Low Dose Aspirin for Preventing Intrauterine Growth Restriction and Preeclampsia in Sickle Cell Pregnancy (PIPSICKLE): a Randomized Controlled Trial
Phase: PHASE3
Conditions: Intrauterine Growth Restriction, Preeclampsia, Sickle Cell Disease, Pregnancy Complications
Sponsor: University of Lagos, Nigeria

CONFIDENTIAL 
[Version 4] 
                             [PIPSICKLE] 
[21st MAY 2024] 
 
Page 1 of 121 
 
[TETFund] 
CLINICAL RESEARCH PROTOCOL 
[PIPSICKLE TRIAL] 
 
PROTOCOL NO. 
 
01 
 
VERSION NO. 
04 
DATE 
21/05/2024 
PROTOCOL NAME 
 
PIPSICKLE 
 
 
FUNDING 
ORGANIZATION 
 
Tertiary Education Trust Fund (TETFund) 
PRINCIPAL 
INVESTIGATOR 
name and contact 
information 
 
Professor Bosede Bukola AFOLABI 
College of Medicine, University of Lagos.  
+2348023154064 
bbafolabi@unilag.edu.ng 
 
 
Chairman DSMC/ 
Clinical MONITOR 
name and contact 
information 
Prof Olayemi Oladapo 
Department of Obstetrics and Gynaecology, College of Medicine, University of Ibadan 
+2348023059558, +2348032197300 
oladapo.olayemi@yahoo.com 
COORDINATING 
CENTER 
(if applicable) 
College of Medicine, University of Lagos 
 
 
APPROVED BY: 
 
 
 
Principle Investigator  Signature and Title          
Date 
 
 
SITE  
 
 
 
 

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[Version 4] 
                             [PIPSICKLE] 
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PROTOCOL AGREEMENT 
I have read and understood the protocol below. In my capacity as site coordinator, my duties 
include making sure of the safety of the study participants enrolled by supervising their care 
and providing Prof. Bosede Afolabi with complete and timely information. This information will 
be provided as outlined in this study protocol. All the information relating to this study will be 
held in strict confidence and these confidentiality requirements apply to all staff at this study 
site or involved with this study.  
I agree to maintain the procedures required to perform this study in accordance with Good 
Clinical Practice principles and to abide by the terms of this protocol.  
 
PROTOCOL DATE  21/05/2024 
PROTOCOL 
VERSION NO 
4 
PROTOCOL TITLE 
Low dose aspirin for preventing intrauterine growth restriction and preeclampsia in 
sickle cell pregnancy (PIPSICKLE): a randomised controlled trial. 
 
 
 
 
Site Coordinator Signature          
Date 
 
 
Name and Title (Print) 
 
 
 
 
 
 
 
CONTACT 
INFORMATION 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
[Version 4] 
                             [PIPSICKLE] 
[21st MAY 2024] 
 
Page 3 of 121 
 
TABLE OF CONTENTS 
PROTOCOL AGREEMENT ............................................................................................................................. 2 
PROTOCOL SYNOPSIS ................................................................................................................................... 4 
1. 
LIST OF TABLE ……………………………………………………………………………………..... 6 
2. 
LIST OF FIGURES .................................................................................................................................. 7 
3. 
LIST OF ABBREVIATIONS AND ACRONYMS ……………………………………………………8 
4.    GLOSSARY OF TERMS …………………………………………………………………………….  10 
5. 
INTRODUCTION .................................................................................................................................. 11 
6. 
STUDY OBJECTIVES ………………………………………………………………………………  13 
7. 
STUDY DESIGN..................................................................................................................................... 14 
8. 
SELECTION OF PARTICIPANTS ..................................................................................................... 21 
9. 
VISIT SCHEDULE AND ASSESSMENTS ......................................................................................... 23 
10. PARTICIPANTS WITHDRAWAL & STUDY DISCONTINUATION ........................................... 29 
11. STUDY PRODUCTS AND TREATMENTS ....................................................................................... 30 
12.  ADVERSE EVENTS AND REPORTING REQUIREMENTS .......................................................... 32 
13.  STATISTICAL SUMMARY.................................................................................................................. 36 
14. MONITORING PLAN SUMMARIES ................................................................................................. 38 
15.   PROTOCOL VIOLATIONS & DEVIATIONS .................................................................................. 41 
16.   STUDY DOCUMENTS ......................................................................................................................... 44 
17.    LABORATORY QUALITY ASSURANCE ....................................................................................... 47 
18.    ETHICS AND RESEARCH INTEGRITY ......................................................................................... 48 
19.    DISSEMINATION STRATEGIES ..................................................................................................... 51 
20.    REFERENCES ...................................................................................................................................... 52 
21.    SUPPLEMENTS / APPENDICES ...................................................................................................... 54 
 

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PROTOCOL SYNOPSIS   
Brief summary in each category 
 
STUDY TITLE 
Low dose aspirin for preventing intrauterine growth restriction and preeclampsia in sickle 
cell pregnancy (PIPSICKLE): a randomised controlled trial. 
 
FUNDING 
ORGANIZATION 
Tertiary Education Trust Fund (TETFund) 
NUMBER OF SITES 
15  
RATIONALE 
Pregnancy in sickle cell disease is fraught with many complications including 
preeclampsia (PE), intrauterine growth restriction (IUGR) and several maternal 
complications. Low dose aspirin (LDA) has been shown to reduce the incidence of 
PE and IUGR in high-risk women due to its reduction of vasoconstrictor 
thromboxane whilst sparing prostacyclin. It has been found to be safe for use in 
pregnancy and has been suggested for use in sickle cell pregnant women, but all 
the studies were conducted in non-SCD pregnant women. To the best of our 
knowledge, there are no studies evaluating the role of low dose aspirin in 
prevention of preeclampsia and IUGR in pregnant SCD women in the scientific 
literature. As women with SCD have such a high incidence of morbidity and 
mortality in pregnancy, the results of this study could potentially save their lives 
and that of their babies. 
STUDY DESIGN 
Multicenter, randomized, placebo controlled, double blind, parallel trial designed to 
evaluate the efficacy, safety and tolerability of a daily dose of 100mg aspirin.  
 
PRIMARY OBJECTIVE 
To determine whether daily administration of 100mg LDA from 12-28 weeks of 
gestation till 36 weeks, reduces the risk of IUGR, miscarriages and perinatal deaths.  
SECONDARY 
OBJECTIVE(S) 
To determine the effect of the use of 100mg LDA during pregnancy in HbSS and 
HbSC women on the incidence of other maternal complications such as pre-
eclampsia, preterm delivery, retained placenta, placental abruption, number of vaso-
occlusive crises, blood transfusion needs, incidence of urinary tract infections, 
respiratory tract infections, acute chest syndrome and potential adverse effects such 
as vaginal bleeding, epigastric pain and heartburn.  

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NUMBER OF SUBJECTS 
 
476 eligible pregnant HbSS and HbSC women 
 
SUBJECT SELECTION 
CRITERIA 
Age 18 years and above 
Singleton fetus,  
Hb genotypes are Haemoglobin SS or SC. 
12-28 weeks gestation at recruitment, estimated from the last menstrual period or 
by an early ultrasound scan.  
PRODUCT, DOSE, AND 
ROUTE OF 
ADMINISTRATION 
Daily administration of 100mg Low Dose Aspirin, oral route. 
(CONTROL) PRODUCT, 
DOSE, AND ROUTE OF 
ADMINISTRATION 
Daily administration of Placebo, oral route. 
DURATION OF SUBJECT  
PARTICIPATION  
AND STUDY DURATION 
2 years. 18 months of active patient’s study participation; 21 total months in the 
field including screening, enrollment, follow-up and data analysis.   
FOLLOW-UP 
2 weekly follow up visits from enrollment to 28 weeks gestation followed by 
weekly visits till delivery 
 
 
 

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LIST OF TABLES  
Table 1 STUDY OUTLINE ………………………………………………………. 26 
Table 2 ASSESSMENT SCHEDULE 
………………………………………. 27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF FIGURES 
Figure 1 PIPSICKLE Trial flowchart ……………………………………………..  21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE 
 
Adverse event  
CRF 
 
Case report form  
CRA  
Clinical research associate  
CMUL  
College of Medicine, University of Lagos  
CI 
 
Confidence interval 
GCP  
Good Clinical Practice  
Hb 
 
Haemoglobin  
IUGR  
Intrauterine growth restriction  
LASUTH 
Lagos State University Teaching Hospital  
LBW  
Low birth weight  
LDA  
Low dose aspirin  
LUTH  
Lagos University Teaching Hospital 
ML 
 
Machine learning  
OR 
 
Odds ratio  
PACTR 
Pan Africa Clinical trials Registry  
PE 
 
Preeclampsia   
RCT 
 
Randomised controlled trial. 
SAE 
 
Serious adverse event  
SCD  
Sickle cell disease  
HbSS  
Sickle cell Anaemia  
HbSC  
Sickle Hb C disease  
SDG  
Sustainable Development Goal  
TETFund 
Tertiary Education Trust Fund  
WHO  
 World Health Organization  
AE 
 
Adverse Event 
SAE   
Serious Adverse Event 
SOP   
Standard Operating Procedure 
DSMC  
Data and Safety Monitoring Committee  

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GCP   
Good Clinical Practice 
IRB 
 
Institutional Review Board 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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GLOSSARY OF TERMS 
 
Assessment 
A procedure used to generate data required by the study 
Control (Placebo) drug 
A study drug used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study 
validity, and/or evaluate comparative effects of the 
investigational drug.    
Investigational (Active) drug The study drug whose properties is being tested in the study.  
Study drug 
Any drug (control or investigational) administered to the 
patient as part of the required study procedures; includes 
investigational drug and any control drugs 
Enrollment 
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e. prior to starting any of 
the procedures described in the protocol) 
Medication number 
A unique identifier on the label of each medication package.   
Study ID                                  A number assigned to each patient that is enrolled into the 
study. When combined with the center number, a unique 
identifier for each patient in the study is created. This is done 
automatically during the randomisation process.     
Randomisation code  
A unique identifier assigned to each randomised patient, 
corresponding to a specific treatment arm assignment 
Premature 
patient 
withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
discontinued and no further assessments are planned 
Study drug discontinuation 
Point/time when patient permanently stops taking study drug 
for any reason; may or may not also be the point/time of 
premature patient withdrawal 
Variable 
Information used in the data analysis; derived directly or 
indirectly from data collected using specified assessments at 
specified time points 
 
 
 
 
 

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1.0       INTRODUCTION 
1.1 
Background 
Nigeria has the highest number of people living with sickle cell disease (SCD) in the world, 
amounting to 2-3% of the population (1). Sickle cell disease is a haemoglobinopathy fraught with 
complications as a result of vaso-occlusion, thrombosis and chronic anaemia. The red blood cells 
become abnormal and fragile when deoxygenated, forming polymers and adhering to vascular 
endothelial tissue with resultant obstruction of the vessels and haemolysis (2,3). These lead to the 
various clinical manifestations, which include splenic sequestration, susceptibility to infections, 
stroke, bone pain crises and acute chest syndrome. Vasoconstriction from nitric oxide depletion 
has also been postulated to be a pathophysiological mechanism for some of its adverse effects such 
as pulmonary hypertension and stroke (4). 
 
Over 50% of females with SCD now achieve pregnancy due to increased survival into adulthood 
but they have a high incidence of complications during pregnancy including preeclampsia (PE) 
and intrauterine growth restriction (IUGR), infections, acute chest syndrome and more frequent 
crises (5,6,7). A number of pregnant women with sickle cell disease are thus more likely to die in 
pregnancy especially in low resource settings like ours (8); pregnancy-related studies in them 
should therefore be a priority. 
Previously, we found a reversal in prostacyclin-thromboxane ratio in pregnant haemoglobin (Hb) 
SS women (9), a situation that is also found in non-sickle pregnancies with preeclampsia and 
unexplained IUGR (10). Low dose aspirin (LDA) has been shown to reduce the incidence of PE 
and IUGR in high-risk women due to its reduction of vasoconstrictor thromboxane whilst sparing 
prostacyclin, in effect correcting the ratio (11). It has been found to be safe for use in pregnancy 
(12) and has been suggested for use in sickle cell pregnant women (13), but all the studies were 
conducted in non-SCD pregnant women. To the best of our knowledge, there are no studies 
evaluating the role of low dose aspirin in prevention of preeclampsia and IUGR in pregnant SCD 
women in the scientific literature. As women with SCD have such a high incidence of morbidity 
and mortality in pregnancy, the results of this study could potentially save their lives and that of 
their babies. 
 

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1.2 Study Purpose:  
The study is a multicentre, randomised, placebo controlled, double blind, parallel trial designed to 
evaluate the efficacy, safety and tolerability of a daily dose of 100mg aspirin, from 12-28 weeks 
gestation until 36 weeks. Pregnancy in sickle cell disease is fraught with many complications 
including preeclampsia (PE) and intrauterine growth restriction (IUGR). Low dose aspirin (LDA) 
has been found to reduce the incidence of PE and IUGR in high-risk women and has been found 
to be safe for use in pregnancy and is recommended in obstetric guidelines for this use, but has not 
been tested in sickle cell pregnancy.  
Findings in this study may gain regulatory approval to recommend low dose aspirin for use in 
pregnant) women with SCD where it is expected to reduce the incidence of IUGR and PE.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.0  
STUDY OBJECTIVES 
2.1 
Aims 
To determine whether daily administration of 100mg LDA from 12-28 weeks of gestation till 36 
weeks, reduces the risk of IUGR, preeclampsia, perinatal deaths or miscarriages and other 
complications (sickling and non-sickling related) in pregnant women with SCD compared with the 
use of placebo.  
 
2.2 
Specific Objectives 
1. To determine the effect of the use of LDA during pregnancy in HbSS and HbSC women on 
the risk of intrauterine growth restriction (IUGR), perinatal death or miscarriage. 
2. To determine the effect of the use of LDA during pregnancy in HbSS and HbSC women on 
the incidence of other maternal complications including preeclampsia, preterm delivery, 
number of vaso-occlusive crises, need for blood transfusion, urinary tract infections, 
respiratory tract infections, acute chest syndrome, retained placenta, placental abruption and 
vaginal bleeding. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3.0 
STUDY DESIGN 
3.1 
Sample size calculation 
Assuming an incidence of intrauterine growth restriction (IUGR) of 20% in sickle cell disease (14) 
and expecting a 50% IUGR reduction with the use of LDA as detected by Bujold et al (15), we 
calculated that 198 women per group would be required to have a 90% power of detecting a 
decrease in IUGR at the 5% significance level, with a total of 396, using the formula for 
proportions in superiority parallel trials (16). Allowing for 20% attrition, this would become 476 
in total. 
3.2  
Sample Population  
A total of 476 eligible pregnant HbSS and HbSC women from 12-28 weeks gestation will be 
enrolled and followed until delivery. Two study groups will comprise of approximately 238 HbSS 
or HbSC pregnant women who are confirmed with Haemoglobin phenotype testing by HPLC 
randomly assigned to each arm. 
 
3.3 Settings and locations 
This will be a multi-center study with the coordinating center at the College of Medicine, 
University of Lagos (CMUL). Study sites will comprise 3 Teaching Hospitals, 12 General 
Hospitals and 1 Federal Medical Centre within and outside Lagos State. 
 
The study sites will include:  
Site Code 
No. 
Name of Study Site 
Site Investigator/Coordinator 
01 
Lagos University Teaching Hospital, 
Lagos State   
Dr. Opeyemi Akinajo,  Dr Babah O.A 
02 
Lagos State University Teaching Hospital 
(LASUTH), Ikeja, Lagos State  
Dr. Yusuf Oshodi 
03 
Alimosho General Hospital, Igando, 
Lagos State 
 
Dr. Ogungbe O.Y 
04 
General Hospital, Gbagada, Lagos State 
Dr. Ojo Oluwole O, Dr Kaka A.A . 

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05 
General Hospital, Ikorodu, Lagos State 
Dr. Aletan O.B. 
06 
General Hospital, Ifako Ijaiye, Lagos State Dr. Awobusuyi Omotayo R. 
07 
Randle General Hospital, Surulere, Lagos 
State 
Dr. Aderolu Monsurat B. 
08 
Island Maternity Hospital, Lagos State 
(LIMH) 
Dr. Agbetoba H.A 
09 
Federal Medical Centre, Ebute Metta, 
Lagos State 
Dr. Uchendu I.A, Dr Olusi A.M 
10 
Ajeromi General Hospital, Ajegunle, 
Lagos State 
Dr. Idowu Adewale, Dr Azie Kingsley 
11 
General Hospital, Isolo, Lagos State 
Dr. Ajayi Akinola B. 
12 
General Hospital, Shomolu, Lagos State 
Dr. Inofomoh Aloysus 
13 
General Hospital, Orile-Agege, Lagos 
State 
Dr. Olodeoku Kayode .O, Dr Omodigbo  
14 
Mother and Child, Amuwo-Odofin, Lagos 
State 
Dr. Alokha Mercy   
15 
General Hospital, Ibeju-Lekki, Lagos 
State 
Dr. Bamisebi A.O, Dr. Hassan Khadijah. 
O 
16 
Obafemi Awolowo University Teaching 
Hospital, Ile-Ife 
Dr. Awowole Ibraheem, Dr Adeniyi, Dr 
Allen 
 
3.4  
Randomisation (Interventions: Investigational and placebo therapy) 
This study will employ a randomised, patient  and  investigator-blinded, multi-centre, parallel-
group, placebo  controlled   design to assess efficacy, safety and tolerability of Low dose aspirin 
for preventing intrauterine growth restriction and preeclampsia in sickle cell pregnancy 
(PIPSICKLE). 
At the baseline visit, a pregnant woman who is referred or is found to have sickle cell disease 
(HbSS or HbSC) on routine haemoglobin genotype testing, meets the eligibility criteria and gives 
informed consent will be enrolled and randomised to one of the two treatments groups (Blinded)  

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Randomisation and allocation concealment will be done with the use of a web-based randomisation 
software known as ‘Sealed envelope’ in a 1:1 ratio in blocks stratified according to centre. Only 
an unblinded pharmacist will be aware of the actual codes and the pharmacist will not be in contact 
with any of the study participants or investigators. 
A total of 476 eligible pregnant HbSS and HbSC women will be randomly assigned to either group.  
Those in the LDA group will receive 100mg aspirin daily while those in the placebo group will 
receive a tablet that looks like the active drug in terms of diameter, thickness and colour.  
The drugs will be started between 12 and 28 weeks’ gestation and continued till 36 weeks or 
delivery, whichever comes earlier. 
The study drugs will be prepared in sachets and dispensed in 2 weekly doses (3 weeks dosage at 
enrollment).  The women will be sent daily reminders by text message, questioned on compliance 
at each visit and asked to bring in their used sachets for sighting. All the women will be followed 
from enrollment till delivery. 
 
The study drugs will be packed in boxes labelled with codes and each box will have sufficient 
study drugs for one patient for 24 weeks with 4 extra weeks’ worth of drug in case the patient loses 
some pills. The drug boxes will be delivered to each centre in batches of 8 (4) and 4 (2) more boxes 
will be sent to the centre whenever a message is received from the centre that there are 4 boxes 
left.  
In the unlikely event that a woman loses all her drugs, the unblinded pharmacist will be asked to 
label another batch for the woman, based on the code list that she holds. If all the relevant drugs 
have been used up, the trial pharmaceutical company Emzor Pharmaceutical Ltd, will be asked to 
produce a new pack of study (investigational or control) drug.  
 
Investigational (active) and control (placebo) therapy:  
• Formulation A: LDA; The investigational drug (Aspirin) 100mg aspirin taken once at about 
same time daily 

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• Formulation B: The placebo (control); tablet that looks like the active drug in terms of  
terms of diameter, thickness and colour,  also taken once at about same time daily.  
 
3.5 Patient numbering 
Each patient will be uniquely identified in the study by a combination of her study site code and a 
three digit number to make a study ID. The study site code has been pre-assigned by the PI. Upon 
signing the informed consent form, the patient is assigned a Study ID as soon as she is randomised 
on the web based randomisation form. 
 
3.6  
Measures to minimize bias 
3.6.1 Randomization and allocation concealment. 
This will be done remotely by “Sealed envelope”, an on-line randomization service. Sealed 
envelope will generate a randomization code list and share it ONLY with the unblinded 
pharmacist, Mrs Edet, by email. The code list will be in blocks of four and the drugs will be sent 
out in blocks of four to each site by the unblinded pharmacist. Once the drugs are received by each 
site, they will let the PI know and she will alert Sealed Envelope so they can load the appropriate 
codes onto the system. As each new patient is recruited in a particular site, her details are entered 
into a tablet and a code is generated, which will be one of the codes that were sent to the site. She 
is then given tablets from the box of drugs that carries the generated code. Only the unblinded 
pharmacist will have the code list that shows the group that the code is assigned to i.e. whether 
active drug or placebo. 
The number of blocks sent to a site will correspond to the expected recruitment frequency at the 
site, based on the average number of sickle cell patients seen in the site. So for Alimosho and 
LASUTH for example, two blocks will be sent initially i.e. 8 packs of drugs, while for Federal 
Medical Centre, Ebute Metta, one block will be sent i.e. 4 packs of drugs.  
 
3.6.2 Blinding 
Our goal is to blind: 1) Participants, 2) Site coordinators, PIPSICKLE research team. The only 
person that will know the codes will be the un-blinded pharmacist. The appearance of the trial drug 

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aspirin and placebo are identical and will be packaged and labelled the same way. There will only 
be unblinding if there are serious adverse events and the PI will be told the correct allocation, after 
the DSMC/External Monitoring Committee (EMC) have agreed that unblinding is necessary.  
3.6.3  Randomization and decoding procedures  
The PIPSICKLE randomisation manager, who in this case is the unblinded pharmacist, will 
maintain the trial treatment randomisation codes. The manager will provide the code to the 
DSMC/EMC during meetings to review the interim data. The manager will provide the code to the 
DSMC/EMC statisticians when they are prepared to unblind the code to review interim data.  
 
3.7  
Physical examination 
Full physical examinations will be performed at baseline, and at each visit .The initial evaluation 
will also include measurement of the patient’s weight, blood pressure and oxygen saturation.   
Information about the physical examination must be entered into the source documentation at the 
study site. Significant findings that are present prior to receiving study medication must be 
included in the relevant medical history/current medical conditions in the Case Report Form 
(CRF).  
 
 3.8    Laboratory evaluations 
Standard clinical laboratory evaluations will be performed as follows: 
Haematology:   
- 
Full blood count (at enrollment and delivery) 
- 
Hb fraction by HPLC (enrollment) 
- 
Haemoglobin concentration with the Hemocue haemoglobinometer every 2 
weeks from 20 weeks’ gestation till delivery.  
Urinalysis:  
- 
Measurements will be performed by dipstick at every visit.  

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- 
Random/Spot urine protein to creatinine ratio (UPCR) will be ordered on a 
random urine sample if there is evidence of significant protein (≥ 1+) in the 
urine by dipstick. 
Blood specimen will be collected in serum separator tubes for storage and use for future research. 
All samples will be processed and analyzed at Synlab (an internationally accredited medical 
laboratory). Complete the laboratory tests request form (Appendix i) to accompany the sample to 
the lab, document date and time samples were taken in participant's case-note. Call courier services 
for sample pickup preferably within 6 hours of sample collection. Store samples at 4-80C 
(refrigeration) immediately after collection before pickup; for not more than 12 hours.  If any 
results are of clinical concern, a repeat sample will be collected at the next scheduled visit. 
 
3.9  
Outcome measures  
Primary outcomes:  
• Birth weight below 10th centile for gestational age on the WHO INTERGROWTH- 21st 
birthweight charts 
• Stillbirth 
• Fetal death 
• Miscarriage. 
 
Secondary outcomes:  
Pregnancy complications: Pre-eclampsia, Preterm delivery, retained placenta, placental 
abruption; 
Maternal complications:  Maternal death, frequency of crises, no of blood transfusions, incidence 
of urinary tract infection, respiratory tract infection, acute chest syndrome, and potential adverse 
effects such as vaginal bleeding, epigastric pain and heartburn. 
Preeclampsia will be diagnosed based on ISSHP classification (17) if there is development of 
hypertension (either systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg 
on two occasions at least 4 h apart) after 20 weeks gestation plus one of the following: proteinuria, 
thrombocytopenia or any multisystem complication.  

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Proteinuria will be defined as a dipstick test with ≥1+ proteinuria (≥30 mg dl−1) on two occasions 
at least 4 hours apart, without any evidence of a urinary tract infection. Or UPCR  >300mg/g Cr. 
Thrombocytopenia will be defined as platelet count < 100,000/Ul. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4.0  
SELECTION OF PARTICIPANTS 
 
The target population is sickle cell pregnant women who are either HbSS or HbSC. 
Eligibility 
4.1 Inclusion criteria 
• Age 18 years and above 
• Singleton fetus 
• Hb genotypes are Haemoglobin SS or SC. 
• 12-28 weeks gestation at recruitment, estimated from the last menstrual period or by an 
early ultrasound scan.  
 
4.2 Exclusion criteria 
• Women with associated medical conditions in pregnancy e.g. HIV infection, diabetes 
mellitus, chronic hypertension, renal disease, sickle nephropathy. 
• Hb genotype other than HbSS & HbSC 
• Gestational age greater than 28 weeks 
• Multiple pregnancy 
• History of hypersensitivity to aspirin 
• A vaso-occlusive crisis in the last 4 weeks 
• Blood transfusion in the last 3 months 
• Women who participated in the PIPSICKLE trial during their previous pregnancy 
 
Once a participant is enrolled, she will be assigned a study ID and a randomisation code, which 
will be entered into the database and written on the patient’s case record. An electronic enrollment 
CRF will be completed using REDCap software installed on electronic tablets. 
 

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Figure 1. PIPSICKLE Trial flowchart 
 
 
 
 
 
 
 

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5.0  
VISIT SCHEDULE AND ASSESSMENTS 
5.1 Screening visit (visit-0) 
All prospective participants will be evaluated to determine their eligibility according to the study 
eligibility criteria. Information will be completed for all prospective participants as required in the 
screening log (Appendix ii).  
The following additional steps must be taken during the screening visit:  
❖ An interview/information disclosure/discussion and interaction with the participant to 
make sure she comprehends the nature and purpose of the study, duration of participation 
and number of participants, procedures to be followed, investigations; if any to be 
performed, foreseeable risk and discomfort, other study requirements and schedule and is 
willing to comply.  
❖ Acceptance/rejection to participate 
❖ Agreement to participate (Consent). Must be recorded (written)/witnessed. Each 
participant will be asked to sign (or provide other mark if need be) an informed consent 
document (Appendix iii) and will be given a signed copy to take home. If the participant 
cannot read, a witness will be present at the time of the study explanation and consent 
process and will witness the signature or mark of the participant. 
❖ The women may be asked to return in 2-4 weeks for the enrollment visit if she met all 
eligibility criteria. However screening (visit-0) and enrollment (visit-1) may take place 
during the same visit.  
Contact information   
For each participant the research staff will obtain contact information. The study site will develop 
its own Patient locator form (Appendix iv) and determine the best way to collect this information 
for its own study site participants. In the event that a participant misses a scheduled appointment 
(enrollment or follow-up or end of study visit), the research staff will try to establish 
communication with the participant through authorized possible means (e.g telephone if this is 
possible, emails or visiting the participant’s home or workplace). The need to return for all 
scheduled follow up visits will be emphasized to all study participants at every visit. 

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5.2 Enrollment visit (visit 1- GA 12-28 weeks) 
Screening (visit-0) and enrollment (visit-1) may take place during the same visit.  
Once the participant is screened and determined to meet study eligibility criteria and consent to 
the study, she will be randomised to one arm of the study and assigned a study ID and 
randomisation code.  
The following additional steps will be taken in the enrollment visit 
❖ Study ID and randomisation code will be written on her case-notes  
❖ Complete study enrollment log (Appendix v).  
❖ Do a physical examination & take relevant medical history and concomitant medications 
❖ Complete enrollment e-CRF (Appendix vi). 
❖ The box corresponding to her randomisation code will be opened and she will be given a 
three-week pack of the drugs from the parcel and scheduled for a follow-up visit in 2 weeks. 
❖ Take blood for full blood count and Hb fraction by HPLC – 4ml each into 2- EDTA bottles.  
❖ Take spot urine sample for urinalysis by dipstick. UPCR if significant proteinuria by 
dipstick.  
If a patient is screened but does not get enrolled, the reason for not being enrolled must be entered 
into the screening log. 
 
5.3 Follow- up visits (visit 2- 28-36 weeks to delivery) 
Each participant will have a follow up visit at the study site. The research staff will be responsible 
for interviewing and re-supplying the participants with the trial drugs.  
The following will be done at follow up visits 
❖ Physical examination 
❖ Evaluate compliance & ADR 
❖ Counselling 
❖ Complete follow-up visit e-CRF  (Appendix vii) and relevant source documents 
❖ Re- supply of trial drugs in an amount sufficient to last until the next follow up visit. 

CONFIDENTIAL 
25 
 
❖ Haemoglobin concentration with the Hemocue haemoglobinometer every 2 weeks till 
delivery.  
❖ Take spot urine sample for urinalysis by dipstick. UPCR if significant proteinuria by 
dipstick.  
 
5.4 Interim contacts and unscheduled visits 
The participant or the investigator may request an interim contact or an unscheduled visit at any 
time during the study. All interim contacts and unscheduled visits will be documented in the 
participants study records and visit e-CRFs. 
Interim or unscheduled visits are AE-related visits in that health related reaction, effect, or 
abnormality is reported. Other examples of reasons for an interim or unscheduled visit not in 
response to an AE are: 
• To get more trial drugs in cases of loss or misplacement. 
• To ask questions and discuss problems with study compliance  
• Interim examination - examination requested but no complaints or symptoms 
 
5.5 Study Completion visit (Pregnancy loss or delivery) 
A participant will be considered to have completed the study once there is a pregnancy loss or 
delivery at any time after randomisation and all relevant data is captured into the appropriate study 
completion CRF.   
The following steps will be taken at the end of study visit 
❖ Physical examination 
❖ Evaluate compliance & ADE 
❖ Complete all relevant documents 
❖ Complete delivery e-CRF (at delivery- Appendix viii) and end of study visit e-CRF at 
completion of all study visits and data entry (Appendix ix) and other relevant source 
documents. 

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26 
 
❖ Counselling and necessary referral (e.g Postpartum and family planning clinics) 
 
Tables below lists all of the assessments and indicates with an “X” the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The Table indicates which data are entered into the database (D) or remain in 
source documents only (S) or both (SD).  
Assessments that generate data for database entry and which are recorded on CRFs are listed using 
the CRF name (Enrollment, Visit, Study completion). Assessments that are transferred to the 
database electronically (e.g. laboratory data) are listed by test name.  
 

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27 
 
Table 1: Study Visit Schedule 
 
 
 
 
 
 
 
 
 
 
Pre-
treatment 
Treatment (Enrollment and follow-up) 
Delivery 
Study Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
GA in weeks 
6-11 
12 
14 
16 
18 
20 
22 
24 
26 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
Screening  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End of study 
  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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28 
 
Table 2: Assessment schedule for study participants 
Phase 
Pre- 
Treatment 
 Treatment (Enrollment and follow-up) 
Delivery 
 
Study visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
GA in weeks 
6-11 
12 
14 
16 
18 
20 
22 
24 
26 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
Inclusion/exclusion 
criteria (S) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Written 
informed 
consent (S) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/ 
PMH (SD) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication (SD) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight (SD) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination (SD) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory  (SD)  
Hb +Urinalysis 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Obstetric Scan (SD) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug (SD) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse 
Events 
(SD) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End of study form 
(D) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

CONFIDENTIAL 
[Version 4] 
                             [PIPSICKLE] 
[21st MAY 2024] 
 
Page 29 of 121 
 
6.0  
PARTICIPANTS WITHDRAWAL & STUDY DISCONTINUATION 
6.1 Premature patient withdrawal 
Patients must be withdrawn from the study for any of the following reasons:  
• Withdrawal of informed consent  
• Use of any of un-prescribed medications  
• 
Patients who discontinue study drug  
Patients could also be withdrawn at any time if the investigator concludes that it would be in the patient’s 
best interest for any reason. Protocol violations should not lead to patient withdrawal unless they indicate a 
significant risk to the patient’s safety. 
Patients may voluntarily withdraw from the study for any reason at any time. They may be considered 
withdrawn if they state an intention to withdraw, or fail to return for visits, or become lost to follow up for any 
other reason.  
If premature withdrawal occurs for any reason, the investigator must determine the primary reason for a 
patient’s premature withdrawal from the study and record this information on the Study Completion CRF. 
Patients who are prematurely withdrawn from the study will not be replaced by newly enrolled patients. 
 
6.2 Loss to follow up 
If a participant fails to appear for a scheduled visit, at least three attempts to contact her will be made over the 
subsequent 30 days. These attempts will be documented in the participant study file. Her file will remain open 
until the study close out. 
For patients who are lost to follow-up (i.e. those patients whose status is unclear because they fail to appear 
for study visits without stating an intention to withdraw), the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone calls, registered 
letters, etc. 
If the participant does not return to the study before the study is closed, the end of study form will only be 
completed at the time of study closeout. The form will indicate that the participant was lost to follow up. The 
“lost to follow up” designation cannot be made for any participant until the closing date of the study 

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7.0           STUDY PRODUCTS AND TREATMENTS 
7.1 Study products: 
• Aspirin 
• Placebo 
7.2 Study drug supply and resupply, storage, and tracking 
Study drugs must be received by a designated person at the study site, handled and stored safely and properly, 
and kept in a secured location to which only the investigator and designated assistants have access. Upon 
receipt, all study drugs should be stored according to the instructions specified on the drug labels. Clinical 
supplies are to be dispensed only in accordance with the protocol. 
The investigator must maintain an accurate record of supplies and dispensing of study drug in a drug 
accountability ledger. Monitoring of drug accountability will be performed by the field monitor during site 
visits and at the completion of the trial. Patients will be asked to return all unused study drug and packaging at 
the end of the study or at the time of study drug discontinuation.  
 
7.3 Treatment assignment 
At enrollment visit, all patients who fulfill all the inclusion/exclusion criteria will be given the lowest available 
number on the randomisation list. This number assigns them to one of the treatment arms. The investigator 
will enter the randomisation number on the enrollment log/CRF. 
Each participant will receive a supply of the trial drugs. Participants will receive supplies in quantities 
anticipated to last until next visit. Research staff will show the participants how the drugs are to be taken. A 
participant will be instructed to return between scheduled visits to obtain more supplies if needed. A product 
dispensing log will be maintained by the clinic and field staff to track distribution of the trial drugs. 
 
7.4 Treatment blinding 
The trial is a double-blinded RCT study. Both treatments will be identically packaged and the pharmacist or 
an independent study site personnel will prepare and give the medication to the patient after randomisation. 
The investigator should remain blinded.  

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31 
 
 
7.5 Dispensing the study drug and labeling 
Each study site will be supplied by the unblinded study pharmacist with the study drugs in identically-
appearing boxes. There will be a label with a unique randomisation code affixed to each of the boxes. Each 
unique code will correspond to a treatment arm. When the batch of study drug is delivered to a site, the 
receiving investigator (site coordinator), will notify the PI of receipt with a list of the randomisation codes 
received. The PI then notifies Sealed Envelope. Once a patient at a particular site is randomised, the code 
generated will correspond to the code on one of the boxes at that site. The investigator or research assistant 
will identify the study drug to dispense to the patient using the randomisation code on the label. Immediately 
before dispensing study drug to the patient, investigator staff will copy the code onto the source document 
(Appendix x: Drug Accountability Form) containing that patient’s unique Study ID. 
 
7.6 Other concomitant treatment 
Use of the following treatments is NOT allowed after the start of study drug: 
• Any drug not prescribed. 
• Herbal medications  
 
7.7 Study drug discontinuation 
Study drug must be discontinued for a given patient if the investigator determines that continuing it would 
result in a significant safety risk for that patient. The following circumstances require study drug 
discontinuation: 
• Emergence of severe adverse events: severe nausea/vomiting, allergy, severe pruritus, life threatening 
symptoms 
• Persistent or heavy vaginal bleeding  
• Abnormal laboratory values: Platelet count ≤ 50 X 109/ml  
• In addition to these requirements for study drug discontinuation, the investigator should discontinue the 
study drug for a given patient if, on balance, he/she thinks that continuation would be detrimental to the 
patient’s well-being.  

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32 
 
Patients who discontinue study drug will be followed for the whole study duration until 36 weeks or delivery 
at which time all of the assessments listed for the final visit will be performed. 
Reasons for Study Drug discontinuation should be completed, giving the date and primary reason for stopping 
the study drug under the relevant portion of the CRF. 
 
7.8 Emergency unblinding of treatment assignment 
- As aspirin is a tried and tested commonly used drug, we do not foresee any need for emergency unblinding. 
However, in the event of an acute hypersensitivity reaction, we will have to perform emergency unblinding. - 
- Any other reason as determined by the DSMC/External monitoring committee. 
 
7.9 Treatment exposure and compliance 
All medication (other than study drug) and significant non-drug therapies administered after the patient starts 
treatment with study drug will be documented under concomitant medications/Significant non-drug therapies 
in the CRF after start of study drug.  
Records of study medication used and exact dosages administration and compliance will be kept during the 
study. Drug accountability will be noted by the field monitor during site visits and at the completion of the 
study. 
 
 
 
 
 
 
 
 
 
 

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8.0         ADVERSE EVENTS AND REPORTING REQUIREMENTS 
8.1 
Adverse Events (AEs) 
❖ An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related to 
study drug. Study drugs include the investigational drug/placebo under evaluation that is given during 
the treatment phase of the study.  
❖ Medical conditions/diseases present before starting study drug are only considered adverse events if 
they worsen after starting study drug.  
❖ Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs 
or symptoms, or are considered clinically significant, or require therapy. 
 
Clinical signs and symptoms will be assessed at baseline, before dosing and all follow-up visits, and recorded 
on the CRF. Any symptom that worsens or starts after baseline will be recorded as a new adverse event on the 
e-CRF.  
The occurrence of adverse events, such as weakness, chills/rigors, headache, myalgia, dizziness, epigastric 
pain, abdominal pain, anorexia, nausea, vomiting, diarrhea, palpitations, insomnia, pruritus, coughing, tinnitus, 
abnormal gait, tremor, clonus or dyskinesia, will be sought by the investigator (or designee) at each study visit 
and recorded in the e-CRF.  
Adverse events also may be detected when they are volunteered by the patient during or between visits or 
through physical examination, laboratory test, or other assessments.  
 
8.2 Relationship of AE to study product 
The investigator must determine the relationship of the AE to the product under investigation and document 
in the appropriate section of the e-CRF. For each AE, an assessment of the relatedness to the study drugs 
should be made using the following scale: 
• Unrelated: Onset of the AE had no reasonable temporal relationship to administration of the study 
product or a causal relationship to administration of the study product is biologically implausible or the 
event is attributed to an alternative etiology. 

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34 
 
• Possibly Related: Onset of the AE has a reasonable temporal relationship to study product 
administration and a causal relationship is not biologically implausible. 
• Probably Related: Onset of the AE has a strong temporal relationship to administration of the study 
product that cannot be explained by the participant’s clinical state or other factors and a causal 
relationship is not biologically implausible. 
• Definitely Related: Onset of the AE shows a distinct temporal relationship to administration of the 
study product that cannot be explained by the participant’s clinical state or other factors or the AE 
occurs on re-challenge or the AE is a known reaction to the product or chemical group or can be 
predicted by the product’s pharmacology. 
These criteria in addition to good clinical judgement should be used as a guide for determining the causal 
assessment. If it is felt that the event is not related to study drug therapy, then an alternative explanation should 
be provided. 
 
8.3 Reporting Adverse Events  
Study site coordinators will document on the appropriate study e-CRF all AEs reported by or observed in 
enrolled study participants regardless of severity and presumed relationship to study product. The study 
clinician must provide on this form information on symptoms, time of onset, severity, frequency, product-
relatedness, actions taken and participant outcome. The PI may request additional information from the site if 
it is needed to evaluate the AE. Site coordinators will report information on SAEs to the local Ethics committee 
in accordance with the local committee requirements.  
All adverse events must be recorded on the e-CRF with the following information: 
1. the severity grade (mild, moderate, severe) 
2. its relationship to the study drug(s) (see section 8.2) 
3. its duration (start and end dates or if continuing at final exam) 
4. whether it constitutes a serious adverse event (SAE) 
• All adverse events recorded at any time after baseline on the CRF will be summarized at analysis.  
 
 

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35 
 
8.4 Serious Adverse Events (SAEs) 
A SAE is defined as an event which: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for: 
➢ routine treatment or monitoring of the studied indication, not associated with any deterioration in 
condition 
➢ elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under 
study and has not worsened since the start of study drug 
➢ treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE 
given above and not resulting in hospital admission  
➢ social reasons and respite care in the absence of any deterioration in the patient’s general condition 
• is medically significant, i.e. defined as an event that jeopardizes the patient or may require medical or 
surgical intervention to prevent one of the outcomes listed above 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements. 
All adverse events should be treated appropriately. Treatment may include one or more of the following:  
❖ No action taken (i.e. further observation only);  
❖ Study drug dosage adjusted/temporarily interrupted;  
❖ Study drug permanently discontinued due to this adverse event;  
❖ Concomitant medication given;  
❖ Non-drug therapy given;  
❖ Patient hospitalized/patient’s hospitalization prolonged.  
The action taken to treat the adverse event should be recorded on the adverse event section of the e-CRF.  

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36 
 
Once an adverse event is detected, it should be followed until its resolution or until it is judged to be permanent, 
and assessment should be made at each visit (or more frequently, if necessary) of any changes in severity, the 
suspected relationship to the study drug, the interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug will be included in the 
patient informed consent and should be discussed with the patient during the study as needed. 
 
8.5 
Reporting SAEs 
All SAEs should be reported to PIP-SICKLE administrative core & steering committee as soon as possible 
after the SAE is identified by site personnel. It is strongly recommended that site personnel report SAEs within 
24 hours of the study site becoming aware of the problem. The investigator should complete SAE report form 
(Appendix xi) and forward to the DSMC/EMC. The investigator may report the SAE via telephone or email; 
however a SAE report form must be completed as soon as possible after the informal report.  
 
 8.6  
Safety 
Adverse events will be monitored throughout the study to assess the general safety and tolerability of the two 
treatment groups. 
Safety assessments will consist of:  
• monitoring and recording all adverse events  
• the monitoring of hematology and urinalysis 
• regular measurement of vital signs  
• physical examinations as indicated 
 
 
 
 
 
 

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37 
 
 
9.0  
STATISTICAL SUMMARY 
9.1     Data collection 
Designated investigator or staff must enter the information required by the protocol onto the electronic CRFs 
on REDCap and source documents as indicated. Field monitors will review the e-CRFs for completeness and 
accuracy and instruct site personnel to make any required corrections or additions.  
 
9.2 Data Management and Analysis 
DATA ANALYSIS; POPULATIONS FOR ANALYSIS 
The assignment of patients into analysis populations will be performed prior to database lock and any data 
analysis.  
Randomised – all patients who receive a randomisation number. 
Intention-to-treat (ITT) – all randomized patients with at least one relevant post-baseline efficacy assessment, 
and who had at least one dose of study drug. Following the intention-to-treat principle, patients will be analyzed 
according to the treatment they were assigned to at randomization. 
Primary Analysis (PA) – all ITT patients that completed 36 weeks or delivery  
Per Protocol (PP) – all PP patients that meet all of the following:  
• Took at least 80% of scheduled study drug  
Safety – all patients that received at least one dose of study drug and had at least one post-baseline safety 
assessment. Patients will be analyzed according to treatment received. 
 
9.3 Data analysis plan 
Data analysis will be by intention-to-treat. Categorical variables will be expressed as frequencies and 
percentages. For continuous variables, a Shapiro–Wilk test of normality will be performed and normally 
distributed data will be presented as means ± SD, while non-normally distributed data will be presented as 
median and interquartile range (IQR). The risk of occurrence of IUGR, perinatal death and other key outcome 
variables will be computed and compared in both groups. A multivariate regression analysis will be performed 
to determine the odds of each of the key outcomes among women who received the intervention with respect 

CONFIDENTIAL 
38 
 
to those who did not, after controlling for common confounders. This will be presented as regression 
coefficients and their 95% confidence intervals. Level of significance will be set at 5%. Post-regression 
analysis will be performed to determine the goodness-of-fit of the final model. STATA version15.0 (StataCorp 
LP, College Station, TX, USA) will be used for statistical analysis. 
 
9.4 Quality control and data management 
The data file will be accessible by the PI and the statistician. Data will be captured in electronic case report 
forms (CRF) at various patient visit types and uploaded real time to the central server after being checked by 
the site coordinator. They will follow the guidelines specified in the SOP developed by the Data handling and 
communications committee for data collection, data entry, and transmission, data compilation and 
management and data quality and security.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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39 
 
 
10.0  MONITORING PLAN SUMMARIES 
10.1 Monitoring and Evaluation Mechanism  
The Project monitoring and evaluation mechanism will help to determine progress being made towards 
achievement of study outcomes and will provide constructive recommendations to address key problems 
identified. It will review the effectiveness, efficiency and timeliness of project implementation; analyse 
effectiveness of implementation and partnership arrangements; identify issues requiring decisions and 
remedial actions; analyse  whether  the  project  is  on  track  with  respect  to  achieving  the  expected results; 
and propose any  mid-course corrections and/or  adjustments to the Work Plan as necessary.   
The project M &E mechanism will include  
i. 
An Administrative Core- this will be the essential infrastructure that will enable synergy and 
coordination of the project, scientific core and the collaborating sites of PIPSICKLE. The 
administrative core will consist of the PI and Ms Rachel Quao, a full time project coordinator. They 
will provide administrative oversight and management of the research study and coordinate all 
internal and external meetings of investigators and staff.  
 
ii. 
Steering committee – this will ensure a successful delivery of the project, maximizing the benefits 
from the projects and ensuring the approved methodology is followed. This committee will provide 
Cross-functional leadership and direction, provide Project Management Governance, and accept 
responsibility for the project strategy and the overall benefit realization of the project. The steering 
committee will comprise the PI, all co-investigators and project site coordinators as may be 
appointed. A patient representative and an external monitor, an Obstetrician with clinical trial 
experience will also be included. The steering committee will monitor project progress by holding 
a bi-weekly on-line meeting (Zoom/Skype) to evaluate enrolment rate, challenges and issues as 
they arise. The committee will also hold a bi-annual face to face meeting to monitor and evaluate 
progress and ensure compliance with regulatory, fiscal and reporting requirements. 
 
iii. 
Clinical Trial Monitors – The Clinical monitor will be responsible for trial monitoring. To verify 
that: (a) the rights and well-being of human subjects are protected. (b) The reported trial data are 
accurate, complete, and verifiable from source documents. (c) The conduct of the trial is in 

CONFIDENTIAL 
40 
 
compliance with the currently approved protocol/amendment(s), with Good Clinical Practice 
(GCP), and with the applicable regulatory requirement(s). Clinical trial monitors will conduct:   
 
i. Pre-Trial Monitoring visit: to ensure feasibility in the centre and interest of the investigator.  
ii. Trial Initiation visit: to deliver study material, documents, products and make sure the 
investigational team understands the protocol and GCP requirements. 
iii. Routine Monitoring visit: Make sure the study is conducted according to the protocol and GCP 
and help the investigational team in solving problems.  
iv. Close-out visit: Make sure the investigator file is archived properly and collect back all unused 
material, documents or products. Appointed site coordinators will be trained in GCP and 
research monitoring to perform the duties of clinical monitors in sites other than theirs. 
 
10.2 Clinical Monitoring plan   
Site visits by the external clinical monitors will be made in accordance with the policy drafted and SOPs. The 
purpose of the monitoring is to ensure the quality and accuracy of data collected on the e-CRF and entered in 
the database and to determine that all regulatory requirements surrounding clinical trials are met. 
The investigator will allow the clinical monitors and designated persons to inspect study documents (e.g 
consent forms, drug distribution forms, CRF and pertinent clinic records for confirmation of the study data). 
Various authorized individuals may visit the study site to audit the progress of this study (e.g monitoring 
committee). A site monitoring visit log (appendix xii) will be maintained at the study site in which all visits 
made by authorized individuals are recorded. All clinical records and the e-CRFs for all the participants 
enrolled in this study will be made available for review to authorized individuals. 
Before the study begins, the clinical monitors will conduct an evaluation visit at each site to determine the 
suitability of the site for the research study. In addition there will be a study initiation visit (study start-up), 
quarterly monitoring visits (to track study progress) and a close out visit. The overall responsibility of the 
monitors is to ensure that the study is being conducted according to the protocol, SOPs, GCP and applicable 
regulatory requirements. 
A detailed monitoring plan will be developed for this study and will be used by all clinical monitors. This plan 
will specify responsibilities and qualifications of the identified clinical monitors, back-up provisions, in house 
monitoring procedure and site monitoring visit procedures. All monitoring visits will be documented. 

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41 
 
10.3 Data and safety monitoring committee 
The steering committee will assemble an independent DSMC/External Monitoring Committee made up of at 
least three members; which will include one clinician and one statistician. Members are Prof Olayemi UCH – 
Chairman, Prof Akanmu and Dr Kamma Okafor. The DSMC/EMC will meet at a minimum once before the 
study begins and twice during the study. The details for the operation and responsibilities of the DSMC will 
be provided in the DSMC/EMC Operational protocol No 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
42 
 
11.0  PROTOCOL VIOLATIONS & DEVIATIONS 
11.1 Protocol violations 
Any deviation that may affect the subject’s rights, safety, or welfare, and/or the completeness, accuracy and 
integrity of the study data. This is considered a major, more serious, variance from an approved protocol than 
a deviation. 
Emergency departures from protocol that eliminate an apparent immediate hazard to participate and are 
deemed crucial for the safety and well-being of that participant may be instituted for that participant only by 
the investigator. The investigator will notify the EMC & Ethics committee in writing as soon as possible and 
document on the Protocol Deviation/Violation Form (appendix xiii) the reasons for violation and ensuing 
events. Protocol violations may also be identified by the clinical monitors during the periodic and closeout 
monitoring visits as well as during in house monitoring. The reporting procedures will be specifically detailed 
in the monitoring plan.  
 
Examples of Protocol Violations 
1. 
Omission or inadequate administration of informed consent. 
2. 
Inclusion/exclusion errors including gestational age limit. 
3. 
Treatment errors: no treatment or incorrect treatment (including dose or regimen, expired product), 
participant compliance problems. 
4. 
Missing or incorrectly timed study procedures and assessments  
5. 
Forcing a participant to enter or remain in the study, failure to withdraw a subject meeting 
withdrawal criteria; 
6. 
Inadvertent loss of samples or data; 
7. 
Participants who should have been discontinued from the study due to protocol criteria, but were 
not  
8. 
Working under an expired professional license/certification, debarred or disqualified status 
9. 
Frequent minor deviations 
 
 
 

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43 
 
11.2 Protocol Deviation 
Any change, divergence, or departure from the approved study design or procedures of a research protocol that 
is under the investigator’s control and that has not been approved by the IRB, and does not affect the 
participant’s safety, rights, or welfare and/or the completeness, accuracy and integrity of the study data. 
Examples of Protocol deviation 
1. implementation of unapproved recruitment procedures;  
2. use of an incorrect informed consent version; 
3. Missing original signed and dated consent form or missing pages from executed consent form; 
4. Inappropriate documentation of consent, including missing signatures  
5. Individual obtaining consent not listed on IRB approved application 
6. Subject visit/procedure falls outside of the window of time indicated by the protocol, or is not done per 
protocol, and there is no increased potential for risk to the subject or any damage to the integrity or 
completeness of the data. 
11.3 Serious Noncompliance 
Failure to comply with federal regulations, state laws, institutional policies, requirements or determinations of 
the Ethics committee, and/or provisions of the approved research study, where the occurrence involves 
substantive potential or actual increased risk to the safety, rights and welfare of participants.  
 
11.4 Reporting Protocol violation and deviations 
▪ The Trial clinical monitors must report deviations and violations to the PI. 
▪ It is the principal investigator’s responsibility to report protocol violation/deviation to the steering 
committee upon discovery. Protocol violations which may be considered serious noncompliance and 
are to be reported to the ethics committee within 5 business days on the Protocol Violation Report. The 
Principal investigator must develop a corrective action plan to present to the committee for review and 
approval. This corrective action plan will outline what steps the investigator has taken or will take to 
resolve the event and to prevent such events from occurring in the future. 
 
 

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44 
 
11.5 Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that must be 
approved by the Ethics committee.  Only amendments that are required for patient safety may be implemented 
prior to ethics committee approval. Notwithstanding the need for approval of formal protocol amendments, 
the investigator is expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the ethics committee at the 
study site should be informed within 10 working days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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45 
 
12.0  STUDY DOCUMENTS 
12.1 Study initiation 
The following documents will be in place and monitored by a clinical monitor at the study site before any 
potential participants are contacted. 
1. Investigators file: Signed Study protocol, screening log, enrollment log, informed consent form, protocol 
violation form, SAE report form, Sample CRFs 
2. Information given to participants: consent form, other written information, advertisements 
3. Financial records  
4. Signed agreement between involved parties   
5. Ethics committee approval 
6. CV for investigator, Co-Investigator and Site coordinators, research nurses and other staff  
7. Laboratory test normal values 
8. Instructions for handling investigational product and trial related materials, drug label form 
9. Site Monitoring visit log  
 
12.2 Study conduct 
During the study the following documents will be in place and periodically monitored by a clinical monitor at 
the study site. Revision of documents will be made if relevant. 
1. Revision to the investigators file  
2. Revision to protocol and amendments 
3. Revision to the CRFs  
4. Revision of information given to participants: consent form, other written information, advertisements 
5. Ethics committee updated approvals  
6. Ethics committee composition changes  

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7. Updated CV for investigator, Co-Investigator and Site coordinator  
8. Update on laboratory test normal values 
9. Documentation of investigational product and trial related materials 
10. Relevant communication other than site visits 
11. Signed consent forms. 
12 Sample of e-CRFs 
13. Copies of documentation of CRF corrections  
14.  Notification of Principal investigator on SAEs 
15. Notification on SAE, protocol; violations by investigator to local Ethics committee 
16. Interim or annual report to Ethics committees  
17. Participant screening log 
18. Participant randomisation code list 
19. Investigational products accountability documents 
20. Staff signature list  
21. Site Monitoring visit logs  
22. Progress reports   
 
12.3 Study completion 
After completion of the study, all of the documents in 12.1 and 12.2 should be in the file together with the 
following: 
1. Investigational products accountability documents 
2. Documentation of product destruction (if destroyed at site) 
3. Complete participant ID code list 
4. Final report by investigators to IRB. 

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12.4 Site record retention and access to documents at the site 
The signed original informed consent documents for each participant, original and copies of CRFs and original 
copies of study documentation (e.g drug inventory forms, participant clinic records, original laboratory reports, 
e.t.c) will be retained by the Principal investigator for a minimum of 10 years. At study completion at various 
study sites, all study documents will be moved and stored at the College of Medicine, University of Lagos and 
retained by the PI for a minimum of 10 years.  
The investigators may be subject to a field audit by the sponsor to validate the participation of study 
participants and to verify the data reported on the CRFs. This audit could occur while the study is in progress 
or several years after the study is completed. All of the participants’ records and other study documentation 
must be filed and accessible on short notice (3-5 days) during the study and subsequent retention period. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13.0  LABORATORY QUALITY ASSURANCE 
All study laboratory tests will be conducted by Synlab Nigeria. The steering committee will put in place a QA 
plan and transportation logistics before initiation of the study. The detailed QA plan will be finalized when the 
sites and the reference laboratories have finalized logistics. Synlab Nig laboratory services has been chosen 
based on the international accreditation and recognition, experience and facilities which comply with Good 
Laboratory practices (GLP) and ISO certification.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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14.0  ETHICS AND RESEARCH INTEGRITY 
14.1 Administrative procedures: Ethical and Environmental Considerations 
This trial has been registered with the Pan African Clinical Trials Registry (PACTR). Ethical approvals by the 
Health Research and Ethics committees of the Lagos University Teaching Hospital, Idi-Araba, Lagos State 
University Teaching Hospital, Ikeja, Federal Medical Centre, Ebute Metta and the Health Service Commission 
of Lagos State for the use of Lagos State University Teaching Hospital (LASUTH) and the general hospitals 
listed above under the section on study sites have been obtained. 
The purpose of the study will be duly explained to all eligible participants prior to recruitment. They will be 
informed of their right to withdraw or refuse to partake in the study without prejudice to the usual standard of 
care given to them at the health facility. All participating women will sign the study’s informed consent form 
prior to entry into the study. The personal data of each participant will be kept strictly confidential. The site 
coordinator of each center will collect all data at his/her facility and send same to the principal investigator at 
periodic intervals. This will be stored securely in a central electronic database by the principal investigator 
who will be the only one who will have access to the data of all participants collated centrally. The statistician 
will be granted access to the electronic database during statistical analysis or at any other time the principal 
investigator might require her to review the data.  
None of the women will be made to pay for any aspect of the study as the medication for the research will be 
given at no cost all through the pregnancy. All investigations pertaining to this research will also be conducted 
at no cost to the participants. 
This proposed research poses minimal or no risk to both mother and baby. Blood specimen collection might 
cause minimal discomfort in form of pain. For this reason all the blood sample collection will be made as 
comfortable as possible for the women. The intervention drug (Aspirin) is known to be safe in pregnancy and 
we will be using a low dose of 100mg, which is not expected to have significant adverse effects on participants. 
All participants will receive other routine medication (malaria prophylaxis, tetanus toxoid prophylaxis and 
folic acid supplementation) as normally prescribed. Malaria prophylaxis and folic acid will be provided to the 
participants all through pregnancy. The participants will enjoy equal rights and quality care all through the 
duration of the research.  
Leftover blood specimen will be stored for future research if participant consents. Ethical approval has been 
obtained for this (LUTH HREC Approval Number: ADM/DSCST/HREC/APP/3301). 

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Environmental issues are not applicable to this study. 
 
14.2 Informed consent 
No participant may be admitted into this study until the investigator has obtained her legally effective informed 
consent. An investigator shall seek such consent only under circumstances that provide the prospective 
participant with sufficient opportunity to consider whether or not to participate in the study. Informed consent 
must be obtained without coercion, undue influence or misrepresentation of the potential benefits or risks that 
might associated with participation in the study  
Informed consent encompasses all oral or written information given to the participants about the study and 
study materials. This includes the consent from signed by the participant, recruitment advertising and any other 
information provided to the participant. All such information that is given to the participant will be in a 
language that is understandable to her. The information will not include any language in which the participant 
is made to waive any of her rights or which releases or appears to release the investigator or the investigators 
institution. 
Informed consent will be documented by the use of a written consent form that is signed by the participant (or 
participant’s mark if she cannot sign). A copy of the signed consent form will be given to each participant. The 
consent form includes each of the basic elements of  an informed consent document and describes each of the 
risks or discomforts to the participant that have been identified as reasonably foreseeable.  
 
14.3 Participant confidentiality  
The confidentiality of all participants enrolled in the study will be protected to the fullest extent possible. 
Study participants will not be identified by name on any document sent or in any report or publication 
resulting from data collected in this study. 
14.4 Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations and with the 
ethical principles laid down in the Declaration of Helsinki.  

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51 
 
14.5 Responsibilities of the investigator and IRB 
The protocol and the informed consent form have been reviewed and approved by a properly constituted 
Independent Ethics Committee/Research Ethics Boards (IRB) before study start. Signed and dated statements 
that the protocol and informed consent have been approved by the IRBs have been obtained by the investigator 
before study initiation.  
Prior to study start, all investigators are required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and procedures found in 
this protocol and to give access to all relevant data and records to monitors, auditors, IRBs, and regulatory 
authorities as required.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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52 
 
 
 
 
15.0  DISSEMINATION STRATEGIES 
This indicates the steps that will be taken to ensure the project outcomes are brought to the attention of 
stakeholders. The findings of the study will be presented at conferences (both international and local) so as to 
disseminate them to a large body of professionals in the field of Obstetrics and Gynaecology. We will also 
publish them in high impact peer reviewed journals for wider dissemination of information. The findings will 
be used in counselling pregnant women with sickle cell disease at the various antenatal clinics on complications 
associated with the disease and preventive measures that may be employed. Charts will be created to facilitate 
counselling at the various antenatal clinics. We will issue press releases about the findings of the study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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53 
 
 
 
 
 
16.0  REFERENCES 
1. WHO. Sickle-cell Anaemia Report by the Secretariat. World Health Organisation. Fifty-ninth World 
Health Assembly; 2006a. Report No.: A59/9 Contract No.: Provisional agenda item 11.4. 
2. Chakravorty S, Williams TN. Sickle cell disease: a neglected chronic disease of increasing global 
health importance. Arch Dis Child. 2015;100(1):48-53. 
3. Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of 
sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 
2014;312(10):1033-48. 
4. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018-31. 
5. Oteng-Ntim E, Ayensah B, Knight M, Howard J. Pregnancy outcome in patients with sickle cell disease 
in the UK-a national cohort study comparing sickle cell anaemia (HbSS) with HbSC disease. Br J 
Haematol. 2015;169(1):129-37. 
6. Villers MS, Jamison MG, De Castro LM, James AH. Morbidity associated with sickle cell disease in 
pregnancy. Am J Obstet Gynecol. 2008; 199(2):125 e1-5. 
7. Afolabi BB, Iwuala NC, Iwuala IC, Ogedengbe OK. Morbidity and mortality in sickle cell pregnancies 
in Lagos, Nigeria: a case control study. J Obstet Gynaecol. 2009;29(2):104-6. 
8. Say L, Souza JP, Pattinson RC. Maternal near miss--towards a standard tool for monitoring quality of 
maternal health care. Best Pract Res Clin Obstet Gynaecol 2009; 23: 287–296. 
9. Obilade OA, Akanmu AS, Broughton Pipkin F, Afolabi BB. Prostacyclin, thromboxane and glomerular 
filtration rate are abnormal in sickle cell pregnancy. PLoS One. 2017;12(9):e0184345. 
10. Lewis DF, Canzoneri BJ, Gu Y, Zhao S, Wang Y. Maternal levels of prostacyclin, thromboxane, 
ICAM, and VCAM in normal and preeclamptic pregnancies. Am J Reprod Immunol. 2010;64(6):376-
83. 
11. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and 
its complications. Cochrane Database of Systematic Reviews. 2007. Issue 2. Art. No.:CD004659 

CONFIDENTIAL 
54 
 
12. Moore GS, Allshouse AA, Post AL, Galan HL, Heyborne KD. Early initiation of low-dose aspirin for 
reduction in preeclampsia risk in high-risk women: a secondary analysis of the MFMU High-Risk 
Aspirin Study. J Perinatol. 2015;35(5):328-31. 
13. RCOG. Management of Sickle Cell Disease in Pregnancy. Royal College of Obstetricians and 
Gynaecologists Green-top Guideline. 2011:1-20. 
14. Al Jama FE, Gasem T, Burshaid S, Rahman J, Al Suleiman SA, Rahman MS. Pregnancy outcome in 
patients with homozygous sickle cell disease in a university hospital, Eastern Saudi Arabia. Arch 
Gynecol Obstet. 2009;280(5):793-7. 
15. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al. Prevention of preeclampsia 
and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet 
Gynecol. 2010;116 (2 Pt 1):402-14. 
16. Sealed Envelope Ltd. Power calculator for binary outcome equivalence trial. [Online]. 2012. Available 
from: https://www.sealedenvelope.com/power/binary-equivalence/. 
17. Brown MA, Lindheimer MD, de Swiet M, Assche AV, Moutquin J-M. The classification and diagnosis 
of the hypertensive disorders of pregnancy: statement from the international society for the study of 
hypertension in pregnancy (ISSHP). Hypertens Pregnancy 2001;20 (1):ix–xiv. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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55 
 
 
 
 
 
APPENDICES 
i. 
Laboratory Request form 
ii. 
Screening Log forms 
iii. 
Informed consent form 
iv. 
Patient locator form 
v. 
Enrollment log 
vi. 
Enrollment e-CRF 
vii. 
Follow-up visit e-CRF 
viii. 
Delivery e-CRF 
ix. 
End of study visit e-CRF 
x. 
Drug Accountability Form 
xi. 
SAE report form 
xii. 
Site monitoring visit log 
xiii. 
Protocol deviation/ violation form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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56 
 
 
 
 
 
APPENDIX 01 
Laboratory Request form 
 
 
Study ID: 
 
Hospital number: 
 
Participant’s name: 
 
Date of birth: 
 
Age:  
 
 
Test  
Date of request 
Time sample 
collection 
FBC 
 
 
UPCR 
 
 
Other tests:  
 
 
 
 
Requesting Clinician  
Name of requesting clinician: …………………………………… 
 
Sign: ……………………………..  
 
Date: ………………………… 
 
Site Name & Code: …………………………………………………………….... 

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Phone number: ………………………. 
 
Email: …………………… 

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APPENDIX 02 
PIPSICKLE TRIAL 
SCREENING LOG 
S/N 
Date 
Name  
(Initial and Surname) 
DOB 
Eligible 
(Yes or 
No) 
Consent 
(Yes or 
No) 
Reason for non-eligibility 
/ Non- Consent  
Hosp. No 
Phone No  
1.   
 
 
 
 
 
 
 
2.   
 
 
 
 
 
 
 
3.   
 
 
 
 
 
 
 
4.   
 
 
 
 
 
 
 
5.   
 
 
 
 
 
 
 
6.   
 
 
 
 
 
 
 
7.   
 
 
 
 
 
 
 
8.   
 
 
 
 
 
 
 
9.   
 
 
 
 
 
 
 
10.   
 
 
 
 
 
 
 
11.   
 
 
 
 
 
 
 
12.   
 
 
 
 
 
 
 
13.   
 
 
 
 
 
 
 
14.   
 
 
 
 
 
 
 
15.   
 
 
 
 
 
 
 
16.   
 
 
 
 
 
 
 
17.   
 
 
 
 
 
 
 
18.   
 
 
 
 
 
 
 
19.   
 
 
 
 
 
 
 

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APPENDIX 03 
REPLACE WITH STUDY SITE NAME 
INFORMED CONSENT DOCUMENT  
 
TITLE OF RESEARCH: 
Low dose aspirin for preventing intrauterine growth restriction and 
preeclampsia in sickle cell pregnancy (PIPSICKLE): a randomized controlled trial. 
 
HREC APPROVAL NO. 
 
 
 
 
       
NAME & AFFILIATION OF RESEARCHER: The study is being led by the Principal Investigator; 
Professor Bosede B. Afolabi of Dept. of Obstetrics and Gynaecology, College of Medicine of University of 
Lagos/Lagos University Teaching Hospital, Idi-Araba, Lagos. 
INTRODUCTION: 
Preeclampsia and intrauterine growth restriction are common complications in 
pregnancy that affect the health of the mother and baby adversely or cause death in them. 
Preeclampsia is a complication in pregnancy in which the woman develops hypertension and starts 
excreting larger amount of protein in her urine and it usually starts after the pregnancy is at least 20 
weeks. Intrauterine growth restriction is a condition in which a baby does not grow at the expected 
rate while in the womb, that is, the growth of the baby is abnormally slow. The risk of these 
complications is more in women with sickle cell disease because of the underlying problems 
associated with sickle cell disease. Low dose aspirin, which is safe in pregnancy have been tried in 
pregnant women who do not have sickle cell disease to reduce the risk of these complications and 
they have been found to be beneficial. For this reason we have decided to conduct this trial in 
pregnant women with sickle cell disease to ascertain if it will be worthwhile to use this medication in 
preventing preeclampsia, intrauterine growth restriction and other complications. You are invited to 
participate in this research because you have been confirmed to have sickle cell disease and 
currently pregnant. 
PURPOSE OF THE RESEARCH: 
       This study is to determine if low dose aspirin will be beneficial 
in preventing preeclampsia, intrauterine growth restriction and other complications in pregnant 
women with sickle cell disease. 

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PROCEDURE OF THE RESEARCH: 
The research involves obtaining information from you directly by 
asking certain questions and using your answers to complete a proforma designed for this study. This 
initial assessment will take approximately 10 minutes of your time. We will also retrieve additional 
information from your case note where necessary. Subsequently 4mls of blood sample will be drawn 
from your vein at your first antenatal visit and sent to the laboratory for full blood count assessment 
and confirmation of your genotype and your haemoglobin fraction. Your urine specimen will also 
be collected for urinalysis and urine culture to rule out infection. These tests will be repeated after 
you have delivered. You will be followed up until you deliver. We will update your records each time 
you come for your antenatal clinic and also take your blood for haemoglobin concentration to 
know your blood level and your urine to know if there is protein or glucose in it. We will also follow up 
whenever you are on admission to monitor your progress and update your records. 
POTENTIAL BENEFITS: By participating in this study, you will have the opportunity of having some of 
your investigations, the test drugs and your routine drugs free at no cost to you all through 
pregnancy. You will have the opportunity of enjoying one-on-one contact with your health care 
providers as phone numbers will be exchanged. You will have the benefits of getting regular 
reminders of your appointments either via phone calls or text messages in order to minimize you 
missing antenatal visits. Generally, you will enjoy a closer monitoring of your health all through 
pregnancy and delivery until discharge from the hospital. The result of this research might enable us 
review our current protocol for management of sickle cell pregnancy, in order to reduce the rate of 
pregnancy complications. The findings will be presented at a conference in order to disseminate 
the findings to other health workers. The findings of this study will be published in a reputable journal 
for wider dissemination of information. 
POTENTIAL RISKS: 
This study involves filling a questionnaire designed for the study and collection 
of blood specimen from your veins using a syringe and needle only. Therefore the harm it poses to 
participants is minimal. The trial drugs are well known and have been found to be safe in pregnancy. 
Call the investigators immediately (see contact details at the end of this pamphlet) if you notice 
any delay in stopping bleeding from minor cuts or pain in your upper tommy, asthma-like symptoms 
such as difficulty in breathing. 
CONFIDENTIALITY: 
All information obtained in this study will be kept strictly confidential by the 
principal investigators. The blood specimen collected will also be labelled using the code assigned 
to each participant only to conceal the identity from the laboratory scientists. The principal 
investigator will have the key to the codes and will use them in tracking records when necessary. All 

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data will be stored in an electronic database which will be in the possession of the principal 
investigator until analyzed. 
WILLINGNESS TO PARTICIPATE: Your participation in this research is entirely voluntary and if you 
choose not to participate, no punishment will be attached to your decision. You will not be paid 
any fees for participating in this research. You can choose to withdraw from the research at any 
time. 
WHAT HAPPENS TO RESEARCH PARTICIPANTS AND COMMUNITY WHEN THE RESEARCH IS OVER: 
The 
researcher will inform you of the outcome of the research if you so wish. There is no conflict of interest 
whatsoever. 
 
For further enquiry, please contact: 
 
Principal Investigator Contact:  
Prof. Bosede B. Afolabi                                 
Mobile Contact: +2348023154064 
E-mail: bbafolabi@unilag.edu.ng 
Dept. of Obstetrics and Gynaecology, 
College of Medicine, University of Lagos/ 
Lagos University Teaching Hospital, 
Idi-Araba, Lagos 
 
 
 
 
Thank you for participating in this research. 
 
 

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REPLACE WITH STUDY SITE NAME 
INFORMED CONSENT FORM 
STATEMENT OF PERSON GIVING INFORMED CONSENT: 
I have read the description of the research. I understand that my participation is voluntary. I know 
enough about the purpose, methods, risk and benefits of the research to judge that I want to take 
part in it. I give consent for the following to be done on me: 
Tick which is applicable 
[     ] 
All information concerning my health and pregnancy to be collected by the investigator 
[     ] 
My blood samples to be taken for various tests relating to this research 
[     ] 
My urine samples to be collected for tests relating to this research 
[     ] 
The whole placenta to be collected and sent for testing (histology) 
[     ] 
Only a little portion of my baby’s placenta to be collected for testing (histology) 
[     ] 
I am not willing to release any portion of the placenta for testing (histology) 
I understand that I may freely stop being part of the study at any time. I have received a copy of 
this consent form to keep for myself. 
Name of (print legal name): …………………………………………………………………….. 
Signature: …………………………………………………………………              Thumb Print 
Date of signature: ……………………………………………………………. 
Study ID/ Hospital Number: …………………………………………  
 
Witness Name: …………………………………………………….. 
Signature: …………………………………  
Date: …………………………….. 
 
 

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STATEMENT OF PRINCIPAL INVESTIGATOR (OR DESIGNEE): 
I have fully explained this research to the respondent and given sufficient information, including the 
risk and benefit to make an informed decision. 
Name: ……………………………………………….. 
 
Title: ……………………………………………………… 
 
Signature: …………………………………………………… 
 
Date of Signature: …………………………………………. 
 
 
Thank you for participating in this research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 04 
 
PATIENT LOCATOR FORM 
 
 
DATE __________________                                           INTERVIEWER Initial______________ 
 
STUDY ID# ____________ 
 
On this form we collect information that will help us reach you when it’s time for your follow-up visit. The 
information you give us will be kept in a separate and secured place from health records. 
It will be used only to locate you for your follow-up if you persistently miss your appointment, and it will not be 
given to anyone else. We will not tell any contact anything except that you are participating in a health study. 
 
1. Full name:_____________________________________________       (_______________) 
                                                   First                        Middle                         Last                                                   (Maiden) 
 
2. Other names or nicknames: ______________________________________________ 
 
3. Where were you born? _____________________________________    (City, State) 
 
4. Residence address: ___________________________________________________________ 
___________________________________________________________________________ 
                                                          (Apartment#, Street address, Major Landmark) 
___________________________________________________________________________ 
(City)                                                                         (State) 
 
5. How long have you lived there? _______________________________ 
 
6. Do you plan to move anytime soon?     Yes                     No 
 
7. Do you know where to? _______________________________________________________ 
 
8. Who else lives there? 
 
a. Full Name: _______________________________________Relationship______________ 
 
Phone no: _______________________ 
  
b. Full Name: ___________________________________  Relationship_______________ 
 
Phone no: ______________________ 
 
9. What is your own Home Phone Nos: (i)____________________; (ii)____________________ 
 
10. Your Mobile Phone Nos: (i)____________________; (ii)____________________ 
 
11. Your Work phone No: _____________________  

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12. Work Address & Company name: ___________________________; ___________________ 
 
13. Your e-mail address: _________________________________ 
 
14.  Best Contacts: Do you have friends or relatives who usually know how to reach you if you should move or leave 
the program? 
(1) Full Name: __________________________________________________ 
                                            (First,                                Middle,                                             Last) 
Address: ______________________________________________________________ 
Phone No: _____________________________________ Relationship: _________________ 
E-mail address: ______________________________________ 
Work phone No: _____________________________ Name of Company __________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 05 
PIPSICKLE TRIAL 
ENROLLMENT LOG 
 
 
 
 
 
S/N 
Enrollmen
t Date  
Study ID 
Randomization 
Code 
                            Name 
Hospital  
Number 
Phone No 
Next 
Appointment 
Date 
1.  
 
 
 
 
 
 
2.  
 
 
 
 
 
 
3.  
 
 
 
 
 
 
4.  
 
 
 
 
 
 
5.  
 
 
 
 
 
 
6.  
 
 
 
 
 
 
7.  
 
 
 
 
 
 
8.  
 
 
 
 
 
 
9.  
 
 
 
 
 
 
10  
 
 
 
 
 
 
11  
 
 
 
 
 
 
12  
 
 
 
 
 
 
13  
 
 
 
 
 
 

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APPENDIX 06 – e-ENROLLMENT 
 
Confidential 
 
Enrollment 
 
 
PIPSICKLE 
 
Page 1 
 
 
 
 
Record ID 
 
__________________________________ 
 
 
Study Site 
 
__________________________________ 
 
 
SECTION A: GENERAL INFORMATION 
 
 
Date of Enrollment 
 
__________________________________ 
 
 
Study ID 
 
__________________________________ 
 
 
Randomization Code 
 
__________________________________ 
 
 
Hospital Number 
 
__________________________________ 
 
 
Patient Name 
 

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__________________________________ 
 
(First Name) 
 
__________________________________ 
 
(Middle Name) 
 
__________________________________ 
 
(Surname) 
Date of Birth 
__________________________________ 
 
(Best Estimate) 
Age 
__________________________________ 
Marital Status 
Married 
Single 
Widow 
Divorced 
Separated 
 
Cohabiting 
Phone Number 
__________________________________ 
Phone Number of Husband/Partner 
__________________________________ 
 
 
 
 
 
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Phone Number of Other Close Relative 
 
__________________________________ 
 
 
Place of Residence 
Urban 
Rural 
Address 
 
__________________________________________ 
Landmark 
__________________________________ 
 
(Nearest Popular Landmark) 
Ethnicity 
Hausa 
Igbo 
Yoruba 
 
Others 
 
 
Others 
 
 
__________________________________ 
Highest Level of Education 
No formal education 
Completed Primary 
Completed Secondary 
Completed Tertiary 
 
Postgraduate 
Occupation 
Unemployed 
Self-Employed 
Government Employment 
 
Private Employment 
Estimated Monthly Income 
Less than N20,000 
N21, 000 - N50,000 
N51, 000 - N100,000 
N101, 000 - N200,000 
 
GREATER THAN N200,000 

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Haemoglobin Genotype 
Hb SS 
Hb SC 
 
 
SECTION B: OBSTETRIC HISTORY 
 
 
 
 
 
No. of Pregnancies 
 
__________________________________ 
 
 
Parity 
 
__________________________________ 
 
 
No. of Miscarriages 
 
__________________________________ 
(including VTOP & Ectopic) 
 
 
No. of Children Alive 
 
__________________________________ 
 
 
 
 
 
 
 
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Last Menstrual Period 
 
__________________________________ 
 
 
Last Menstrual Period Given?                               
 By Known Date  
 By Scan Date 
 
 
Expected Delivery Date 
 
__________________________________ 
 
 
Estimated Gestational Age at booking by LMP 
 
 
__________________________________ 
 
(weeks) 
 
 
 
__________________________________ 
 
(days) 
 
 
SECTION C: HISTORY OF CHRONIC MEDICAL CONDITION 
 
 
Have you been diagnosed as having diabetes? 
Yes 
No 
Don't Know 
Have you been diagnosed as being HIV positive? 
Yes 
No 
Don't Know 
Have you been diagnosed as having hypertension? 
Yes 
No 
Don't Know 
Have you been diagnosed as having renal disease? 
Yes 
No 
Don't Know 

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Have you been diagnosed as having sickle cell 
Yes 
No 
Don't Know 
nephropathy? 
Do you have any other chronic medical condition? 
Yes 
No 
Specify 
 
 
__________________________________________ 
 
(Other Medical Conditions) 
 
 
SECTION D: DRUG USE AND ALLERGY HISTORY 
 
 
Do you react to aspirin? 
Yes 
No 
What is the nature of reaction? 
 
__________________________________________ 
Do you have Penicillin Allergy? 
Yes 
No 
What is the nature of reaction? 
 
__________________________________________ 
 
 
 
 
 
 
 
 
 
 
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Are you on any of the following drugs? 
None 
Paludrine 
Hydroxyurea 
Folic Acid 
Penicillin V 
Multivitamin 
Ciklavit 
Astymin 
Jobelyn 
Vitamin B 
Vitamin C 
 
Others 
 
 
Other Drugs 
 
__________________________________ 
 
 
SECTION E: PHYSICAL EXAMINATIONS 
 
 
Weight 
 
__________________________________ 
(kg - 2 Decimal Places) 
 
 
Weight 
 
__________________________________ 
(g) 
 
 
Height 
 
__________________________________ 
(cm - 2 decimal places) 

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BMI 
 
__________________________________ 
 
 
Fundal Height 
 
__________________________________ 
(corresponding to week size) 
 
 
BP 
 
 
__________________________________ 
 
(Systolic) 
 
 
 
__________________________________ 
 
(Diastolic) 
 
 
Pulse Rate 
 
__________________________________ 
 
 
Pulse Oximetry (SpO2) 
 
__________________________________ 
(%) 
 
 
Respiratory Rate 
 
__________________________________ 
 
 
 
 
 

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Temperature 
 
__________________________________ 
 
 
LABORATORY 
 
 
Sample for Haemoglobin Fraction Taken                      
 Yes  
 No 
 
 
Sample for Full Blood Count                                
 Yes  
 No 
 
 
Haemoglobin Level (At Today Visit) 
 
__________________________________ 
(g) 
 
 
URINALYSIS TODAY 
 
 
Leukocyte 
- 
±
+ 
++ 
 
+++ 
Nitrite 
- 
±
+ 
Urobilinogen 
Negative 
Positive 
Protein 
- 
±
+ 
++ 
 
+++ 
++++ 
Random Urine Sample Sent for UPCR 
Yes 
No 
pH 
__________________________________ 
Blood 
Negative 
Positive 
Specific Gravity 
__________________________________ 

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Ketones 
Negative 
Positive 
Bilirubin 
Negative 
Positive 
Glucose 
- 
±
+ 
++ 
 
+++ 
++++ 
 
 
ULTRASOUND 
 
 
Date of Result 
 
__________________________________ 
 
 
Ultrasound Report 
 
__________________________________________ 
 
 
Ultrasound result 
 
 
 
 
 
 
 
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STUDY DRUG 
 
 
Patient Given Study Drug?                                 
 Yes  
 No 
 
 
Name of Clinician 
 
__________________________________ 

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APPENDIX 07 e-follow up visit 
 
Confidential 
 
Visit 
 
 
PIPSICKLE 
 
Page 1 
 
 
 
 
Record ID 
 
__________________________________ 
 
 
Date of Follow-up Visit 
 
__________________________________ 
 
 
 
__________________________________ 
 
 
Gestational Age at FollowUp Visit 
 
 
 
__________________________________ 
 
(weeks) 
 
__________________________________ 
 
(days) 
FollowUp Visit Type 
Scheduled 
Unscheduled 
Reason for Unscheduled Follow-Up Visit 
Sickle Cell Crisis 
Pregnancy Complications 
Adverse Event Report 

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Others 
Sickle Cell Crisis 
Vaso-occlusive 
 
 Haemolytic 
 Sequestration 
 Acute Chest Syndrome (ACS) 
 Anaemia/Haemolytic 
 Others 
(Specify) 
 
 
Others 
 
__________________________________ 
 
 
Pregnancy Complications 
 
__________________________________________ 
 
(Specify) 
 
 
Other Reason for Unscheduled Followup 
 
__________________________________ 
(please specify) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ADVERSE EVENTS REPORT 
 
 
Is there an Adverse Event (AE)? 
Yes 
No 
Adverse Event (AE) - 1 
__________________________________ 
 
(Brief description of the nature of AE) 
Start Date 
__________________________________ 
 
(dd-mm-yyyy) 
Stop Date 
__________________________________ 
 
(dd-mm-yyyy) 
Severity 
Mild 
Moderate 
Severe (SAE) 
Category of AE 
Life Threatening 
Hospitalization 
Congenital anomaly 
Required intervention to prevent permanent 
impairment 
Persistent Disability / Incapacity 
 
Other 
Other (Category of AE) 
__________________________________ 
Relationship of AE to Study Drug 
Unrelated 
Possibly Related 
Probably Related 

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Definitely Related 
Action Taken 
No action taken (i.e. further observation only) 
Study drug dosage adjusted/temporarily interrupted 
Study drug permanently discontinued due to this 
adverse event 
Concomitant medication given 
Non-drug therapy given 
Patient hospitalized/patient's hospitalization 
 
prolonged 
Add Another Adverse Event (AE)? 
Yes 
No 
Adverse Event (AE) - 2 
__________________________________ 
 
(Brief description of the nature of AE) 
 
 
Start Date 
 
__________________________________ 
(dd-mm-yyyy) 
 
 
Stop Date 
 
__________________________________ 
(dd-mm-yyyy) 
 
 
 
 
 
 
 
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Severity 
Mild 
Moderate 
Severe (SAE) 
Category of AE 
Life Threatening 
Hospitalization 
Congenital anomaly 
Required intervention to prevent permanent 
impairment 
Persistent Disability / Incapacity 
 
Other 
Other (Category of AE) 
__________________________________ 
Relationship of AE to Study 
Unrelated 
Possibly Related 
Probably Related 
 
Definitely Related 
Action Taken 
No action taken (i.e. further observation only) 
Study drug dosage adjusted/temporarily interrupted 
Study drug permanently discontinued due to this 
adverse event 
Concomitant medication given 
Non-drug therapy given 
Patient hospitalized/patient's hospitalization 
 
prolonged 
Add Another Adverse Event (AE)? 
Yes 
No 
Adverse Event (AE) - 3 
__________________________________ 
 
(Brief description of the nature of AE) 

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Start Date 
__________________________________ 
 
(dd-mm-yyyy) 
Stop Date 
__________________________________ 
 
(dd-mm-yyyy) 
Severity 
Mild 
Moderate 
Severe (SAE) 
Category of AE 
Life Threatening 
Hospitalization 
Congenital anomaly 
Required intervention to prevent permanent 
impairment 
Persistent Disability / Incapacity 
 
Other 
Other (Category of AE) 
__________________________________ 
Relationship of AE to Study Drug 
Unrelated 
 
Possibly Related 
 
 Probably Related 
 Definitely Related 
 
 
 
 
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Action Taken 
No action taken (i.e. further observation only) 
Study drug dosage adjusted/temporarily interrupted 
Study drug permanently discontinued due to this 
adverse event 
Concomitant medication given 
Non-drug therapy given 
Patient hospitalized/patient's hospitalization 
 
prolonged 
Any Admission since last visit? 
Yes 
No 
if yes: Specify reason 
__________________________________ 
Duration 
__________________________________ 
 
Day(s) 
Week(s) 
 
Month(s) 
Have you had blood transfusion since last visit? 
Yes 
No 
Date of blood transfusion? 
__________________________________ 
How many units of blood? 
__________________________________ 
Are you on any of the following drugs? 
None 
Paludrine 
Hydroxyurea 
Folic Acid 
Penicillin V 

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Multivitamin 
 
 Ciklavit 
 
 Astymin 
 
 Jobelyn 
 
 Vitamin B 
 
 Vitamin C 
 
 Others 
 
 
Others 
 
__________________________________ 
 
 
PHYSICAL EXAMINATIONS 
 
 
Weight 
 
__________________________________ 
(kg - 2 Decimal Places) 
 
 
Weight 
 
__________________________________ 
(g) 
 
 
Fundal Height 
 
__________________________________ 
(corresponding to week size) 
 
 
 
 
 
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BP 
 
 
 
__________________________________ 
 
(Systolic) 
 
__________________________________ 
 
(Diastolic) 
Pulse Rate 
__________________________________ 
Pulse Oximetry (SpO2) 
__________________________________ 
Respiratory Rate 
__________________________________ 
Temperature 
__________________________________ 
LABORATORY 
Haemoglobin Level (At Today Visit) 
__________________________________ 
 
(g) 
Urinalysis Today 
Leukocyte 
- 
±
+ 
++ 
 
+++ 
Nitrite 
- 
±
+ 
Urobilinogen 
Negative 
Positive 
Protein 
- 
±
+ 
++ 
 
+++ 
++++ 
Random Urine Sample Sent for UPCR 
Yes 
No 
pH 
__________________________________ 

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Blood 
Negative 
Positive 
Specific Gravity 
__________________________________ 
Ketones 
Negative 
Positive 
Bilirubin 
Negative 
Positive 
 
 
 
 
 
 
 
 
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Glucose 
 -  
 ±  
 +  
 ++ 
 
 +++  
 ++++ 
 
 
Full Blood Count 
 
 
Date of Full Blood Count Result 
 
__________________________________ 
 
 
PCV 
__________________________________ 
 
(%) 
Haemoglobin 
__________________________________ 
 
(g/dl) 
Total WBC 
__________________________________ 
 
(cells/ml) 
Neutrophils 
__________________________________ 
 
(%) 
Lymphocytes 
__________________________________ 
 
(%) 
Basophils 
__________________________________ 
 
(%) 

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Eosinophils 
__________________________________ 
Monocytes 
__________________________________ 
 
(%) 
Platelet Count 
__________________________________ 
 
(cells/ml) 
FBC Result 
Is Urine M/C/S Result Available? 
Yes 
No 
Urine M/C/S Result Date 
__________________________________ 
 
 
Urine M/C/S Result 
 
__________________________________________ 
 
 
 
 
 
 
 
 
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Haemoglobin Fraction 
 
 
Date of Haemoglobin Fraction 
 
__________________________________ 
 
 
 Hb S 
 
 
 Hb F 
 
 Hb A2 
 
 Hb A1C 
 
 Hb C 
 
 Other 
 
 
Hb S 
 
__________________________________ 
 
 
Hb F 
 
__________________________________ 
 
 
Hb A2 
 
__________________________________ 
 
 
Hb A1C 
 
__________________________________ 
 
 
Hb C 
 

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__________________________________ 
 
 
Hb Other 
 
__________________________________ 
 
 
Haemoglobin Fraction Result 
 
 
Date UPCR Done 
 
__________________________________ 
 
 
UPCR Result 
 
__________________________________ 
(Last Sample Collected) 
 
 
ULTRASOUND 
 
 
Date of Ultrasound Result 
 
__________________________________ 
 
 
Ultrasound Report 
 
__________________________________________ 
 
 
Ultrasound Result 
 
 
Clinical Plan                                             
 Stable continue present management 
 
 
 Change in clinical plan 
 
 Change in other co-medication 
 
 Additional Medication or Discontinuation 
 

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 Others 
 
 
 

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Confidential 
 
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Change in Clinical Plan 
 
 
__________________________________________ 
 
(Specify) 
Change in Medication 
 
__________________________________________ 
 
(Specify) 
Additional Medication or Discontinuation 
 
__________________________________________ 
 
(Specify) 
Other 
__________________________________ 
Referrals Made 
None 
Hospitalization 
Blood Transfusion 
Nutritional Support 
Psychosocial counseling 
Social support 
 
Other 
Other 
__________________________________ 
 
 
STUDY DRUG 
 
 
Patient Given Study Drugs?                                 
 Yes  
 No 
 
 

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Pill Count from Last Visit 
 
__________________________________ 
(Pill Remaining) 
 
 
Study Drug Adherence (Since Last Visit) 
 
__________________________________ 
(%) 
 
 
Name of Clinician 
 
_________________________________

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APPENDIX 08 – e-Delivery 
 
Confidential 
 
Delivery 
 
 
 
PIP-SICKLE 
 
Page 1 
 
 
 
 
Record ID 
 
 
__________________________________ 
Pregnancy Outcome 
Miscarriage 
Pre-term Delivery 
 
Term Delivery 
Date of Miscarriage / Delivery 
__________________________________ 
 
 
Gestation Age at Miscarriage / Delivery 
 
 
 
__________________________________ 
 
__________________________________ 
 
(weeks) 
 
__________________________________ 
 
(days) 
 
BABY'S CONDITION AT BIRTH 
Foetal Outcome 
Alive 
Still Born 
Early Neonatal Death - Within 7 days of birth 
NNU Admission after 24 hrs Initial Observation 
 
Congenital Abnormality 

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Indication for Admission / Diagnosis 
 
__________________________________________ 
Congenital Abnormality 
(Describe or Diagnosis) 
__________________________________________ 
Baby's Birth Weight 
__________________________________ 
 
(g) 
Head Circumference 
__________________________________ 
 
(cm - 2 decimal places) 
Baby's Length 
__________________________________ 
 
(cm - 2 decimal places) 
 
 
 
 
 
 
 
 
 
 
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Apgar Score 
 
 
 
__________________________________ 
 
(at 1 minute) 
 
__________________________________ 
 
(at 5 minutes) 
 
__________________________________ 
 
(at 10 minutes) 
 
MATERNAL CONDITION AT MISCARRIAGE / DELIVERY 
Maternal Complications 
Pre-Eclampsia 
Eclampsia 
Sepsis 
Pneumonia 
Sickle Cell Crisis 
Maternal Death 
 
Others 
Others 
 
__________________________________________ 
 
(Specify) 
Sickle Cell Crisis 
Vaso-occlusive 
Haemolytic 
Sequestration 
Acute Chest Syndrome (ACS) 
Severe Anaemia 
 
Others 

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Others 
 
__________________________________________ 
 
(Specify) 
Estimated Blood Loss 
< 500 ml 
500 - 1000 ml 
 
> 1000 ml 
 
 
Mother Physical Examination Within 1 Hour of Delivery 
 
 
Maternal Weight 
 
__________________________________ 
(kg - 2 Decimal Places) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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BP 
 
 
 
__________________________________ 
 
(Systolic) 
 
__________________________________ 
 
(Diastolic) 
Pulse Rate 
__________________________________ 
Pulse Oximetry (SpO2) 
__________________________________ 
Respiratory Rate 
__________________________________ 
Temperature 
__________________________________ 
LABORATORY 
Haemoglobin Level 
__________________________________ 
 
(At Today Visit) 
Urinalysis Today 
Leukocyte 
- 
±
+ 
++ 
 
+++ 
Nitrite 
- 
±
+ 
Urobilinogen 
Negative 
Positive 
Protein 
- 
±
+ 
++ 
 
+++ 
++++ 
Random Urine Sample Sent for UPCR 
Yes 
No 
pH 
__________________________________ 

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Blood 
Negative 
Positive 
Specific Gravity 
__________________________________ 
Ketones 
Negative 
Positive 
Bilirubin 
Negative 
Positive 
 
 
 
 
 
 
 
 
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Full Blood Count 
 
 
Sample Taken for FBC                                     
 Yes  
 No 
 
 
PCV 
 
__________________________________ 
(%) 
 
 
Haemoglobin 
 
__________________________________ 
(g/dl) 
 
 
Total WBC 
 
__________________________________ 
(cells/ml) 
 
 
Neutrophils 
 
__________________________________ 
(%) 
 
 
Lymphocytes 
 
__________________________________ 
(%) 
 
 
Basophils 
 
__________________________________ 
(%) 
 

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Eosinophils 
 
__________________________________ 
 
 
Monocytes 
 
__________________________________ 
(%) 
 
 
Platelet Count 
 
__________________________________ 
(cells/ml) 
 
 
Full Blood Count Result 
 
 
Name of Clinician 
 
_________________________________

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APPENDIX 09 – e-End of study 
 
Confidential 
 
End of Study 
 
 
 
PIP-SICKLE 
 
Page 1 
 
 
 
 
Record ID 
 
 
__________________________________ 
Please enter the date this form is completed 
__________________________________ 
End of Study Category 
Normal 
Withdraw 
Death 
 
LTFU 
Date of death 
__________________________________ 
Cause of Death 
 
__________________________________________ 
 
__________________________________ 
Gestational Age At Death 
__________________________________ 
 
(weeks) 
 
__________________________________ 
 
(days) 
Outcome of Severe Adverse Event (SAE) 
Never had SAE 
SAE Resolved 

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Recovered with minor sequelae 
Recovered with major sequelae 
Ongoing treatment 
Condition worsening 
Death 
 
Unknown 
 

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APPENDIX 09 – DRUG ACCOUNTABILITY FORM 
 
  
 
 
PIPSICKLE TRIAL 
INVESTIGATIONAL DRUG ACCOUNTABILITY RECORD 
 
 
RC- Randomisation code   E= Enrollment    F- Follow-up  
 
 
 
 
 
 
 
 
 
 
 
 
 
Study site Name:   
 Site Code:  
Total Quantity Received/Date:  
(including Replacement kits) 
 Site Investigator:  
Test Drug:  
 Study Title: 
Batch No.    : 
Mfg Date     : 
Expiry Date :  
Subject 
initials 
Subject 
ID 
Drug Kit 
Number/
RC 
Visit 
type 
(E or F) 
Date 
dispense
d 
Dispensed 
By/Initials 
Date 
Returne
d 
Amount of 
Drug 
present 
Site 
personnel 
Signature 
CRA/Monito
r Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 11– SAE REPORT FORM 
SEVERE ADVERSE EVENT (SAE) REPORT FORM  
 
STUDY TITLE 
Low dose aspirin for preventing intrauterine growth restriction and preeclampsia in sickle cell 
pregnancy (PIPSICKLE): a randomised controlled trial. 
Site No. 
 
SITE Name 
 
PATIENT ID 
 
DATE OF REPORT 
dd-mm-yyyy 
 
1. 
SAE Date of 
Onset: 
dd-mm-yyyy 
2. 
SAE Date 
Stopped: 
dd-mm-yyyy 
3. 
Location of SAE: 
 
4. 
Was this an unexpected adverse 
event?   
☐ Yes     ☐ No 
5. 
Brief 
description of 
participants 
(do not 
include 
personal 
identifiers): 
Age 
 
Diagnosis  
for study participation 
 
6. 
Brief 
description of 
the nature of 
the SAE: 
 
attach description, 
 if applicable 
 
7. 
Category  
of SAE: 
☐  Date of Death: 
dd-mm-yyyy 
☐ Life threatening 
☐ Congenital anomaly, birth defects 
☐ Life threatening 
☐ Required intervention to prevent impairment 
(permanent) 
☐ Hospitalization 
☐ Disability 

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☐ Other:  
 
 
8. 
Describe 
study 
intervention 
 
9. 
Relationship of event to intervention: 
☐ Unrelated 
☐ Possible 
☐ Definite 
10. 
Was the study intervention discontinued due to 
the event? 
☐ Yes          ☐ No 
11. 
What steps 
were taken 
to treat the 
SAE? 
 
12. 
List relevant 
tests, lab 
data, 
history, and 
pre-existing 
medical 
conditions: 
 
13. 
Report 
type: 
☐ Initial 
☐ Follow-up 
☐ Final 
 
 
 
Print Name of Site Investigator 
 
 
Signature of Principal Investigator 
Date 
 
 
Print Name of Principal Investigator 

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Signature of Principal Investigator 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 12 – STUDY MONITORING LOG 
PIPSICKLE TRIAL STUDY INITIATION CHECKLIST 
 
 
List personnel in attendance from site, below. Attach attendance sheet. 
NAME, TITLE 
ROLE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY TITLE 
Low dose aspirin for preventing intrauterine growth restriction 
and preeclampsia in sickle cell pregnancy (PIPSICKLE): a 
randomised controlled trial. 
SITE NAME ; CODE 
 
SITE INVESTIGATOR 
 
MONITOR NAME 
 
DATE OF VISIT 
 
METHOD OF VISIT 
 
 ☐ On-Site 
 ☐ Teleconference 
 ☐ Other, specify: 
 
 
 
 

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Verify each document or activity required below. Attach any supporting documentation. 
NO. 
DOCUMENT OR ACTIVITY 
(DISCUSSED/VERIFIED) 
YES 
NO 
N/A 
COMMENTS 
1 
Staff CVs signed/dated 
☐ 
☐ 
☐ 
 
2 
Staff trained on protocol 
☐ 
☐ 
☐ 
 
3 
Staff read investigator brochure 
for product 
☐ 
☐ 
☐ 
 
4 
Check required number of forms 
delivered to site (i.e. consent 
forms, case forms). 
☐ 
☐ 
☐ 
 
5 
PI and site have agreed to study 
contract and budget. 
☐ 
☐ 
☐ 
 
6 
HREC/IRB approval 
granted/renewed for study. 
☐ 
☐ 
☐ 
 
7 
Staffing allocation complete.  
☐ 
☐ 
☐ 
 
8 
Specific staff responsibilities 
discussed with staff 
☐ 
☐ 
☐ 
 
9 
Required facilities are 
available/functional. 
☐ 
☐ 
☐ 
 
10 
Study drugs stored appropriately. 
☐ 
☐ 
☐ 
 
11 
Materials/equipment for study 
available/received. 
☐ 
☐ 
☐ 
 
12 
Materials/equipment for study 
stored and maintained 
appropriately 
☐ 
☐ 
☐ 
 
13 
Investigator’s file prepared and 
maintained 
☐ 
☐ 
☐ 
 
14 
Final contract and budget signed 
and filed.  
☐ 
☐ 
☐ 
 
15 
e-case forms available (if 
applicable) 
☐ 
☐ 
☐ 
 
16 
Drug shipment received (if 
applicable) 
☐ 
☐ 
☐ 
 
 

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NO. 
DOCUMENT OR ACTIVITY 
(DISCUSSED/VERIFIED) 
YES 
NO 
N/A 
COMMENTS 
 
17 
Other supplies received (if 
applicable) 
☐ 
☐ 
☐ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Monitor (Print) 
 
 
Monitor Signature          
Date 
 
 
 
 
 
Name of Principal Investigator (Print) 
 
 
Principal Investigator Signature          
Date 

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APPENDIX 13-   
 
PROTOCOL DEVIATION TRACKING LOG 
 
  
NO. 
SUBJECT ID 
NO. 
DEVIATION  
DATE 
DEVIATION DESCRIPTION 
DEVIATION REASON 
AND CORRECTIVE 
MEASURES 
IRB / IEC 
NOTIFICATION  
Yes / No 
INVESTIGATOR 
INITIALS  
INVESTIGATION 
DATE 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 

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PIPSICKLE 
Pg _ of _