Clinical trial NCT03100123
Conditions: Antiphospholipid Syndrome in Pregnancy Pregnancy Loss
Sponsor: Ottawa Hospital Research Institute
Start date: 2017-11-06; Completion date: 2019-10-07
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The APPLE pilot trial is a feasibility study that is a multicentre, open-label, randomized controlled trial. Pregnant women with antiphospholipid syndrome (APS) and a history of late (≥10 weeks gestation) or recurrent early (2 \<10 weeks) pregnancy loss will be recruited.

Eligible and consenting subjects will be assigned to one of two study arms: open-label low-molecular-weight heparin (LMWH) prophylaxis until 37 weeks gestation AND low-dose aspirin (ASA) daily until delivery, or open-label low-dose aspirin daily from randomization until delivery.

Detailed description:
The purpose of this pilot trial is to determine the feasibility of conducting a multicenter randomized full trial evaluating antepartum prophylaxis with ASA versus LMWH/ASA in women with confirmed APS and a history of late or recurrent early pregnancy loss.

Given the large sample size needed to adequately power a large multicenter trial that assesses the efficacy of ASA alone versus LMWH/ASA, the investigators first need to determine if it is possible to meet minimum recruitment rates needed for a full multicenter trial. If the pilot feasibility trial is successful, then the secondary outcomes collected will be used in the analysis of the full multicenter trial.

Arms: arm 1: Open-label low-molecular-weight heparin (LMWH) prophylaxis until 37 weeks gestation AND low-dose aspirin daily until delivery. arm 2: Open-label low-dose Aspirin 81 mg daily from randomization until delivery.
Interventions: intervention 1: Aspirin 81 mg intervention 2: Low-molecular-weight heparin
Intervention descriptions: intervention 1: Aspirin 81 mg po daily in tablet form. intervention 2: The LMWH regime will be at the discretion of the treating physician, with a suggested regime as follows: tinzaparin 4,500 IU sc daily until 20 weeks gestation, and then 4,500 IU sc twice daily until 37 weeks gestation.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
APPLE 
AntiPhospholipid syndrome low-molecular-weight heparin Pregnancy Loss Evaluation: 
The pilot study 
 
 
 
 
Protocol Title:  A pilot study assessing the feasibility of a randomized controlled trial 
evaluating aspirin versus low-molecular-weight heparin (LMWH) and aspirin in women 
with antiphospholipid syndrome and pregnancy loss 
 
 
 
 
Co-Principal Investigators 
Dr. Leslie Skeith and Dr. Marc Rodger 
Ottawa Hospital – General Campus 
501 Smyth Road 
Ottawa, ON, K1H 8L6 
 
Coordinating Centre 
Ottawa Hospital Research Institute 
 
Funding Mechanism 
CanVECTOR Network 
 
Sponsor 
Ottawa Hospital Research Institute 
 
Protocol Version 
V4 (November 7, 2017) 
 
 
 
 
 
 
Confidentiality agreement 
This protocol contains confidential information belonging to Drs. Leslie Skeith and Marc 
Rodger. Except as may be otherwise agreed to in writing, by accepting or reviewing 
these materials, you agree to hold such information in confidence and not to disclose it 
to others (except where required by applicable law) nor use it for unauthorized purposes. 
In the event of actual or suspected breach of this obligation, Dr. Leslie Skeith or Marc 
Rodger, The Ottawa Hospital should be promptly notified. 
 
 
 
______________________________________    _____________________________ 
  Signature 
 
 
 
 
  
  Date 
 
 
 
 


APPLE: Anti Phospholipid syndrome low-molecular-weight heparin Pregnancy Loss Evaluation 
Version: 4 (November 7, 2017) 
SIGNATURE PAGE  
Co-Principal Investigator 
Dr. Leslie Skeith 
Ottawa - Coordinating Centre 
Ottawa Hospital Research Institute 
The Ottawa Hospital — General Campus 
501 Smyth Road 
Ottawa, ON K1H 8L6 
CANADA 
Ph: 613-915-5215 (cell) 
Fax: 613-739-6102 
n0.4  erv,V.w.-  %i  'Loa-
Date  
Co-Principal Investigator 
Dr. Marc A. Rodger 
Ottawa - Coordinating Centre 
Ottawa Health Research Institute 
The Ottawa Hospital- General Campus 
501 Smyth Road, Rm W6120 
Ottawa, ON K1H 8L6 
CANADA 
Ph: 613-737-8899 ext. 74641 
-6102 
r4O) qarl-
Date 
Signatu 
Signature 


APPLE: Anti Phospholipid syndrome low-molecular-weight heparin Pregnancy Loss Evaluation 
 
 
Version: 4 (November 7, 2017) 
 
Table of Contents 
 
Pilot Study Synopsis........................................................................................................ 6 
Purpose of Pilot Trial ................................................................................................... 6 
Pilot Trial Endpoints .................................................................................................... 6 
Trial Design/Methodology ............................................................................................ 7 
Visit Schedule ............................................................................................................. 8 
Number of Subjects ..................................................................................................... 8 
Study Population ......................................................................................................... 8 
Schedule of Mandatory Events ...................................................................................... 10 
Abbreviations and Definitions of Terms ......................................................................... 11 
1. BACKGROUND ........................................................................................................ 12 
1.1 Why is a randomized clinical trial (RCT) needed?................................................ 12 
1.2 Why is a clinical trial needed now? ...................................................................... 13 
1.3 What are the risks with the standard of care regime of prophylactic LMWH/ASA?
 .................................................................................................................................. 13 
1.4 What are the risks with the experimental arm (ASA alone)? ................................ 13 
1.5 Why is a pilot RCT needed before a full RCT can be completed? ........................ 14 
1.6 Need for an open-label trial ................................................................................. 14 
1.7 Need for ‘pragmatic’ use of LMWH ...................................................................... 14 
1.8 Why are women with 2 losses included? ............................................................. 14 
2. TRIAL OBJECTIVES ................................................................................................. 15 
2.1 Trial Purpose ....................................................................................................... 15 
2.2 Pilot Trial Objectives ............................................................................................ 15 
2.3 Pilot Trial Endpoints ............................................................................................. 15 
2.4 Full Trial Objectives ............................................................................................. 16 
2.5 Full Trial Endpoints .............................................................................................. 16 
2.6 Endpoint Definitions ............................................................................................. 16 
3. TRIAL DESIGN ......................................................................................................... 18 
3.1 Trial Design ......................................................................................................... 18 
3.2 Screening, Baseline and Randomization ............................................................. 19 
3.3 Antenatal Follow-Up ............................................................................................ 19 
3.4 Labour and Delivery ............................................................................................ 20 
3.5 Postpartum Follow-up .......................................................................................... 20 
3.6 End of Study ........................................................................................................ 20 
4. SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 20 
4.1 Inclusion Criteria .................................................................................................. 20 


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4.2. Exclusion Criteria................................................................................................ 21 
4.3 Withdrawal of Subjects ........................................................................................ 22 
5. RECRUITMENT ........................................................................................................ 23 
5.1 Treatment Schedule ............................................................................................ 23 
5.2 Randomization .................................................................................................... 23 
5.3 Web Base Randomization ................................................................................... 24 
5.4 Study drug management ..................................................................................... 24 
6. MEASURMENTS AND EVALUATIONS .................................................................... 24 
6.1 Demographic and Baseline Characteristics (Screening Period) ........................... 24 
6.2 Laboratory and Imaging Assessments ................................................................. 25 
6.3 Prior and Concomitant Therapy ........................................................................... 25 
6.4 Antenatal Follow-up ............................................................................................. 26 
6.5 Postpartum Follow-up .......................................................................................... 26 
6.6 Labour and Delivery Record ................................................................................ 26 
6.7 Adjudication ......................................................................................................... 26 
6.8 Adverse Events ................................................................................................... 26 
7. ADVERSE EVENTS .................................................................................................. 27 
7.1 Definition ............................................................................................................. 27 
7.2 Eliciting Adverse Event Information ..................................................................... 27 
7.3 Adverse Event Reporting Period .......................................................................... 27 
7.4 Recording Instructions ......................................................................................... 28 
7.5 Seriousness (Gravity) – Serious Adverse Events (SAE) ...................................... 28 
7.6 Reporting of SAEs ............................................................................................... 29 
7.7 Follow-Up of Adverse Event ................................................................................ 30 
8. STATISTICS ............................................................................................................. 30 
8.1 Statistical and Analytical Plans ............................................................................ 30 
8.1.1 Analysis of Baseline Characteristics ............................................................................ 30 
8.1.2. Pilot Trial Primary Analysis ......................................................................................... 31 
8.1.3. Pilot Trial Secondary Analyses ................................................................................... 31 
8.1.4. Full Trial Analyses ....................................................................................................... 31 
8.2 Determination of Sample Size ............................................................................. 31 
9. QUALITY ASSURANCE (QA) ................................................................................... 32 
9.1. Quality Assurance .............................................................................................. 32 
9.2 Monitoring ........................................................................................................... 32 
10. ETHICS ................................................................................................................... 32 
10.1 Ethical Conduct of the Trial ................................................................................ 32 
10.2 Research Ethics Board (REB) ........................................................................... 32 


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10.3 Subject Information and Consent ....................................................................... 32 
11. DATA SAFETY MONITORING BOARD .................................................................. 32 
12. DATA HANDLING AND RECORD KEEPING .......................................................... 33 
12.1 Personal Health Information .............................................................................. 33 
12.2 Case Report Forms ........................................................................................... 33 
12.3 Record Retention ............................................................................................... 33 
REFERENCES .............................................................................................................. 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PILOT STUDY SYNOPSIS 
 
Title 
A pilot study assessing the feasibility of a randomized controlled trial evaluating 
aspirin versus low-molecular-weight heparin (LMWH) and aspirin in women with 
antiphospholipid syndrome and pregnancy loss  
 
Protocol Version 
Version 4, November 7, 2017 
 
Study Centres 
The Ottawa Hospital, General Campus, Ottawa, ON 
McMaster University Medical Centre, Hamilton, ON  
 
Timeline 
November 2017 - October 2019 
 
 
Purpose of Pilot Trial 
The purpose of this pilot trial is to determine the feasibility of conducting a 
multicenter randomized trial evaluating antepartum prophylaxis with aspirin versus 
LMWH/aspirin in women with confirmed APS and a history of late or recurrent early 
pregnancy loss. 
 
Purpose of Full Trial: 
The purpose of the full trial is to determine the efficacy and safety of antepartum 
prophylaxis with aspirin alone to improve the live birth rate in women with confirmed 
APS and a history of late or recurrent early pregnancy loss, compared to the 
standard of care regime of LMWH/aspirin prophylaxis. 
 
 
Pilot Trial Endpoints 
The primary feasibility outcome is the mean recruitment rate per center per month, 
calculated over 24 months. The secondary feasibility outcomes are: (defined in 
section 2.2) 
1. Proportion of sites requiring >18 months to obtain all required 
approvals/contracts from time of delivery of all study documents  
2. Proportion of screened patients who meet eligibility criteria  
3. Proportion of eligible subjects who provide consent  
4. Proportion of withdrawals/loss to follow-up among randomized patients  
5. Proportion of subject crossover between study arms 
6. Rate of compliance with antepartum LMWH use 
7. Reasons for physician and patient non-consent 
 
Full Trial Endpoints (Will be collected in the Pilot APPLE Trial) 
The primary full trial outcome is the live birth rate. The secondary full trial outcomes 
are: (defined in section 2.3) 
1. Livebirth rate according to central laboratory test results 
2. Pregnancy loss by gestational age (<10 weeks, 10-19 weeks, ≥20 weeks)  


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3. Pre-eclampsia 
4. Early onset pre-eclampsia 
5. Severe pre-eclampsia 
6. Small-for-gestational age (SGA) <10th percentile 
7. SGA <5th percentile 
8. SGA <3rd percentile 
9. Placental abruption requiring delivery 
10. Pre-term delivery <37 weeks gestation 
11. Symptomatic venous thromboembolism (VTE) 
12. Symptomatic arterial thromboembolism (ATE) 
13. Major bleeding 
14. Clinically relevant non-major bleeding 
15. Peripartum major bleeding 
16. Peripartum minor bleeding 
17. Non-major non-CRNM bleeding  
18. Heparin induced thrombocytopenia (HIT) 
19. Symptomatic fracture 
20. Allergic reaction 
21. All-cause mortality 
 
 
Trial Design/Methodology 
The APPLE pilot trial is a feasibility study that is a multicentre, open-label, 
randomized controlled trial. Pregnant women with antiphospholipid syndrome (APS) 
and a history of late (≥10 weeks gestation) or recurrent early (2 <10 weeks) 
pregnancy loss will be recruited. Women with APS and a past history of venous or 
arterial thrombosis are not eligible for the trial (see below for the full list of exclusion 
criteria). 
 
The study consists of four periods: screening, baseline and randomization, antenatal 
follow-up, labour and delivery, and post-partum follow-up. 
 
Eligible and consenting subjects will be assigned to one of two study arms. 
Randomization is stratified by ‘high-risk’ or ‘non-high risk’ laboratory criteria and the 
timing of pregnancy loss (late loss or no late loss) (section 5.3): 
 
Experimental arm 
Open-label low-dose aspirin daily from randomization until delivery 
 
Standard of care arm 
Open-label LMWH prophylaxis until 37 weeks gestation AND low-dose aspirin daily 
until delivery.  
 
The recommended “standard of care” arm is tinzaparin 4,500 IU sc daily until 20 
weeks gestation, then tinzaparin 4,500 IU sc twice daily until 37 weeks gestation and 
aspirin 81 mg po daily until delivery. Treating physicians do have access to other 
LMWH (dalteparin, enoxaparin) as standard of care, but the suggested regime with 
tinzaparin is recommended. The use of LMWH prophylaxis beyond 37 weeks 
gestation and in the 6 week postpartum period will be left up to the discretion of the 
treating physician. 
 


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Each subject will receive education regarding LMWH administration, potential 
adverse effects and symptoms of VTE by clinic personnel (not research personnel), 
based on standard of care.  
 
Visit Schedule 
Screening, Baseline and Randomization 
The subject will be evaluated for study eligibility by the investigator or delegated 
research personnel and once the consent has been assigned, a baseline assessment 
will be completed. Randomization is done at, or within 7 days of, the baseline visit. 
The feasibility outcomes will be collected using detailed screening and enrollment 
logs. Baseline blood work and an obstetrical ultrasound are recommended within 7 
days of study enrolment. 
 
Antenatal Follow-up 
Subjects will attend a clinic visit at 20 ± 4 weeks gestation. All subjects will be 
monitored for study outcomes and adverse events (AE).  Compliance of study 
medication will be measured at this visit. 
 
Labour and Delivery 
Study outcomes and AEs will be assessed through a review of subjects’ medical 
records, which may include blood work, urinalysis and ultrasound reports. Data 
pertaining to the labour and delivery, as well as fetal health at birth will be 
documented. 
 
Postpartum Follow-up 
Subjects will attend a clinic visit at 6-12 weeks postpartum. Compliance of study arm 
during pregnancy will be measured at this visit. All subjects will be monitored for study 
outcomes and adverse events (AE). 
 
Number of Subjects 
The goal recruitment rate is recruitment of 1 subject every 2 months per centre, or a 
total of 24 patients in 24 months. The primary endpoint is the mean recruitment rate 
per month. 
 
 
Study Population 
Inclusion Criteria 
Participants must be 18 years or older, have a confirmed pregnancy, and require at 
least one laboratory criteria and one clinical criteria, as listed below: 
 
Clinical criteria: Past history of pregnancy loss defined as either: 
A. Two or more unexplained pregnancy loss before the 10th week of gestation  
B. One or more unexplained pregnancy loss at or beyond the 10th week of 
gestation 
AND 
Laboratory Criteria: At least one positive laboratory test listed below that is positive on 
two or more occasions at least 12 weeks apart*:   
A. Presence of lupus anticoagulant (LAC)  


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B. Anticardiolipin antibody (aCL) of IgG or IgM with a titre > 99th percentile or > 
40 GPL or MPL  
C. Anti-β2 glycoprotein antibody of IgG or IgM with a titre > 99th percentile 
 
*according to the diagnostic criteria of APS, diagnosis should be avoided if more than 5 
years is separated between positive antibody testing and a clinical manifestation, such 
as pregnancy loss 
 
Exclusion Criteria 
1. Greater than 11 weeks +6 days gestational age at time of randomization 
2. Indication(s) for prophylactic or therapeutic-dose anticoagulation  
a. Venous thromboembolism (VTE) 
b. Arterial thromboembolism (ATE) 
c. Small-vessel thrombosis 
d. Mechanical heart valve 
e. Other indication for prophylactic or therapeutic-dose anticoagulation, at 
the discretion of the treating physician 
3. Contraindication to heparin or aspirin including: 
a. History of known heparin or LMWH allergy 
b. History of known aspirin allergy 
c. History of HIT 
d. History of osteoporosis 
e. Major bleeding within 7 days*.  
f. Known thrombocytopenia, based on platelet count < 50 x 109/L in the 
previous 3 months 
g. Known hepatic disease, based on a medical history of elevated liver 
enzymes (3x ULN) and/or bilirubin (2xULN) documented within the last 3 
months  
h. Known renal failure, based on Creatinine Clearance < 30 mL/min 
(Cockcroft Gault) in the previous 3 months  
i. 
Known severe hypertension, based on SBP > 200 mmHg and/or DBP > 
120 mmHg in the previous 3 months 
4. Received 7 or more doses of LMWH 
5. Previous participation in the trial  
6. Geographic inaccessibility**  
7. Refused consent 
 
*All other active or recent bleeding is at the discretion of the treating physician. 
**At the discretion of the patient or the treating physician 
 
 
Please note: Investigators should use caution when prescribing LMWH to patients with a 
history of gastric ulceration or whom weight >120kg or <45kg. 
 
 
 
 
 
 
 
 


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SCHEDULE OF MANDATORY EVENTS 
 
 
 
Screening, 
Baseline and 
Randomization 
Antepartum: 
Week 20 ± 4 
weeks visit 
Labour & 
Delivery* 
6-12 weeks 
Postpartum 
Inclusion/Exclusion 
√ 
 
 
 
Consent 
√ 
 
 
 
Randomization 
√ 
 
 
 
Demographic 
√ 
 
 
 
Med/ObGyn Info/History 
√ 
 
 
 
Blood work1 
√ 
 
 
 
Dating ultrasound2 
√ 
√ 
 
 
Concomitant Medication 
√ 
√ 
√ 
√ 
Treatment Compliance 
 
√ 
 
√ 
Drug Regime** 
 
√ 
 
√ 
Labour & Delivery Data 
 
 
√ 
 
Infant Health 
 
 
√ 
 
Epidural Use 
 
 
 
√ 
Outcome Information3 
 
√ 
√ 
√ 
Adverse Events4 
 
√ 
√ 
√ 
 
1 – BhCG is required to document current pregnancy, if not previously available. A 
complete blood count and creatinine will be drawn, if not previously available within the 
past 3 months. Lupus anticoagulant, anticardiolipin IgG and IgM antibodies and beta-2 
glycoprotein IgG and IgM antibodies (if available) will be drawn to confirm eligibility if 
required, as well as bloodwork stored for central lab testing.  
2 – Dating ultrasound results will be recorded, if available. An obstetrical ultrasound is 
recommended within 7 days of study enrolment as a baseline, starting at 6-7 weeks 
gestation. 
3 – Outcome events will be recorded up to 6 weeks postpartum 
4 – Adverse events requiring medical intervention will be followed until resolution or up 
to 90 days in which the AE will be considered chronic (at the discretion of the 
investigator). 
* – Labour and delivery data will be gathered retrospectively by medical chart review. 
Any additional information and details required will be gathered by patient recall at the 
postpartum follow-up visit. 
** – As applicable. 
 


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ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
Adverse Event 
ASA 
Aspirin 
APS 
Antiphospholipid syndrome 
AT 
Antithrombin  
bid 
Twice Daily 
BP 
Blood Pressure 
CBC 
Complete Blood Count 
DBP 
Diastolic Blood Pressure 
DVT 
Deep Vein Thrombosis 
IUGR 
Intrauterine Growth Restriction 
LMP 
Last menstrual period 
LMWH 
Low Molecular Weight Heparin 
o.d. 
Once Daily 
PE 
Pulmonary Embolism 
PIH 
Pregnancy Induced Hypertension 
RCT 
Randomized Clinical Trial 
RFTs 
Renal function tests 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SLE 
Systemic Lupus Erythematosus 
U/S 
Ultrasound 
ULN 
Upper Limit of Normal 
VTE 
Venous Thromboembolic Event 
Wk 
Weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. BACKGROUND 
 
1.1 Why is a randomized clinical trial (RCT) needed? 
Women with APS are at increased risk of pregnancy loss compared to the general 
population1-3. The current standard of care, outlined in the CHEST guidelines, is to 
give antepartum prophylactic-dose LMWH and aspirin (ASA) to prevent future 
pregnancy loss4. Specifically, the CHEST guidelines mention “For women who fulfill 
the laboratory criteria for APLA syndrome and meet the clinical APLA criteria based 
on a history of three or more pregnancy losses, we recommend antepartum 
administration of prophylactic- or intermediate-dose UFH or prophylactic LMWH 
combined with low-dose aspirin, 75 to 100 mg/d, over no treatment”. In contrast, the 
Society of Obstetrics and Gynecology of Canada (SOGC) clinical practice guidelines 
recommend “Low-dose acetylsalicylic acid or low-dose acetylsalicylic acid plus low 
molecular weight heparin is recommended in pregnant women with confirmed 
antiphospholipid syndrome” 
 
These guideline recommendations vary, and are based on trials with significant 
methodological flaws5-9. Three trials showed improved live birth rates with 
unfractionated heparin/ASA versus ASA alone5-7. Kutteh published a single-center 
non-randomized trial of 50 patients with at least 3 pregnancy losses and positive 
anticardiolipin antibodies, alternatively assigned to PTT-adjusted heparin or not5. 
There was a significant difference in live birth rate (80 versus 44%), however, the 
non-randomized study design significantly limits interpretation of these results5. Rai et 
al. completed a randomized trial of 90 patients with a history of 3 consecutive 
pregnancy losses and positive lupus anticoagulant or anticardiolipin antibodies (IgG > 
5 GPL or IgM > 3 MPL) tested over 8 weeks apart, randomizing women to 
antepartum unfractionated heparin 5000 units sc Q12H and ASA versus ASA alone6. 
The live birth rate was improved, from 71 versus 42%6. Lastly, Goel et al. included a 
subset of 72 patients within a larger trial of 450 pregnant women with a history of 2 
pregnancy losses and positive anticardiolipin antibodies7. Patients who received 
unfractionated heparin/ASA during pregnancy had improved live birth rate (84.8%) 
versus ASA alone (61.5%)7. Both trials were limited by small sample sizes and 
varying definitions of positive anticardiolipin antibodies.  
 
In contrast, two subsequent trials evaluated LMWH/ASA versus ASA alone found no 
difference in live birth rates8,9. Farquharson et al. randomized 98 women with at least 
3 consecutive pregnancy losses or 2 pregnancy losses with proven fetal death after 
10 weeks gestation with persistently positive lupus anticoagulant and/or 
anticardiolipin antibodies at least 6 weeks apart8. Women were randomized to 
antepartum LMWH/ASA versus ASA alone until delivery. There was no difference in 
live birth rate between treatment arms (78% versus 72%, p=0.49)8. One limitation to 
this study is a 25% reported crossover rate between study arms, based on physician 
or patient preference. Lastly, Laskin et al. completed a randomized trial of women a 
history of 2 or more pregnancy losses, including patients with one of: ANA positivity, 
lupus anticoagulant or anticardiolipin antibodies, or inherited thrombophilia, 
randomizing participants to LMWH/ASA versus ASA alone during pregnancy9. Of the 
subgroup with lupus anticoagulant or anticardiolipin antibody positivity, there was no 
difference in the live birth rate (77% versus 75%) among 42 patients9. Laskin et al. 
conclude “these findings contribute to the growing body of literature that contests the 
emerging standard of care comprising LMWH/ASA”. Limitations to these negative 
studies include a 25% crossover rate between study arms8, small sample size and 


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varying definitions of APS8,9. Furthermore, no trial has evaluated prophylaxis in 
women with pregnancy loss and persistent anti-β2 glycoprotein antibodies. Given the 
poor quality evidence and mixed results for the use of LMWH/ASA prophylaxis in this 
setting, a large randomized trial is still needed.  
 
When uncertainty exists in pregnancy, health care providers and patients often err on 
the side of treatment in hopes of preventing complications. Our goal is to minimize 
uncertainty, to provide clear recommendation to women with APS and pregnancy loss 
based on high-quality evidence. The full APPLE trial will compare the live birth rates 
in women assigned to the standard of care arm, prophylactic LMWH and ASA, 
compared to the experimental arm, ASA alone. 
 
1.2 Why is a clinical trial needed now? 
Data from the TIPPS trial and two meta-analyses have recently shown that LMWH 
likely does not prevent pregnancy loss or complications in women with or without 
inherited thrombophilia10-12. Given the poor-quality of existing evidence, evaluation of 
LMWH/ASA prophylaxis is still needed in APS patients4-9. We conducted an online 
survey of 109 CanVECTOR Network and Thrombosis Canada physician members, 
22 (20%) responded, and 91% would hypothetically approach a patient for enrollment 
in our trial, in either all (68%) or a subset (23%) of APS patients.  
 
1.3 What are the risks with the standard of care regime of prophylactic 
LMWH/ASA? 
Downsides of LMWH include burden of injections (up to 400 injections/pregnancy), 
cost ($4,000/pregnancy) and side effects of LMWH. In a systematic review of LMWH 
use in pregnancy, the most common side effects were bleeding (1.98%) which 
included significant antepartum bleeding, postpartum hemorrhage, and abdominal 
hematomas13. Allergic skin reactions (1.8%) were also reported, some of which may 
be associated with HIT antibodies13. Being on heparin lowers the likelihood that a 
woman receives epidural analgesia at the time of delivery, given the documented risk 
of epidural hematoma and associated hemiplegia when LMWH is not held prior to 
epidural analgesia14-16. Serious and life-threatening complications of LMWH are rare, 
but possible. HIT has rarely been reported in pregnancy with the use of LMWH17,18. 
The risk of osteoporosis and symptomatic fracture is rare, and significantly lower 
compared to unfractionated heparin19,20. 
 
1.4 What are the risks with the experimental arm (ASA alone)?  
As outlined in Section 1.0, given the poor quality of evidence in the LMWH/ASA arm, 
further evaluation of LMWH/ASA versus ASA is still needed. Based on data from 
meta-analyses and large randomized controlled trials, aspirin has no excess bleeding 
risk or neonatal complications in other populations of pregnant women, such as those 
with pre-eclampsia and women with prior pregnancy loss with or without inherited 
thrombophilia. There may be a possible small increased risk of gastroschisis with 
early exposure to aspirin21-23.  
 
A small randomized double-blind placebo controlled trial of 50 women with a history 
of recurrent pregnancy loss and positive antiphospholipid antibodies showed no 
difference in live birth rate or neonatal complications when treated with aspirin alone 
versus placebo during pregnancy24. While a ‘no treatment’ arm could be considered 
for the experimental arm, there was a low proportion (23%) of physician acceptability 
of a no ASA arm in a national survey of CanVECTOR and Thrombosis Canada 


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members. Given the established safety profile of ASA in pregnancy and physician 
acceptability, ASA alone was chosen as the experimental arm. 
 
1.5 Why is a pilot RCT needed before a full RCT can be completed? 
Because the use of antepartum prophylactic-dose LMWH and aspirin have become 
the standard of care in women with APS and past pregnancy loss, and is 
recommended in clinical practice guidelines4, the recruitment of subjects into a 
randomized clinical trial may be challenging. Therefore, a pilot trial to 
assess feasibility is first needed.  
 
1.6 Need for an open-label trial 
Because of initial poor recruitment in the TIPPS trial that evaluated LMWH in a 
double-blinded fashion (24 women enrolled after 3 years), the design of that trial was 
changed to open-label use of LMWH, which subsequently led to improved recruitment 
rates11. Similarly, the pilot trial APPLE will use an open-label trial design to increase 
eligible women’s acceptance of the trial and eliminate the burden of placebo 
injections. The primary endpoint in the larger multi-center trial is the live birth rate, 
which is objective and, therefore, not expected to change with the open-label use of 
LMWH. 
 
1.7 Need for ‘pragmatic’ use of LMWH 
The use of prophylactic-dose LMWH and ASA has become the standard of care to 
prevent future pregnancy loss in women with APS, despite limited evidence for their 
use. Our pilot trial is looking at the feasibility of removing LMWH use in the 
antepartum setting, by comparing LMWH/ASA versus ASA alone. We recommend a 
“standard of care” regime of tinzaparin 4,500 IU sc daily until 20 weeks gestation, 
then tinzaparin 4,500 IU sc twice daily until 37 weeks gestation and aspirin 81 mg po 
daily until delivery. Treating physicians do have access to other LMWHs (dalteparin, 
enoxaparin) as standard of care, but this suggested regime with tinzaparin is 
recommended for consistency.  
 
There is pharmacokinetic data in pregnant patients to suggest an increased dose 
after 20 weeks gestation is needed to maintain anti-Xa levels in the reference range, 
based on increased renal clearance later in pregnancy26. While the recommended 
LMWH regime includes tinzaparin27, pharmacokinetic data exists for all available 
LMWHs (dalteparin25, enoxaparin28). 
 
1.8 Why are women with 2 losses included? 
The Sapporo Criteria definition of APS is based on a pregnancy loss definition of 1 
late loss at ≥10 weeks gestation, or 3 recurrent early losses <10 weeks gestation29. 
However, women are often referred for a question of thromboprophylaxis after 2 early 
pregnancy losses and with little evidence to guide therapy, it is not uncommon for 
physicians to offer antepartum LMWH/ASA prophylaxis after 2 losses. Knowing if 
ASA is as good as ASA/LMWH in women with 2 losses would be an important finding. 
The APPLE pilot trial will include women with 2 or more early pregnancy losses, in 
order to provide data for this important subgroup of women.  
 
 
 
 
 


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2. TRIAL OBJECTIVES 
 
2.1 Trial Purpose 
The purpose of this pilot trial is to determine the feasibility of conducting a multicenter 
randomized trial evaluating antepartum prophylaxis with ASA versus LMWH/ASA in 
women with confirmed APS and a history of late or recurrent early pregnancy loss. 
Given the large sample size needed to adequately power a large multicenter trial that 
assesses the efficacy of ASA alone versus LMWH/ASA (section 8.2), we first need to 
determine if we can meet minimum recruitment rates needed for a full multicenter trial 
to be possible. To test this, we will open the trial at 2 centers with the goal of 
recruiting one patient every two months. The randomization design for 
the pilot feasibility trial is the same as the full trial, to best represent what actual 
recruitment rates and trial conditions would be like in the full trial. If the pilot feasibility 
trial is successful, then the secondary outcomes collected will be used in the analysis 
of the larger full multicenter trial.  
The purpose of the full trial will be to determine the efficacy and safety of antepartum 
prophylaxis with aspirin alone to improve the live birth rate in women with confirmed 
APS and a history of late or recurrent early pregnancy loss, compared to the standard 
of care regime of LMWH/ASA prophylaxis. 
 
2.2 Pilot Trial Objectives 
The primary objective of the pilot trial is the mean recruitment rate per center per 
month, calculated over 24 months.  
 
Secondary objectives of the pilot trial will include evaluating: 
• 
The feasibility of obtaining all required approvals/contracts in a timely fashion 
• 
The number of patients who are ineligible based on the exclusion criteria 
• 
The consent rate for eligible women who are approached 
• 
The crossover rate between study arms 
• 
The compliance rate of antepartum LMWH use 
• 
Explore the reasons for non-consent among physician and patients 
 
2.3 Pilot Trial Endpoints 
The primary feasibility outcome of the pilot trial is a mean recruitment rate of 0.5 
subjects per center per month. The secondary feasibility outcomes of the pilot trial 
and associated a priori feasibility targets are as follows: 
1. Proportion of sites requiring >18 months to obtain all required 
approvals/contracts from time of delivery of all study documents: <50%. 
2. Proportion of screened patients who meet eligibility criteria (i.e. patients who 
meet inclusion criteria and are also eligible based on exclusion criteria): >30% 
of subjects 
3. Proportion of eligible subjects who provide consent: >30% of subjects 
4. Proportion of withdrawals/loss to follow-up among randomized patients: <10% 
of subjects 
5. Crossover rate between standard of care and experimental study arms: <20% 
6. Level of compliance with study drug: >80% compliance rate of total 
antepartum LMWH use 
7. Reasons for physician and patient non-consent  
 


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2.4 Full Trial Objectives 
The primary objective of the full trial will be to determine the efficacy of ASA in 
improving live birth rate among women with APS and past pregnancy loss, compared 
to the standard of care arm of LMWH/ASA.  
 
Secondary objectives of the full trial will include assessing the efficacy of ASA to 
prevent other pregnancy complications (pre-eclampsia, SGA, placental abruption, 
pre-term labor) and thrombotic complications (VTE, death from VTE, ATE) in women 
with APS and past pregnancy loss, versus LMWH/ASA. Safety data will also be 
reported, including bleeding and other adverse events. 
 
2.5 Full Trial Endpoints 
The full trial endpoints will also be collected in the Pilot APPLE Trial. The primary full 
trial outcome is the livebirth rate. The secondary full trial outcomes are:  
1. Livebirth rate according to central laboratory test results 
2. Pregnancy loss by gestational age (<10 weeks, 10-19 weeks, ≥20 weeks)  
3. Pre-eclampsia 
4. Early onset pre-eclampsia  
5. Severe pre-eclampsia 
6. Small-for-gestational age (SGA) <10th percentile 
7. SGA <5th percentile 
8. SGA <3rd percentile 
9. Placental abruption requiring delivery 
10. Pre-term delivery <37 weeks gestation 
11. Symptomatic venous thromboembolism (VTE) 
12. Symptomatic arterial thromboembolism (ATE) 
13. Major bleeding 
14. Clinically relevant non-major bleeding 
15. Peripartum major bleeding 
16. Peripartum minor bleeding 
17. Non-major non-CRNM bleeding  
18. Heparin induced thrombocytopenia (HIT) 
19. Symptomatic fracture 
20. Allergic reaction 
21. All-cause mortality 
 
2.6 Endpoint Definitions 
Livebirth 
A birth in which a baby is born alive. If there are multiple births (i.e. twins) then it is 
counted as one live birth if at least one is born alive.  
 
Pregnancy loss by gestational age 
Will record the pregnancy loss based on the gestational age in weeks. Will use the 
best information available to determine the gestational age at the time of the 
pregnancy loss. First, pathological examination of products of conception then 
ultrasound dating assessment at the time of pregnancy loss then medical 
documentation of timing of pregnancy loss then patient recall of timing of pregnancy 
loss. A pregnancy loss of one or more multiple births (i.e. twins) will be recorded. 
 
 


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Pre-eclampsia 
Systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg and 
proteinuria >0.3 g/ 24 hours or ≥ 30 mg/mmol urinary creatinine in a spot (random) 
urine sample.  
a. Early onset pre-eclampsia: Pre-eclampsia < 34 weeks gestation 
b. Severe pre-eclampsia: At least one criterion: systolic blood pressure ≥ 160 
mm Hg or diastolic blood pressure ≥ 110 mm Hg, proteinuria > 5 g/24 hours, 
AST, ALT, or bilirubin greater than 2xULN, platelets < 100 x 109 /L, pulmonary 
edema, seizures (eclampsia), headache or other neurological manifestations 
(stroke, intracranial hemorrhage, cerebral edema, hyperreflexia and visual 
impairment), coagulopathy (elevated INR/PT or PTT greater than 1.5xULN or 
fibrinogen <2 g/L), oliguria (< 30 mL/hour for 3 hours), or HELLP syndrome. 
HELLP syndrome requires 3 criteria: hemolysis [lactate dehydrogenase (LDH) 
> 600 IU/L or serum bilirubin >1.2 mg/dl] an abnormal elevation of liver 
enzymes (AST or ALT greater than 2xULN) and platelets <100 x109 /L. 
 
Small-for-gestational age (SGA)  
Percentile of birth weight determined using local gender and gestational age specific 
birth weight charts. 
a. SGA: <10th birth weight determined using local gender and gestational age 
specific birth weight charts. 
b. Severe SGA: < 5th percentile of birth weight determined using local gender 
and gestational age specific birth weight charts. 
c. Very Severe SGA: <3rd percentile of birth weight determined using local 
gender and gestational age specific birth weight charts. 
 
Placental abruption  
Clinical diagnosis of placental abruption leading to delivery. 
 
Pre-term delivery 
Delivery at <37 weeks gestation.  
 
Symptomatic VTE 
VTE is defined as symptomatic deep vein thrombosis (DVT) or pulmonary embolism 
(PE). DVT is defined as a non-compressible segment or filling defect proximal to the 
calf trifurcation based on ultrasonography, venography or magnetic resonance 
imaging. PE is diagnosed by a new intraluminal filling defect on CT pulmonary 
angiogram (segmental artery or more proximal), a high probability perfusion defect on 
a ventilation-perfusion study based on PIOPED criteria with planar images, or PE as 
a definite or probably cause of death.  
 
Symptomatic ATE 
Symptomatic arterial events include ischemic stroke, transient ischemic attack, 
myocardial infarction, peripheral embolism, or death due to a vascular cause based 
on autopsy findings (excluding PE or intracranial hemorrhage).  
 
Major bleeding 
Clinical or radiographical evidence of bleeding associated with one of: with a fall in 
hemoglobin of 20 g/L (2 g/dL) or more; or a requirement for transfusion of two or more 
units of red blood cells or whole blood; or symptomatic bleeding occurring in a critical 
site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with 


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compartment syndrome, or retroperitoneal, or was considered to have contributed to 
maternal death. 
 
Clinically relevant non-major bleeding (CRNMB) 
Any sign or symptom of hemorrhage that does not fit into the definition of major 
bleeding, peri-partum major bleeding, postpartum major bleeding, or peri-partum 
minor bleeding, and meets at least one of the following criteria: requiring medical 
intervention by a health care professional, leading to hospitalization or increased level 
of care, prompting a face to face (not just telephone or electronic communication) 
evaluation. CRNMB will be sub-categorized into the antepartum and postpartum (24 
hours-6 weeks postpartum) period.  
 
Non-major non-CRNM bleeding 
All other bleeding that does not fit into major bleeding, CRNMB, or peripartum 
bleeding. 
 
Peripartum major bleeding 
Hemorrhage occurring after the onset of labour or start of surgical delivery and within 
24 hours postpartum that meets at least one of the following: necessitating a surgical 
procedure, or associated with a fall in hemoglobin of 40 g/L (4 g/dL) or more, or a 
requirement for transfusion of two or more units of red blood cells or whole blood, or 
estimated peripartum blood loss >1000 ml, or considered to have contributed to 
maternal death.  
 
Peripartum minor bleeding 
Hemorrhage occurring after the onset of labour or start of surgical delivery and within 
24 hours postpartum that does not meet any criterion above and with estimated 
peripartum blood loss between 500 and 1000 ml.  
 
HIT 
Heparin-induced thrombocytopenia (HIT) is defined as a clinical diagnosis of HIT 
(based on a 4T score that is intermediate or high probability) and a minimum of a 
positive PF4 HIT ELISA assay. 
 
Symptomatic Fracture 
A symptomatic fracture confirmed by radiography. 
 
Allergic reaction 
A reaction following the administration of LMWH that results in anaphylaxis or a rash 
requiring discontinuation of the allocated LMWH. 
 
All-cause mortality 
The cause of death will be based on all available information, including clinical 
documents, autopsy if available, and official death certificate.  
 
 
3. TRIAL DESIGN 
 
3.1 Trial Design 
APPLE is a feasibility pilot, open-label, randomized controlled clinical trial in 2 
centers, Ottawa and Hamilton, Ontario. Pregnant women with antiphospholipid 


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syndrome and past late (≥10 weeks gestation) or recurrent early (2 <10 weeks) 
pregnancy loss will be randomized to low-dose ASA daily (experimental arm) or 
prophylactic-dose LMWH/ASA (standard of care arm). Other than LMWH use, the two 
arms will have identical follow-up care.  
 
The study consists of four periods: screening and randomization, antenatal follow-up, 
labour and delivery, and post-partum follow-up. Maximum time on study will vary 
between 34 and 52 weeks. 
 
3.2 Screening, Baseline and Randomization 
Feasibility outcomes will be collected using detailed screening and enrollment logs. 
Screening logs will document reasons for ineligibility. We will also explore and 
document reasons for non-consent from patients and local investigators in order to 
refine the larger multicenter study. 
 
Randomization is done within 7 days of completing the baseline assessment.  
Subjects who meet the inclusion/exclusion criteria and have signed informed consent 
will be assigned to one of the two treatment groups (ASA vs LMWH/ASA), stratified 
by pregnancy loss history and laboratory testing. Details on how a subject is 
randomized are provided in section 5.3. 
 
Prior to randomization and study entry, a BHCG is needed to confirm the current 
pregnancy, if not already available. CBC and creatinine blood work will be drawn at 
baseline, if not previously available within the past 3 months. Past obstetrical history 
will be recorded.  
 
Subjects can still be enrolled and randomized in the study if they only have one 
positive antiphospholipid antibody result. A second set of labs would then be drawn 
12 weeks apart from the first set, and if the second set is positive they will continue in 
the study. If the second set is negative, the subject will be withdrawn from the study. 
 
Within 7 days of enrollment, a baseline obstetrical ultrasound is recommended. If the 
subject is enrolled in early first trimester (<6 weeks gestation) then the ultrasound will 
be completed at 6-7 weeks gestation. Blood work will also be drawn on enrollment 
and stored to be tested in a central laboratory (lupus anticoagulant, anticardiolipin 
antibody, beta-2 glycoprotein antibody).  
 
Each subject will receive education regarding LMWH administration, potential 
adverse effects and symptoms of VTE by clinic personnel (not research personnel), 
based on standard of care.  
 
3.3 Antenatal Follow-Up 
The antenatal follow-up visit will take place at 20 ± 4 weeks gestation. Study 
outcomes and/or adverse events will be assessed and documented. If available, 
obstetrical ultrasound results will be recorded. 
 
The subject will be asked to bring the Patient Medication Diary to the follow-up visit. 
Using subject recall and the Medication Diary, treatment compliance will be 
documented. 
 


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For subjects randomized to LMWH/ASA, the suggested protocol is tinzaparin 4,500 
IU sc daily until 20 weeks gestation, then tinzaparin 4,500 IU sc twice daily until 37 
weeks gestation and ASA 81 mg po daily until delivery. 
 
Use of trial medication beyond 37 weeks gestation is left up to the discretion of the 
treating physician. Discontinuing the study medication at 37 weeks will minimize the 
possibility of being anticoagulated at the time of delivery or epidural analgesia.  
 
3.4 Labour and Delivery 
Subjects randomized to receive LMWH/ASA will be instructed to discontinue LMWH 
at 37 weeks, or at the onset of labour if they have not already done so.  
For all subjects, information regarding labour, anaesthesia, delivery, complications, 
fetal weight and health at birth will be recorded. Outcomes of interest and adverse 
events will be recorded based on available hospital records.  
Subjects who prefer to deliver at another hospital or at home, may participate in the 
study, so long as arrangements are made to collect the labour and delivery data 
retrospectively.  
 
3.5 Postpartum Follow-up 
The use of postpartum LMWH and ASA prophylaxis will be left up to the treating 
physician, and will be documented. At the postpartum visit at 6-12 weeks postpartum, 
outcome events will be recorded up until 6 weeks postpartum. Adverse events 
requiring medical intervention will be followed until resolution or will be classified as 
chronic/ongoing after 90 days at the discretion of the investigator. 
 
3.6 End of Study 
Study crossover, compliance, and early termination will be documented. Reasons for 
study crossover (patient or physician preference) will be documented. If a subject 
terminates the study early, ASA and/or LMWH will be left to the treating physician, 
and documented.  Primary and secondary outcomes will be captured. 
 
 
4. SELECTION AND WITHDRAWAL OF SUBJECTS 
 
4.1 Inclusion Criteria 
All of the following inclusion criteria must be met to be eligible: 1) confirmed 
pregnancy, 2) 18 years or older, 3) one or more clinical criteria as outlined below, 3) 
one or more laboratory criteria as outlined below, and 4) written informed consent. 
 
Clinical criteria: Past history of pregnancy loss defined as either: 
A. Two or more unexplained* pregnancy loss before the 10th week of gestation**  
B. One or more unexplained* pregnancy loss at or beyond the 10th week of 
gestation** 
AND 
Laboratory Criteria: At least one positive laboratory test listed below that is positive 
on two or more occasions at least 12 weeks apart***: 
A. Presence of lupus anticoagulant (LAC)  


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B. Anticardiolipin antibody (aCL) of IgG or IgM with a titre > 99th percentile or > 
40 GPL or MPL  
C. Anti-β2 glycoprotein antibody of IgG and/or IgM with a titre > 99th percentile 
 
Subjects can initially be eligible for enrollment and randomization if they only have 
one positive lab result. A second set of labs would be drawn 12 weeks apart from the 
first lab result, and if the second set is positive they will continue in the study. If the 
second set is negative, the subject will be withdrawn from the study. 
 
*Examples of explained miscarriage or fetal loss include: loss associated with severe 
congenital malformations, chromosomal abnormalities, neonatal alloimmune 
haemolytic anaemia, recent CMV infection, positive fetal or placental Listeria cultures, 
and women with known abnormal uterine anatomy.   
 
**Determining timing of pregnancy loss: in reviewing the past obstetrical history the 
investigator will use the best available information (First, pathological examination of 
products of conception then ultrasound dating assessment at the time of pregnancy 
loss then medical documentation of timing of pregnancy loss then patient recall of 
timing of pregnancy loss) to determine the gestational age at the time of pregnancy 
loss.   
 
***According to the diagnostic criteria of APS, diagnosis should be avoided if more 
than 5 years is separated between positive antibody testing and a clinical 
manifestation, such as pregnancy loss 
 
4.2. Exclusion Criteria 
1. Greater than 11 weeks +6 days gestational age at time of randomization 
2. Indication(s) for prophylactic or therapeutic-dose anticoagulation  
a. Venous thromboembolism (VTE) 
b. Arterial thromboembolism (ATE) 
c. Small-vessel thrombosis 
d. Mechanical heart valve 
e. Other indication for prophylactic or therapeutic-dose anticoagulation, at 
the discretion of the treating physician 
3. Contraindication to heparin or aspirin including: 
a. History of known heparin or LMWH allergy 
b. History of known aspirin allergy 
c. History of HIT 
d. History of osteoporosis 
e. Major bleeding within 7 days*.  
f. Known thrombocytopenia, based on platelet count < 50 x 109/L in the 
previous 3 months 
g. Known hepatic disease, based on a medical history of elevated liver 
enzymes (3x ULN) and/or bilirubin (2xULN) documented within the last 3 
months 
h. Known renal failure, based on Creatinine Clearance < 30 mL/min 
(Cockcroft Gault) in the previous 3 months  
i. 
Known severe hypertension, based on SBP > 200 mmHg and/or DBP > 
120 mmHg in the previous 3 months 
4. Received 7 or more doses of LMWH 
5. Previous participation in the trial 


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6. Geographic inaccessibility** 
7. Refused consent 
 
*All other active or recent bleeding is at the discretion of the treating physician. 
**At the discretion of the patient or the treating physician 
 
Note: Subjects currently receiving aspirin are eligible for the study. 
 
Please note: Investigators should use caution when prescribing LMWH to patients 
with a history of gastric ulceration or whom weight >120kg or <45kg. 
 
 
4.3 Withdrawal of Subjects 
A subject has completed the study once all follow-up procedures have been 
completed.   
Study drug is discontinued and appropriate clinical management is initiated in the 
case of the following outcome events (as defined in section 2.6). For the subjects who 
reach a study endpoint, LMWH and aspirin prophylaxis will be left up to the discretion 
of the treating physician, and documented.  
1. Pregnancy loss  
2. Pre-eclampsia  
3. Placental abruption  
4. Preterm delivery (<37 weeks) 
5. VTE (objectively documented DVT, PE or sudden death)  
6. Major bleeding 
7. Thrombocytopenia (Platelet count <50 x 109/L) 
8. Symptomatic fracture 
 
In the event that the outcome does not result in infant delivery (ie. diagnosis of a VTE, 
fracture, thrombocytopenia, major bleed), antenatal follow-up will continue as 
scheduled in the protocol and data will be collected until 6 weeks post-partum or 
pregnancy related outcome. 
 
A subject can be withdrawn from the trial treatment if, in the opinion of the 
investigator, it is medically necessary. This does not always correspond to study 
withdrawal – in which case antenatal follow-up will continue as scheduled in the 
protocol and data will be collected until the 6-12 weeks post-partum clinic visit, up 
until 6 weeks postpartum. 
 
If the subject is prematurely discontinued from participation in the study, the study 
personnel will make every effort to obtain, and record, information about the reasons 
for discontinuation and any adverse events and if possible perform all safety 
assessments.  
 
A subject may voluntarily withdraw participation in this study at any time, including for 
future data collection.  If the subject does not return for a scheduled visit, every effort 
will be made to contact the subject.  In any circumstance, every effort will be made to 
document the reason for withdrawal and when possible all safety assessments will be 
done. 
 


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All data will be reported for any subject randomized and not completing the study.  
Subjects withdrawn as a result of an adverse event thought to be related to the study 
drug will not be replaced.  All safety data collected from all subjects during the study 
will be analyzed. 
 
 
5. RECRUITMENT 
 
5.1 Treatment Schedule 
Upon enrolment into the study, subjects will be randomized to receive low dose 
aspirin alone until delivery, or low-dose ASA (until delivery) and prophylactic-dose 
LMWH until 37 weeks gestation or the onset of labour.  The LMWH regime will be at 
the discretion of the treating physician, with a suggested regime as follows: tinzaparin 
4,500 IU sc daily until 20 weeks gestation, and then 4,500 IU sc twice daily until 37 
weeks gestation. Treating physicians will have access to other LMWHs as alternative 
‘standard of care’ options, however, one regime is recommended for consistency 
(Figure 1). Dosing frequency after 20 weeks gestation is at the discretion of the 
treating physician based on practice-pattern differences, however, a twice daily 
dosing is recommended. The use of daily tinzaparin in the 6 week postpartum period 
is left to the discretion of the treating physician. Concomitant NSAID use is not 
recommended. 
 
Figure 1. Recommended LMWH protocol 
*Alternatives include dalteparin 5,000 IU or enoxaparin 40 mg, however, tinzaparin 
4,500 IU is preferred when possible. 
 
Each subject will receive education regarding LMWH administration, potential 
adverse effects and symptoms of VTE by clinic personnel (not research personnel), 
based on standard of care.  
 
5.2 Randomization 
Consenting subjects will be randomized up to 7 days after baseline visit.  
Treatment allocation is determined by central web-randomization. A randomization list 
has been generated by the trial statistician prior to embarking on the trial. 
Randomization is in permuted blocks of 10, prepared using random number tables, 
and is stratified according to laboratory criteria (‘High-risk’ versus ‘Non-high risk’ 
laboratory groups, defined below) and the timing of pregnancy loss (late loss versus 
no late loss) Any past history of loss ≥ 10 weeks gestation will be included in the late 
loss group.  
 
Aspirin 81 mg daily (Experimental arm) 
Up to 11 weeks + 6 days 
Postpartum prophylaxis left up 
to the discretion of the treating 
physician 
Once daily dosing 
Up to week 20 
BID dosing from wk 
20 to 37 wks or L&D 
RANDOMIZATION 
Aspirin 81 mg daily AND tinzaparin 4,500 IU 
prophylaxis* (Standard of care arm) 
All subjects 
LABOUR & DELIVERY 


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Definitions of groups: 
 
No Late Loss: Defined as only unexplained pregnancy loss(es) less than 10 weeks 
gestation 
 
Late loss: Defined as one or more unexplained pregnancy loss(es) at or beyond the 
10th week of gestation 
 
‘Non-high risk’ laboratory results are defined by both of: 
1) aCL of IgG and/or IgM positivity (>99th percentile) < 40 GPL or MPL 
2) No ‘High risk’ laboratory results present 
  
‘High risk’ laboratory results are defined by the presence of at least ONE of:  
1) Lupus anticoagulant present 
2) aCL of IgG and/or IgM with a titre > 40 GPL or MPL 
3) Anti-β2 glycoprotein antibody of IgG and/or IgM with a titre > 99th percentile 
 
Randomization groups: 
Non-high risk and no late loss: Group A 
Non-high risk and late loss: Group B 
High risk and no late loss: Group C 
High risk and late loss: Group D 
 
5.3 Web Base Randomization 
The randomization process is started by the local study personnel (investigator or 
study coordinator) who initiates a randomization request by accessing the APPLE 
webpage and randomization request form. This portion of the webpage requires 
authorised users to enter a username and password. To randomize a subject the 
following information is required: category of ‘high’ versus ‘non-high’ risk laboratory 
criteria, and category of early versus late pregnancy loss. The program will request 
that the information entered be verified for accuracy and will prompt any errors or 
missing fields to be completed.  When the information is accepted, the program will 
provide the delegated study coordinators, Qualified Investigator, and pharmacy team  
the treatment allocation by using the next allocation from that block.   
 
5.4 Study drug management 
The study drug (ASA and LMWH) will be dispensed by the local site hospital 
Pharmacy Department for all participants in both treatment arms. The local site 
hospital Pharmacy Department will be responsible for labeling, handling, and 
dispensing of the study drug. 
 
 
6. MEASURMENTS AND EVALUATIONS 
 
6.1 Demographic and Baseline Characteristics (Baseline Period) 
Subjects will be required to sign a consent form prior to any study procedures being 
undertaken. During the baseline period, before randomization (up to 11 weeks + 6 
days gestation), the following information will be measured and/or recorded: 
• 
Demographic data: 
o Age and birth month 
o Race/Ethnicity 


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o Height and weight prior to pregnancy 
• 
Current pregnancy data: 
o Gestational age/estimated date of delivery 
o Type of test used to confirm pregnancy and date performed 
o Method of conception 
o Number of fetuses 
• 
Medical history: 
o Presence of SLE diagnosed by rheumatologist or internist 
o Presence of livedo reticularis 
o Presence of hypertension 
o Presence of type 1 diabetes 
o Presence of type 2 diabetes 
o Smoking status 
o Known inherited thrombophilia present and details 
• 
Obstetrical History: 
o Age at start of each pregnancy 
o Gravida, term deliveries, premature deliveries, spontaneous abortions, 
therapeutic abortions, living children and multiple pregnancies 
o Number, timing and reason of past pregnancy losses  
 
According to < 10 weeks, ≥ 10 weeks 
o Past pregnancy complications 
 
Pre-eclampsia, SGA, placental abruption, pre-term delivery  
o Treatment of past pregnancies (use of LMWH and/or ASA) 
 
6.2 Laboratory and Imaging Assessments 
A baseline BHCG will be drawn at the screening period, if not already available for the 
current pregnancy. A CBC and creatinine will be drawn at baseline, if not previously 
available within the past 3 months. A second set of antiphospholipid labs can be 
drawn if required to meet the eligibility laboratory criteria, 12 weeks apart from the first 
set. The subject can be enrolled and randomized to a treatment arm prior to receiving 
the second set of lab results. According to the diagnostic criteria of APS, diagnosis 
should be avoided if more than 5 years is separated between positive antibody testing 
and a clinical manifestation, such as pregnancy loss. 
 
Within 7 days of enrollment, a baseline obstetrical ultrasound is recommended. If the 
subject is enrolled in early first trimester (<6 weeks gestation) then the ultrasound will 
be completed at 6-7 weeks gestation. Blood work will also be drawn on enrollment 
and stored and tested in a central laboratory (lupus anticoagulant, anticardiolipin IgG 
and IgM antibodies, beta-2 glycoprotein IgG and IgM antibodies).  
 
Additional blood work or imaging assessments will be ordered if an outcome is 
clinically suspected, and will be left up to the discretion of the treating physician. 
 
6.3 Prior and Concomitant Therapy 
Concomitant therapy will be at the discretion of the primary physician. Selected 
concomitant medications will be documented on the case report forms. Investigators 
who decide to discontinue antenatal LMWH at 37 weeks gestation and initiate the use 
of unfractionated heparin will be required to document this on the concomitant 
medication record in the case report form. NSAID use is not recommended. 


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6.4 Antenatal Follow-up 
Antenatal follow-up will occur at 20 (±4) weeks gestation and the following information 
will be recorded: 
• 
Gestational age 
• 
Medication regime plan  
• 
Medication compliance 
• 
Possible adverse events and outcomes 
 
6.5 Postpartum Follow-up 
Postpartum follow-up will occur at 6-12 weeks postpartum and the following information 
will be recorded: 
• 
Number of weeks postpartum at time of visit 
• 
Postpartum medication regime plan (if applicable) 
• 
Epidural use during labour 
• 
Medication compliance 
• 
Possible adverse events and outcomes 
 
6.6 Labour and Delivery Record 
Available labor and delivery information will be recorded: 
• 
Date of delivery 
• 
Gestational age at delivery 
• 
Mode of delivery 
o Vaginal delivery versus caesarian section, including reason for C-
section (scheduled versus unscheduled/emergency)  
• 
Estimated blood loss in mL, if available 
• 
Spontaneous versus induction of labor, and reason for induction if available 
• 
Live birth 
• 
Infant data 
o Sex, weight and percentile 
o NICU admission 
o Infant survival (record cause if known) 
 
6.7 Adjudication 
A blinded adjudication committee will be assembled to review the following suspected 
outcomes: pre-eclampsia, placental abruption, symptomatic VTE, symptomatic ATE, 
suspected bleeding, suspected HIT and/or death.  
 
Each suspected event will be reviewed by two committee members to determine if it 
meets the criteria for the full trial outcomes as outlined in the protocol. If the two 
reviewers disagree, a third member will review to act as a tie-breaker.  
 
All relevant medical records, imaging results, etc. will be collected to prepare an 
adjudication report. 
 
6.8 Adverse Events 
AEs will be elicited, monitored and recorded throughout the study.  For each subject, 
AEs will be submitted to the trial office following visits at gestational week 20 ± 4 
weeks, labour and delivery, and 6-12 weeks postpartum.  
 


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7. ADVERSE EVENTS 
 
7.1 Definition 
An adverse event (AE) is any untoward medical occurrence in a subject or trial 
subject administered a drug or biologic (medicinal product) or using a medical device; 
the event does not necessarily have a causal relationship with that treatment or 
usage. 
AEs include the following: 
• 
All suspected adverse medication reactions. 
• 
All reactions from medication abuse, withdrawal, sensitivity, or toxicity.   
• 
Apparently unrelated illnesses, including the worsening of a pre-existing 
illness (definition below). 
• 
Injury or accidents. 
o Note that if a medical condition is known to have caused the injury or 
accident (e.g., a fall secondary to dizziness), the medical condition 
(dizziness) and the accident (fall) will be reported as two separate AEs.   
• 
Abnormalities in physiological testing or physical examination (findings that 
require clinical intervention or further investigation beyond ordering a repeat 
[confirmatory] test). 
• 
Laboratory abnormalities that require clinical intervention or further 
investigation (beyond ordering a repeat [confirmatory] test) unless they are 
associated with an already reported clinical event.  Laboratory abnormalities 
associated with a clinical event (e.g., elevated liver enzymes in a subject with 
jaundice) will be described as a separate AE. 
 
Pre-existing Conditions 
In this trial, a pre-existing condition (i.e., a disorder present before the AE reporting 
period started and noted on the pre-treatment medical history/physical examination 
form, this will include pregnancy) is not to be reported as an AE unless the condition 
worsens or episodes increase in frequency during the AE-reporting period.   
 
Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
are not to be reported as AEs.  However, the medical condition for which the 
procedure is performed is to be reported if it meets the definition of an AE.  For 
example, an acute appendicitis that begins during the AE reporting period is to be 
reported as the AE and the resulting appendectomy noted under Comments. 
 
7.2 Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously 
reported by the trial subject.  In addition, each trial subject will be questioned about 
AEs at each clinic visit following initiation of treatment 
 
7.3 Adverse Event Reporting Period 
The AE reporting period for this trial begins upon randomization, and ends 30 days 
after receiving the last dose of trial medication.  The AE reporting period for neonates 
begins upon randomization and ends 30 days after the subject has received the last 
dose of trial medication. 


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All AEs that occur in trial subjects during the AE reporting period specified in 
the protocol must be recorded in the CRF, WHETHER OR NOT THE EVENT IS 
CONSIDERED MEDICATION/PRODUCT RELATED. 
 
IN ADDITION, any known untoward event that occurs subsequent to the AE reporting 
period that the investigator assesses as possibly related to the investigational 
medication/product is also to be reported as an AE. 
 
Note that in view of this trial: 
• 
Injection-site ecchymosis will not be reported as an AE. 
• 
The following pregnancy-related symptoms will not be reported as an 
AE:  
o Nausea, vomiting 
o Minor vaginal bleeding 
o Gradual onset dyspnea 
o Fatigue 
o Bilateral leg, arm or facial swelling 
o Heart burn, weight gain, abdominal distension  
 
7.4 Recording Instructions 
AEs are to be recorded in the case report forms as specified.  
If required on the AE case report forms, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE. For purposes 
of consistency, these intensity grades are defined as follows:  
 
MILD 
Does not interfere with subject's usual function 
MODERATE 
Interferes to some extent with subject's usual function 
SEVERE 
Interferes significantly with subject's usual function 
 
A distinction is made between the gravity and the intensity of an AE.  Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction.  
For example, a headache may be severe in intensity, but is not to be classified as 
serious unless it meets one of the criteria for serious events listed in section 7.5.  
The investigator will also be asked to assess the possible relationship between the 
AE and the investigational medication as well as any concomitant medications. 
 
7.5 Seriousness (Gravity) – Serious Adverse Events (SAE) 
Each AE is to be classified by the investigator as SERIOUS or NONSERIOUS.  This 
classification of the gravity of the event determines the reporting procedures to be 
followed.  
 
A SERIOUS adverse event (SAE) is an AE that meets one or more of the following 
criteria/outcomes: 
• 
Death 
• 
Life-threatening (i.e., immediate risk of death) 
• 
In-subject hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant disability/incapacity (any sight-threatening event with 
ophthalmic products is a significant incapacity) 


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• 
Permanent impairment of function or permanent damage to a body structure 
or requires intervention to prevent permanent impairment or damage 
• 
Congenital anomaly/birth defect 
• 
Any other AE that the investigator or company judges to be serious or which is 
defined as serious by the regulatory agency in the country in which the AE 
occurred. 
 
Note that in view of this trial: 
• 
Pregnancy losses where the fetus shows no gross visual evidence of 
congenital anomalies (when available), will not be reported as a SAE, 
unless considered to be related to the investigational product.  
• 
Admission to hospital for the purpose of term spontaneous vaginal 
delivery and/or elective caesarean section will not be reported as an 
SAE. 
 
Exposure In Utero 
If the outcome of the pregnancy meets the criteria for immediate classification as a 
SAE (i.e., congenital anomaly [including that in an aborted fetus]), the investigator is 
to follow the procedures for reporting SAEs; i.e., report the event to the APPLE 
Multicentre Trial Office in Ottawa Canada by fax and follow up by submission of 
appropriate case report forms and source documentation. 
Additional information regarding pregnancy outcomes that are classified as SAEs 
follows:  
• 
"Spontaneous abortion" includes miscarriage and missed abortion, if 
considered to be related to the investigational product (i.e. congenital 
anomaly) 
• 
All neonatal deaths that occur within one month of birth are to be reported, 
without regard to causality, as SAEs.  In addition, any infant death after one 
month that the investigator assesses as possibly related to the in utero 
exposure to the investigational medication are also to be reported. 
• 
The "normality" of an aborted foetus can be assessed by gross visual 
inspection unless there are preabortion laboratory findings suggestive of a 
congenital anomaly. 
 
7.6 Reporting of SAEs 
If a SAE occurs, the APPLE Multicentre Trial office, Ottawa Canada is to be 
notified within 24 hours of awareness of the event by the investigator.  The SAE 
report form should be sent to the multicentre coordinator and Principal 
Investigator as outlined in the APPLE Pilot Resource Manual. 
 
In turn, the Principal Investigator will: 
• 
Review all SAEs and comment via email within 24 hours should clarification 
be required, and 
• 
If the SAE is related or probably related, and unexpected, the principal 
investigator will report the SAE to Health Canada using the CIOMS form and 
notify the REB board of record, Ottawa Health Science Network REB (OHSN-
REB) through Clinical Trials Ontario (CTO), as appropriate. Participating sites 
are responsible for informing their institutions of the event according to their 
local standard operating procedures. 


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The initial report is to be followed by submission of more detailed SAE information on 
the SAE form within 15 working days of the event.  
 
 
Table 1  REPORTING REQUIREMENTS FOR ADVERSE EVENTS 
Gravity 
Reporting Time 
Type of Report 
SERIOUS 
(life-
threatening 
or death) 
Within 24 hours 
Initial report on SAE 
Within 7 days 
Final report on SAE 
SERIOUS  
Within 24 hours 
Initial report on SAE 
Within 15 days 
Final report on SAE 
NON-
SERIOUS 
Following each of these subject visits:  
- 20 ± 4 weeks gestational age 
- Labour & delivery  
- 6-12 weeks postpartum 
Adverse Event CRFs 
NOTE:   In the rare event that the investigator does not become aware of the 
occurrence of a SAE immediately (e.g., if a trial subject initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it 
and document his/her first awareness of the SAE. 
All SAEs are to be reported to and reviewed by the Data Safety Monitoring Board 
(DSMB) according to the DSMB Terms of Reference.   
 
7.7 Follow-Up of Adverse Event 
All AEs are to be followed until they are resolved or the subject's participation in the 
trial ends (i.e., until a final report is completed for that subject).  
In addition, all SAEs and those non serious events assessed by the investigator as 
possibly related to the investigational medication/product are to continue to be 
followed even after the subject's participation in the trial is over.  Such events are to 
be followed until they resolve or until the investigator assesses them as "chronic" or 
"stable."  Resolution of such events is to be documented on the appropriate CRF. 
 
 
8. STATISTICS 
 
8.1 Statistical and Analytical Plans 
8.1.1 Analysis of Baseline Characteristics 
Descriptive statistics will be used to examine the baseline characteristics of excluded 
subjects and those in the experimental and standard of care arm. Standard deviations 
will be reported for all characteristics expressed as continuous variables. Medians 
and ranges will be presented for discrete data. 
 
 
 


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8.1.2. Pilot Trial Primary Analysis 
The primary analysis will involve a simple estimate of the mean monthly recruitment 
rate per site along with the 95% confidence interval of the mean. 
 
8.1.3. Pilot Trial Secondary Analyses 
Proportions with 95% confidence intervals will be calculated using Wilson’s score 
method for the following secondary analyses: 1) proportion of screened subjects who 
meet eligibility criteria, 2) proportion of eligible subjects who provide consent, 3) 
proportion of withdrawals/losses to follow-up among randomized subjects, 4) 
proportion of sites requiring >18 months to obtain all required approvals/contracts 
from time of delivery of all study documents, and 5) proportion of crossover between 
study arms. Reasons for non-consent will be collected and analyzed using qualitative 
thematic analysis. 
 
8.1.4. Full Trial Analyses 
Several secondary outcomes will be collected in the pilot trial, which will be included 
in the analysis of the full trial if there are no significant changes to the trial design. 
 
Primary analysis: Analysis will be performed by intention to treat. Intention to treat 
analysis will be supplemented by a sensitivity analysis that excludes subjects who did 
not complete the allocated treatment plan. The live birth rate will be compared in the 
experimental and standard of care arm by an unadjusted Fisher’s test of proportions, 
with 95% confidence intervals provided. 
 
Secondary analysis: Analysis will be performed by intention to treat. Intention to 
treat analysis will be supplemented by a sensitivity analysis that excludes subjects 
who did not complete the allocated treatment plan. Proportions will be compared 
between study arms by an unadjusted Fisher’s test, with 95% confidence intervals 
reported. The following outcomes will be analyzed: Pregnancy loss by central 
laboratory testing, pregnancy loss by gestational age (<10 weeks, 10-19 weeks, ≥20 
weeks gestation), pre-eclampsia, early onset pre-eclampsia, severe pre-eclampsia, 
SGA <10th percentile, SGA <5th percentile, SGA <3rd percentile, placental abruption 
requiring delivery, pre-term delivery <37 weeks gestation, symptomatic VTE, 
symptomatic ATE, major bleeding, clinically relevant non-major bleeding, non-major 
non-CRNMB, major peripartum bleeding, minor peripartum bleeding, HIT, 
symptomatic fracture, allergic reaction, and all-cause mortality.  
 
8.2 Determination of Sample Size 
The sample size of the pilot trial is 24 participants, based on a recruitment rate of 1 
participant per 2 months per site. This sample size was derived based on the full trial 
sample size, which factored in that these 2 sites are highly motivated and will have 
higher recruitment rates compared to other potential sites. 
The full trial sample size is 828 participants, which is based on a 60% absolute event 
rate in the ASA arm, minimal clinically important difference (MCID) of 10%, 80% 
power at alpha 0.05, and a drop-out rate of 10%. The MCID was determined based 
on a survey of 22 physicians (20% response rate) among CanVECTOR Network and 
Thrombosis Canada members.  
 
With involvement from 40 centers over 5 years, this sample size calculation of 828 
equates to 4 participants per year per center, however, we acknowledge that the 2 


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pilot sites are highly motivated and will have higher recruitment rates on average, 
therefore we have set a minimum recruitment rate of 1 patient per 2 months per site.  
 
 
9. QUALITY ASSURANCE (QA) 
 
9.1. Quality Assurance 
Quality assurance at trial sites will be supported through training and monitoring.  At 
each site this will consist of an initiation visit or teleconference, ongoing training (as 
needed), central and on-site monitoring, and a close-out visit or teleconference.  
Details about the process and content of the initiation and close-out visits are 
included in the Resource Manual. 
 
9.2 Monitoring 
Study monitoring is a sponsor responsibility that ensures that the rights and well-being 
of human subjects are protected, the reported trial data are accurate, complete, and 
verifiable from source documents, and that the conduct of the trial complies with the 
protocol, GCP, and regulatory requirements.   
Monitoring for the trial will be performed by the sponsor, according to the detailed 
monitoring plan for the trial.   
 
 
10. ETHICS 
 
10.1 Ethical Conduct of the Trial 
The trial will be performed in accordance with the recommendations guiding 
physicians in biomedical research involving human subjects adopted by the 18th 
World Medical Assembly (Helsinki, Finland, 1964 and later revisions), the Tri-Council 
Policy Statement and the ICH GCP Guidelines. 
 
10.2 Research Ethics Board (REB)  
REB approval will be obtained and maintained annually with OHSN-REB, the REB 
board of record, through CTO.  
 
10.3 Subject Information and Consent 
The investigator, or his designee, will inform each subject (or the subject’s acceptable 
representative) prior to inclusion in the trial, full and adequate verbal and written 
information regarding the objective and procedures of the trial and the possible risks 
involved.  The subjects must be informed about their right to withdraw from the trial at 
any time.  Written subject information will be given to each subject before enrolment. 
Furthermore, it is the responsibility of the investigator or his designee to obtain signed 
informed consent from all subjects prior to inclusion in the trial. 
 
 
11. DATA SAFETY MONITORING BOARD 
 
11.1 Data Safety Monitoring Board (DSMB) 
A DSMB will complete a safety analysis after 16 patients are recruited with a pre-defined 
stopping rule. The DSMB Terms of Reference outline the DSMB operating procedures. 
 
 


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11.2. Interim Stopping Rule 
 The pilot study will be halted early if 0 out of 8 subjects in either arm have a live birth. 
The upper bound of the confidence interval is 32.4%, which would be lower than 
expected. If only 1/8 patients had a live birth, while the point estimate is 12.5%, the 
upper bound of the 95th confidence interval is 47.1%, which is still in the realm of 
expected results. 
 
 
12. DATA HANDLING AND RECORD KEEPING 
 
12.1 Personal Health Information 
Medical records will be reviewed in compliance with applicable provincial privacy laws 
as well as local hospital privacy policies.  All personal health information will be 
treated in a confidential manner with respect to its collection, use, and disclosure.    
Participant names or potentially identifying personal health information will not leave 
the institution.  Any source documents provided to the sponsor for monitoring 
purposes must first be de-identified. The consent form will describe to the participant 
who will have access to their information and for what purposes (e.g., Health Canada, 
Research Ethics Board (REB), research sponsors and personnel monitoring/auditing 
the research on their behalf).  A master list that links participant identities to their 
unique participant numbers will be maintained at all study sites and stored separately 
from all other study records.  
 
12.2 Case Report Forms 
A Case Report Form (CRF) is required and will be completed for each randomized 
subject.  The completed original CRFs are the sole property of The Ottawa Hospital 
and are not to be made available in any form to third parties, except for authorized 
representatives of appropriate Regulatory Authorities.  
 
12.3 Record Retention 
To enable evaluations and/or audits, the investigator will keep records according to 
section 8.0 in ICH/GCP, including the identity of all participating subjects (sufficient 
information to link records, e.g., CRFs and hospital records), all original signed 
Informed Consent Forms and source documents, copies of all CRFs and detailed 
records of drug disposition.  To comply with Canadian regulations, the records are to 
be retained for 25 years. 
 
 


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