his or her research, the physician is obliged to preserve the 
accuracy of the results. Reports of experimentation not in accordance with the principles 
laid down in this Declaration should not be accepted for publication.
9. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, anticipated benefits and potential hazards of the study and the 
discomfort it may entail. He or she should be informed that he or she is at liberty to 
abstain from participation in the study and that he or she is free to withdraw his or her 
consent to participation at any time.  The physician should then obtain the subject's 
freely given informed consent, preferably in writing.


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10. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress.  In that case the informed consent should be obtained by a 
physician who is not engaged in the investigation and who is completely independent of 
this official relationship.
11. In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation. Where physical or mental incapacity 
makes it impossible to obtain informed consent, or when the subject is a minor, 
permission from the responsible relative replaces that of the subject in accordance with 
national legislation.
Whenever the minor child is in fact able to give consent, the
minor's consent must be obtained in addition to the consent of the minor's legal guardian.
12. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration are 
complied with.
II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE (Clinical
Research)
1. In the treatment of the sick person, the physician must be free to use a new diagnostic and 
therapeutic measure, if in his or her judgment it offers hope of saving life, reestablishing 
health, or alleviating suffering.
2. The potential benefits, hazards and discomfort of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods.
3. In any medical study, every subject including those of a control group, if any - should 
be assured of the best proven diagnostic and therapeutic method. This does not exclude 
the use of inert placebo in studies where no proven diagnostic or therapeutic method 
exists.
4. The refusal of the subject to participate in a study must never interfere with the 
physician-subject relationship.
5. If the physician considers it essential not to obtain informed consent, the specific reasons 
for this proposal should be stated in the experimental protocol for transmission to the 
independent committee (I, 2).
6. The physician can combine medical research with professional care, the objective being 
the acquisition of new medical knowledge, only to the extent that medical research is 
justified by its potential diagnostic or therapeutic value for the subject.
III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN 
SUBJECTS (Non-Clinical Biomedical Research)
1. In the purely scientific application of medical research carried out on a human being, it is 
the duty of the physician to remain the protector of the life and health of that person on 
whom biomedical research is being carried out.
2. The subject should be volunteers - either healthy persons or subjects for whom the 
experimental design is not related to the subject's illness.


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3. The investigator or the investigating team should discontinue the research if in his/her or 
their judgment it may, if continued, be harmful to the individual.
4. In research on man, the interest of science and society should never take precedence over
considerations related to the wellbeing of the subject.


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Appendix 2. Study Drug (dalteparin sodium) Dosing Calculation Examples (Additional 
dosing administration instructions can be found in the Investigational Product (IP) 
Manual)
Example:
Subject DOSING LEVEL (IU/kg) X Pt Weight (kg) = Dose to administer (IU)
Dose to administer (IU)/Drug concentration (IU/mL) = Volume to administer 
(mL)
Protocol 
Age 
Group
Example 
Patient 
Age
Required 
Starting 
Dose
Example
weight 
(kg)
Dose to 
Administer 
(IU)
Drug 
Concentration* 
Used (IU/mL)
Volume to 
Administer 
(mL)
0 to 
<8 Weeks
4 wks
125 IU/kg
4 kg
500 IU
2500 IU/mL PF
0.2 mL
≥8 Weeks 
to 
<2 Years
10 wks
150 IU/kg
7 kg
1050 IU
2500 IU/mL PF
0.42 mL
≥2 years 
to 
<8 Years
3 yrs
125 IU/kg
12 kg
1500 IU
2500 IU/mL PF
0.6 mL
≥8 Years 
<12 Years
8 yrs
125 IU/kg
24 kg
3000 IU
10,000 IU/mL 
PF
0.3 mL
≥12 Years 
<19 years
15 yrs
100 IU/kg
82 kg
8200 IU
10,000 IU/mL 
PF
0.82 mL
≥12 Years 
<19 years
15 yrs
100 IU/kg
82 kg
8200 IU
25,000 IU/mL 
0.33 mL

*Important to note the concentration of dalteparin sodium being used in order to 
determine the correct volume to administer to the subject


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Appendix 3. Dalteparin Simulation Strategy
Background:
In support of this trial, simulations of dalteparin activity (anti-Xa activity) in response to SC
administration are suggested to support the sampling scheme and sample size requirements. 
Simulations will be based on a nonlinear mixed effect model defined in the NONMEM 
algorithm and constructed for an analysis of children at increased risk for TE receiving
once-daily SC dalteparin.1 The analysis of these study results (n=43 subjects/31 evaluable), 
suggests that differences in the rate of uptake of dalteparin may be expected across various
age strata. This effect was evaluated by the calculation of the time of maximum anti-Xa
activity (Tmax) across the age group. In this situation Tmax serves as a surrogate for
absorption rate (ka) as there was little data collected with the sparse sampling scheme
during the absorption phase.  Likewise, simulations for the this study will be consider
various sampling schemes and examine the bias and precision in key PK parameters 
(principally CL and Vd but including ka) as well as the likely sample size required to
demonstrate a statistical difference in Fragmin® anti-Xa clearance in pediatric versus adult
populations.
Plan:
Two sampling designs will be considered:
1. Blocked randomization design: This design will consider the randomization of subjects
into single sample collection groups within age strata (4, 7, 12 and 24 hour collections)
for each age range category.
2. Two-sequence, two-sample randomization design: This design will consider
randomization to two different sampling windows (1 to 3 h, 5 to 8 h or 3 to 5 h, 8 to 12 h).
Demographic data from the pediatric TE study will be used as sampling characteristics for
the various age strata. The population model will be used to simulate anti-Xa activity
profiles for each of the proposed sampling schemes for sample sizes of 10, 20, 30 and
40 subjects per strata.  One hundred trials for each of sample size and scheme scenario will
be simulated (4x2x100 = 800 simulated trials). Data will be refit to the population model
and bias and precision of PK parameters will be evaluated.  The impact of sample size to
detect a 30% difference in CL between historical adult values will also be examined.
                                                
1 Barrett JS, Mitchell LG, Patel D, et al. A Population based Analysis of Dalteparin Pharmacokinetics in 
Pediatric Patients at Risk for Thromboembolic Events. Abstract submitted (American College of Clinical 
Pharmacology).


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Appendix 4. Regional Amendment for Highly Effective Methods of Contraception
As per the European Heads of Medicines Agency’s Clinical Trial Facilitation Group’s 
recommendation (Recommendations related to contraception and pregnancy testing
in clinical trials – Final Version 2014-09-15) any European Union Member State or other 
country that follows these recommendations and does not recognize condoms with 
spermicide as a highly effective method of contraception will follow the highly effective 
methods of contraception as indicated below in the revised Section 9.1.5, Pregnancy Test.
9.1.5. Pregnancy Test
For female subjects of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 IU/mL, will be performed at screening, before investigational 
product administration at the Baseline visit, unless the Baseline visit is conducted within 
2 days of the Screening Visit, and at all other study visits.  During the Dose Adjustment 
Phase, if multiple study visits are conducted, the pregnancy test will only be required once in 
the 7-day Dose Adjustment period.  A negative pregnancy result is required before the 
subject may receive the investigational product.  Pregnancy tests will also be done whenever 
1 menstrual cycle is missed during the active treatment period (or when potential pregnancy 
is otherwise suspected), and repeated at follow up visits and at the end of the study to 
confirm the subject has not become pregnant during the study.  Pregnancy tests may also be 
repeated as per request of institutional review boards (IRBs)/ethics committees (ECs) or if 
required by local regulations. 
In the case of a positive confirmed pregnancy, the subject will be withdrawn from 
administration of investigational product and from the study.
All male subjects who are able to father children and female subjects who are of childbearing 
potential and are sexually active and at risk for pregnancy must agree to use a highly 
effective method of contraception consistently and correctly for the duration of the active 
treatment period and for at least 28 days after the last dose of investigational product.  The 
investigator or his or her designee, in consultation with the subject, will confirm that the 
subject has selected an appropriate method of contraception for the individual subject and his 
or her partner from the permitted list of contraception methods (see below) and instruct the 
subject in its consistent and correct use.  Subjects need to affirm that they meet the criteria 
for correct use of at least 1 of the selected methods of contraception.  The investigator or 
his/her designee will discuss with the subject the need to use highly effective contraception 
consistently and correctly according to the schedule of activities and document such 
conversation in the subject’s chart.  In addition, the investigator or his or her designee will 
instruct the subject to call immediately if the selected contraception method is discontinued 
or if pregnancy is known or suspected in the subject or the subject’s partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:


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1. Use of oral, inserted, injected, implanted or transdermal hormonal methods of 
contraception is not allowed due to risks of VTE. 
2. Correctly placed copper containing intrauterine device (IUD). 
3. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
4. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
Female partner who meets the criteria for non-childbearing potential, as described below:
Female subjects of non-childbearing potential must meet at least one of the following 
criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.  If this option is selected for a female subject of childbearing 
potential, then the subject would be required to undergo interval urine pregnancy testing 
(specify a schedule) and would be asked to record stop and start dates for menstruation 
throughout the course of the study.
The use of oral, inserted, injected, implanted or transdermal hormonal methods of 
contraception are not allowed due to risks of VTE.  If a subject was using a hormonal based 
contraceptive prior to study entry, it should be discontinued prior to study entry.  There is no 
required wash-out period required for recently discontinued hormonal based contraception.
All other female subjects (including females with tubal ligations) will be considered to be of 
childbearing potential.  All sexually active male subjects must agree to prevent potential 
transfer of and exposure to drug through semen to their partners by using a condom 
consistently and correctly, beginning with the first dose of investigational product and 
continuing for at least 28 days after the last dose.

SAP_001.pdf: 
A6301094 Statistical Analysis Plan
Page 1
Protocol A6301094
A THREE MONTH PROSPECTIVE OPEN LABEL STUDY OF THERAPY WITH 
FRAGMIN® (DALTEPARIN SODIUM INJECTION) IN CHILDREN WITH
VENOUS THROMBOEMBOLISM WITH OR WITHOUT MALIGNANCIES
Statistical Analysis Plan 
(SAP)
Version:
2
Author:
Date:
18-NOV-2015
PPD


A6301094 Statistical Analysis Plan
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Objectives .......................................................................................................4
2.2. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES: DEFINATIONS AND 
CONVENTIONS ..................................................................................................................6
3.1. PD Endpoint(s)..........................................................................................................6
3.1.1. Primary PD Endpoints..................................................................................6
3.1.2. Secondary PD endpoints...............................................................................6
3.2. Efficacy Endpoint(s) .................................................................................................7
3.3. Baseline Variables.....................................................................................................7
3.3.1. Stratification and Randomization .................................................................7
3.3.2. Covariates .....................................................................................................7
3.4. Safety Endpoints .......................................................................................................7
3.4.1. Adverse Events.............................................................................................8
3.4.2. Laboratory Data............................................................................................8
4. ANALYSIS SETS .................................................................................................................8
4.1. PD Analysis Set.........................................................................................................8
4.2. Safety Analysis Set....................................................................................................8
4.3. Protocol Deviations...................................................................................................8
5. GENERAL METHODOLOGY AND CONVENTIONS......................................................8
5.1. Hypotheses and Decision Rules ................................................................................9
5.2. General Methods .......................................................................................................9
5.2.1. Analyses for Binary Endpoints.....................................................................9
5.2.2. Analyses for Continuous Data......................................................................9
5.2.3. Analyses for Categorical Data......................................................................9
5.2.4. Analyses for Time to Event Data..................................................................9
5.3. Methods to Manage Missing Data ............................................................................9
6. ANALYSES AND SUMMARIES ........................................................................................9


A6301094 Statistical Analysis Plan
Page 3
6.1. Endpoint(s)................................................................................................................9
6.1.1. PD Endpoints................................................................................................9
6.1.1.1. Primary PD Endpoint ................................................................10
6.1.1.2. Secondary PD Endpoints...........................................................10
6.1.2. Efficacy Endpoints......................................................................................10
6.1.2.1. Efficacy Analysis ......................................................................10
6.2. Baseline and Other Summaries and Analyses.........................................................11
6.2.1. Demography and Baseline Summaries.......................................................11
6.2.2. Study Conduct and Subject Disposition .....................................................11
6.2.3. Study Treatment Exposure .........................................................................11
6.2.4. Concomitant Medications and Non-Drug Treatments................................12
6.3. Safety Endpoint Summaries and Analyses..............................................................12
6.3.1. Safety analysis ............................................................................................12
6.3.2. Adverse Events...........................................................................................12
6.3.3. Laboratory Data..........................................................................................13
6.3.4. Vital Signs and Physical Examination........................................................13
7. INTERIM ANALYSES.......................................................................................................13
8. REFERENCES ....................................................................................................................13
9. APPENDICES .....................................................................................................................14
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments................................................4
LIST OF FIGURES
Figure 1.
Schematic Trial Design...........................................................................................5
APPENDICES
Appendix 1. STATISTICAL METHODOLOGY DETAILS..................................................14
Appendix 1.1. Time to Event...................................................................................................14


A6301094 Statistical Analysis Plan
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1. VERSION HISTORY
Table 1.
Summary of Major Changes in SAP Amendments
SAP 
Version
Change
Rationale
1
Not Applicable
Not Applicable
2
Administrative 
Changes due to 
protocol amendments
Transition of study to Pfizer Inc from Eisai; Updating of 
Safety Section per Pfizer safety reporting processes and 
procedures, and other relevant sections per Pfizer Inc 
processes and procedures
Include protocol modifications endorsed by FDA in a 
Type C Meeting conducted on 05 November 2015, 
including updating age cohort groups, inclusion of all 
patients with VTE and removal of the central imaging 
reader and Adjudication Committee
2. INTRODUCTION
This protocol implements a post approval clinical commitment between Pfizer Inc., and the
Food and Drug Administration (FDA) relating to the dalteparin sNDA 20-287/S-035, “for the
extended treatment of symptomatic venous thromboembolism [VTE (proximal deep vein
thrombosis [DVT] and/or pulmonary embolism [PE])] to reduce recurrent VTE in
subjects with cancer”. This phase II pharmacodynamic (PD) study is intended to provide
information to guide the conditions under which dalteparin may be used for the treatment of
acute and secondary prophylaxis of VTE in children. The PD profiles for treatment doses of 
dalteparin using anti-Xa levels will also be assessed in a population PD analysis 
methodology.
2.1. Study Objectives
The primary objective of this study is to:

To determine the PD profiles for treatment doses of dalteparin in pediatric
subjects of different ages with venous thromboembolism (VTE), and with or without 
cancer, using anti-Xa (Xa) levels and a population PD analysis methodology.

To determine the median dose (IU/kg) required to achieve therapeutic anti-Xa levels
(0.5-1.0 IU/mL) based on subject age and weight.


A6301094 Statistical Analysis Plan
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Secondary objectives will be:

To assess the proportion of subjects with major bleeding events during dalteparin 
treatment.

To assess the proportion of subjects with minor bleeding events during dalteparin 
treatment.

To explore the proportion of subjects with objectively documented new or
progressive symptomatic VTE during dalteparin treatment.

To explore the relationships of recurrent VTE and major bleeding events with anti-Xa
levels if data permits.

To assess proportion of subjects achieving an anti-Xa therapeutic range of 0.5 to 
1.0IU/mL during the Dose Adjustment Phase.

To explore the proportions of subjects with progression, regression, resolution or no
change in the qualifying VTE during dalteparin treatment.

To describe the overall safety profile of dalteparin in pediatric subjects of different
ages with VTE.
2.2. Study Design
The study is a 3 month prospective, multicenter, open-label cohort study in North America
and Europe to determine twice daily dosing recommendations of dalteparin as a function
of age in order to achieve anti-Xa levels of 0.5 to 1.0 IU/mL at 4 hour postdose in
children with or without various cancers and requiring anticoagulation for the treatment
and secondary prophylaxis of VTE. The study is divided into 3 phases (Figure 1): 1) Dose
Adjustment Phase of up to 7 days; 2) PD Phase; and 3) Follow-up Phase, to complete up to
90 days of treatment.
Figure 1.
Schematic Trial Design
Visit 1           Visit 2               Visit3                   Visit4                    Visit 5, 6 &7/EOT/ET
Screening           Baseline               Dose adjustment              PD Phase
         Follow-up
(Day-3 to 1)
(Day 1)
         (Day 1 up to 7)       (Day 2 or 3 to 14)        (Days 30, 60 
&90/ET)
Subjects will be enrolled into one of the following five age groups (cohorts):
newborn (0-<8 weeks), infants (>=8weeks - <2 years), preschool (>=2 years - <8 years), 
school (>= 8 years - < 12 years), and teen (>= 12 years - < 19 years).
The target enrollment is a total of 50 subjects who have completed the PD Phase.


A6301094 Statistical Analysis Plan
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All age groups will receive dalteparin twice daily. The initial dose for each age group are: 
125 IU/kg for 0 to <8 weeks, 150 IU/kg for >=8 weeks to < 2 years, 125 IU/kg for 
>=2 weeks to < 8 years and >=8 years to < 12 years, and 100 IU/kg for >=12 years to 
<19 years.
The Dose Adjustment Phase will begin following the first dose and continue for up to
7 days. During the Dose Adjustment Phase, doses are adjusted according to anti-Xa levels. 
The first anti-Xa level may be taken 4 hours ±1 hour after the first, second or third dose per 
institutional standard. Subsequent anti-Xa levels will be drawn at 4 hours ±1 hour
postdose. Doses will be adjusted in increments or decrements of 25 IU/kg in order to achieve
target anti-Xa levels (0.5-1.0 IU/mL).
Subjects completing the Dose Adjustment Phase will enter into the PD Phase and continue on 
the final twice daily dosing (Q12h ±1 hour) regimen from the Dose Adjustment Phase. 
The PD Phase will last for up to 7 days in order to complete two PD samples. After subjects
successfully complete the PD Phase, they will enter the Follow-up Phase.
During this phase, subjects will continue receiving twice daily dalteparin q12h (±1 hour) and
will be followed according to the visit schedule. The maximum duration is 90 days after first 
dose of dalteparin.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINATIONS AND 
CONVENTIONS
3.1. PD Endpoint(s)
3.1.1. Primary PD Endpoints

Anti-Xa activity versus time profile following dalteparin treatment in pediatric 
subjects of different ages with VTE.
Note: This is beyond the scope of the SAP and it will be detailed in a separated 
population modeling analysis plan (PMAP-EQDD-A630c-DP4-560).

Median dose required per age group to achieve an anti-Xa level of 0.5 to 1.0 IU/mL 
during the dose adjustment phase.
3.1.2. Secondary PD endpoints

Proportion of children achieving an anti-Xa therapeutic range of 0.5 to 1.0 IU/mL
during the Dose Adjustment Phase.

Proportion of subjects who remain within therapeutic range during the follow up 
phase (Visit 5, Visit 6 and Visit 7).

The percentage of anti-Xa levels measured 4 hours post dose 1 hour that are outside 
the target range will be calculated during the follow up phase of study (Visit 5, Visit 6 
and Visit 7).


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
The maintenance dose, time to achieve the target range, and number of dose 
adjustment during dose adjustment phase.
3.2. Efficacy Endpoint(s)
All efficacy endpoints are secondary endpoints.

Proportion of subjects with objectively documented new or progressive
symptomatic VTE during dalteparin treatment.

Relationship between objectively documented new or progressive symptomatic 
VTE and the anti-Xa level during dalteparin treatment if data permits.

The proportions of subjects with progression, regression, resolution or no change in 
the qualifying VTE during dalteparin treatment.

Time to first episode of symptomatic recurrent VTE during dalteparin treatment.
3.3. Baseline Variables
3.3.1. Stratification and Randomization
Enrolled subjects who achieve the target therapeutic anti-Xa level in Dose Adjustment Phase
will advance to the PD phase. These subjects will be centrally randomized (at baseline) to 
two different blood sampling scheme (1-3 h & 5-8 h or 3-5 h & 8-12 h) for the PD phase with 
a ratio of 1:1 and the randomization will be blocked and stratified by age group.  
3.3.2. Covariates
As an objective of the study is to examine safety and efficacy within different age groups, 
subjects will be presented split into the age categories: 0-<8 weeks, >=8weeks - <2 years, 
>=2 years - <8 years, >= 8 years - < 12 years, and >= 12 years - < 19 years.
3.4. Safety Endpoints
All safety endpoints are secondary endpoints.

Proportion of subjects with major bleeding events during dalteparin treatment.

Relationship between major bleeding event and the Anti-Xa level during dalteparin 
treatment if data permits.

Proportion of subjects with minor bleeding events during dalteparin treatment.

Time to first major bleeding events during dalteparin treatment.
Safety will also be assessed by adverse event reports, physical examination, laboratory test 
results, and vital signs in the safety population. Both all-causality and treatment related 
adverse events will be assessed.  The latest Pfizer Data Standard (PDS) will be used for 
reporting. 


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3.4.1. Adverse Events
An adverse event is considered treatment emergent if:

the event occurs for the first time during the effective duration of treatment and was 
not seen prior to the start of treatment, or

the event was seen prior to the start of treatment but increased in severity during 
treatment.
The effective duration of treatment is determined by the lag time (30 days).  Any event 
occurring within the lag time, whether this occurs during a break in treatment or at the end of 
treatment, is attributed to the previous treatment period.   
3.4.2. Laboratory Data
To determinate if there are any clinically significant laboratory abnormalities, the 
hematological and clinical biochemistry and other safety tests will be assessed against the 
criteria specified in the Pfizer reporting standards. This assessment will take into account 
whether each subject’s baseline test results are within or outside the laboratory reference 
range for the particular laboratory parameter.
4. ANALYSIS SETS
The main subject populations to be used for the analysis are a pharmacodynamics (PD) 
population and a safety population.
The PD population will be the analysis population for efficacy.
4.1. PD Analysis Set
The PD analysis set (PD population) will include all subjects who receive at least one dose of 
study drug and achieve therapeutic range of anti-Xa during dose adjustment phase. 
4.2. Safety Analysis Set
The safety analysis set (safety population) will include all the subjects who receive at least 
one dose of study drug.
4.3. Protocol Deviations
Protocol deviations relevant to the PD population and the safety population will be 
summarized.
5. GENERAL METHODOLOGY AND CONVENTIONS
The final primary analysis will be performed at database release after last subject last visit. 


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5.1. Hypotheses and Decision Rules
Because of the descriptive nature of this study, there will be no statistical hypotheses tested 
and decisions rules. Two-sided 95% confidence interval (CI) will be provided to aid decision 
making.  
5.2. General Methods 
The following sub-sections contain the descriptions of the methods that will be used in the 
analysis of the various endpoints in this study.  The choice of analysis method will be 
dependent on the endpoint of interest (eg, whether the endpoint is a primary or secondary, or
whether the endpoint is efficacy or safety).  The analysis methods to be used for each 
endpoint will be covered in the following section.  
5.2.1. Analyses for Binary Endpoints
Response rates (eg, proportion of subjects with objectively documented new or progressive 
symptomatic VTE) will be presented with exact 95% confidence intervals for binomial 
proportion, using the Clopper-Pearson method (Collett 1991).
5.2.2. Analyses for Continuous Data
Continuous data are variables that are continuous or considered continuous for the purpose of 
analysis, the following descriptive statistics will be provided at each visit (including the 
baseline, when applicable): N, mean, median, standard deviation (SD), minimum and 
maximum.
5.2.3. Analyses for Categorical Data
Categorical data will be presented with frequency and percentage.
5.2.4. Analyses for Time to Event Data
Time-to-event endpoints will be summarized using the Kaplan-Meier method and estimated 
survival curves will be displayed graphically when appropriate.  Kaplan-Meier graphs will 
describe the number of patients at risk over time. In addition, the Cox Proportional Hazard 
Regression model will be employed to assess the hazard ratio of the event with prognostic 
factors. 
5.3. Methods to Manage Missing Data
For efficacy endpoints, missing data will not be imputed.
6. ANALYSES AND SUMMARIES
All statistical analyses will be performed using SAS® (Version 9.1 or higher), and 
statistical tests will be assessed at the two-sided 0.05 level of significance.
6.1. Endpoint(s)
6.1.1. PD Endpoints
Unless otherwise noted, all PD endpoints will be analyzed within the PD population.


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6.1.1.1. Primary PD Endpoint

Anti -Xa activity versus time profile following dalteparin treatment in pediatric 
subjects of different ages with VTE (detailed in a separated population modeling
analysis plan [PMAP-EQDD-A630c-DP4-560]).

Median dose required to achieve an anti-Xa level of 0.5 to 1.0 IU/mL during the dose 
adjustment phase.
The median dose will be presented overall and by each age group for patients who 
achieved an anti-Xa level of 0.5 to 1.0 IU/mL during the dose adjustment phase.
6.1.1.2. Secondary PD Endpoints

Proportion of subjects achieving an anti-Xa therapeutic range of 0.5 to 1.0 IU/mL 
during the Dose Adjustment Phase.
The count and proportion will be summarized overall and by each age group within 
the safety population, along with the two-sided exact 95% CI.

Proportion of subjects who remain within therapeutic range at each visit during the 
follow up phase (Visit 5, Visit 6 and Visit 7).
The count and proportion will be summarized overall and by each age group, along 
with the two-sided exact 95% CI.

The percentage of anti-Xa levels measured 4 hours post dose 1 hour that are outside
the target range will be calculated at each visit during the follow up phase of study
(Visit 5, Visit 6 and Visit 7).
The count and percentage will be summarized overall and by each age group, along 
with the two-sided exact 95% CI.

The maintenance dose, time to achieve the target range, and number of dose 
adjustment during dose adjustment phase.
The maintenance dose, time to achieve the target range, and number of dose
adjustments will be summarized overall and by each age group.
6.1.2. Efficacy Endpoints 
All efficacy endpoints will be analyzed within the PD population.
6.1.2.1. Efficacy Analysis

Proportion of subjects with objectively documented new or progressive symptomatic 
VTE during dalteparin treatment.
The count and proportion will be summarized overall and by each age group, along 
with the two-sided exact 95% CI.


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
Relationship between objective documented new or progressive symptomatic VTE 
assessed by investigators and the anti-Xa level during dalteparin treatment.
Logistic regression for new/progressive VTE assessed by investigators on anti-Xa 
level at end of dose adjustment and other prognostic factors (eg, age, baseline tumor 
status), will be performed. For each of the covariates, the odds ratio, and the 
corresponding 95% CI, will be displayed. 
Subjects who experience at least one new or progressive VTE while on study will be 
counted as Yes.

Time to event (first episode of recurrent VTE) during dalteparin treatment.
The time to event (first recurrent VTE) will be described by using the Kaplan-Meier
method. In addition, the Cox Proportional Hazard Regression model will be 
employed to assess the hazard ratio of the event with prognostic factors.
See Appendix 1 for a general description of censoring of time-to-event variables.

Proportions of subjects with progression, regression, resolution and no change in the 
qualifying VTE (in comparison with the assessment at study entry) during dalteparin 
treatment.
The count and proportion will be summarized overall and by each age group, along 
with the two-sided exact 95% CI.
6.2. Baseline and Other Summaries and Analyses
6.2.1. Demography and Baseline Summaries
The demographic characteristics will be summarized, overall and by each age group, within 
the safety population and the PD population. This will include age, gender, race, height, and 
baseline weight.
All baseline disease characteristics will be summarized overall and by each age group based 
within the safety population and the PD population. This will include diagnosis of cancer, 
previous history of VTE, risk factors for VTE and qualifying episodes of VTE.
6.2.2. Study Conduct and Subject Disposition
Study conduct and subject disposition will be summarized within the safety population. The 
number of subjects screened, randomized, treated, completing and discontinuing from the 
study, as well as the number of subjects in each analysis set will be summarized overall and 
by each age group.  For subjects who did not complete the study, the reasons for withdrawal 
from the study will be presented.
6.2.3. Study Treatment Exposure
Duration of treatment will be summarized, overall and by each age group, within the safety 
population and the PD population.


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6.2.4. Concomitant Medications and Non-Drug Treatments
All concomitant medications as well as non-drug treatments will be summarized overall and
by each age group within the safety population.
6.3. Safety Endpoint Summaries and Analyses
The safety summaries below will be performed within the safety population.
6.3.1. Safety analysis

Proportion of subjects with major bleeding assessed by investigators during dalteparin 
treatment.
The count and proportion will be summarized overall and by each age group, along 
with the two-sided exact 95% CI.

Relationship between major bleeding event and the Anti-Xa level during dalteparin 
treatment.
Logistic regression for major bleeding event assessed by investigators on anti-Xa 
level observed at the end of dose adjustment and other prognostic factors (eg, age, 
gender), will be performed. For each of the covariates, the odds ratio, and the 
corresponding 95% CI, will be displayed. 
Subjects who experience at least one major bleeding event while on study will be 
counted as Yes.

Proportion of subjects with minor bleeding events during dalteparin treatment.
The count and proportion will be summarized overall and by each age group, along 
with the two-sided exact 95% CI.

Time to first major bleeding event during dalteparin treatment.
The time to first major bleeding event assess by investigators will be described by 
using the Kaplan-Meier method. In addition, the Cox Proportional Hazard Regression 
model will be employed to assess the hazard ratio of the event with prognostic 
factors.
See Appendix 1.1 for a general description of censoring of time-to-event variables.
6.3.2. Adverse Events
All adverse events will be coded using the most current version of the MedDRA dictionary
available at the time of database lock. Frequencies of adverse events will be presented by 
system organ class, preferred term, and severity level.

All causality treatment emergent adverse events will be summarized overall and by 
each age group.


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
Treatment related treatment emergent adverse events will be summarized overall and 
by each age group. 

Adverse events and serious adverse events will be listed by subjects for all age 
groups.

Adverse events leading to discontinuation or temporary dose reduction will be 
presented.
Adverse events will be reported in accordance with the Pfizer Data Standards for safety 
reporting. 
6.3.3. Laboratory Data
Descriptive statistics will be summarized overall and by each age group as well as median 
change from baseline for laboratory parameters. 
All laboratory data will be reported in accordance with Pfizer Data Standards for safety 
reporting.
6.3.4. Vital Signs and Physical Examination
All vital sign and physical exam data will be reported in accordance with the Pfizer Data 
Standards for safety reporting.
7. INTERIM ANALYSES
In August 2014, analyses for an interim report were performed by the previous study 
sponsor, Eisai Inc. on the data available at that time. The corresponding interim report was 
submitted to the FDA for review by Eisai Inc. These analyses did not contain any provisions 
for early stopping of the study.
8. REFERENCES 
1.
Collett, D. (1991), Modelling Binary Data, London: Chapman & Hall.


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9. APPENDICES 
Appendix 1. STATISTICAL METHODOLOGY DETAILS
Appendix 1.1. Time to Event
For this analysis, time to event will be measured from the first dose of study medication in 
days. For subjects who have event, time to event is defined as:
   T = date of event – first treatment date +1
Subjects who do not have the event of interest will be censored at the latest date in the 
database. Time to event is defined as:
  T=latest date in the database – first treatment date +1
The latest date is expected to be the date of the End of Study visit.