Pharmacokinetics of Apixaban in Subjects With End-stage Renal Disease Treated With Peritoneal Dialysis: the ApiDP Study
Phase: PHASE1
Conditions: Chronic Renal Insufficiency, Peritoneal Dialysis
Sponsor: University Hospital, Caen

Interventional Research (Medicinal Product) 
TITLE 
Pharmacokinetics of apixaban in subjects with end-stage renal disease treated with 
peritoneal dialysis 
 
STUDY SPONSOR 
Avenue de la Côte de Nacre 
14033 CAEN CEDEX 
France 
Tel: +33 (0)2 31 06 57 81 
 
COORDINATING INVESTIGATOR 
Dr Maxence FICHEUX 
Department of Nephrology 
University Center for Kidney Disease 
CHU Caen Normandie 
Tel: +33 (0)2 31 20 26 / Fax: +33 (0)2 31 06 50 68 
Email: ficheux-m@chu-caen.fr 
 
SCIENTIFIC LEAD 
Dr Laure PEYRO SAINT PAUL 
Department of Clinical Research and Innovation 
CHU Caen Normandie 
Tel: +33 (0)2 31 06 53 42 / Fax: +33 (0)2 31 06 50 68 
Email: peyrosaintpaul-l@chu-caen.fr 
 
PROTOCOL VERSION HISTORY 
 
Initial version V03 – 24/07/2019 
 
Amended version V10 – 08/03/2022 
Substantial amendment: correction of a non-inclusion criterion concerning healthy 
volunteers 
 
Favorable opinion from Ethics Committee (CPP): 07/06/2019 
 
Authorization by ANSM: 24/05/2019 

Protocol Update History 
Summary of significant changes in the protocol ApiDP 
Version of the 
protocol 
Reason of modification
Date of Authorities 
autorisation 
2019-07-24
2019-07-18
2019-09-26
Accuracy of the time of taking the tablet
2019-12-17
2019-12-12
Removal of the T0 sample, redundant with the pre-
dose sample. 
2020-02-24
2020-11-30
Extension of the inclusion period (COVID-19)
2021-02-17
2021-04-21
Extension of the inclusion period (COVID-19)
2021-06-14
2021-06-15
Modify the time of tablet taking in healthy volunteers 
to avoid hospitalization 
2021-11-05
2021-12-17
SPC ELIQUIS update
2022-02-21
2022-03-08
glomerular filtration rate of healthy volunteers: 
decrease in the inclusion threshold 
2022-05-17
 
 
TABLE OF CONTENTS 
(structure preserved – translated headings available on request) 
 
1. GENERAL INFORMATION 
1.1 Regulatory Information 
 
Acronym: API-DP 
 
Title: Pharmacokinetics of apixaban in subjects with end-stage renal disease treated 
with peritoneal dialysis 
 
EudraCT number: 2019-001307-20 
 
CHU number: 19-060 
 
Approved protocol version: V10 – 08/03/2022 
 
 
 
2. PARTICIPATING INVESTIGATORS 
(table content translated faithfully; formatting can be adapted to Word/ICH template if 
needed) 
 
3. SCIENTIFIC TEAM 

 
Nephrology: Maxence Ficheux, Clémence Béchade, Thierry Lobbedez, Mélanie 
Hanoy 
 
Pharmacology: Danièle Debruyne, Laure Peyro Saint Paul, Joachim Alexandre, 
Sophie Fedrizzi, Alexandre Cesbron, Véronique Lelong-Boulouard 
 
Hematology: Marie-François Brionne 
 
4. INDEPENDENT DATA MONITORING COMMITTEE 
The Independent Data Monitoring Committee includes: 
 
A nephrologist specialized in peritoneal dialysis: Dr Courivaud (CHU Besançon) 
 
A pharmacologist specialized in pharmacokinetics: Dr Jean-Baptiste Woillard (CHU 
Limoges, INSERM U850) 
 
A cardiologist specialized in DOACs: Dr Guillaume Duthoit (Pitié-Salpêtrière 
Hospital, AP-HP, Paris) 
The committee will be consulted in the event of any new safety issue, particularly any serious 
adverse event, and will provide its opinion on the benefit–risk balance. 
 
5. ABBREVIATIONS 
 
ESRD: End-Stage Renal Disease 
 
PD: Peritoneal Dialysis 
 
CAPD: Continuous Ambulatory Peritoneal Dialysis 
 
APD: Automated Peritoneal Dialysis 
 
DOAC: Direct Oral Anticoagulant 
 
ISPD: International Society of Peritoneal Dialysis 
 
VKA: Vitamin K Antagonist 
 
6. STUDY SYNOPSIS 
Study title: Pharmacokinetics of apixaban in subjects with end-stage renal disease treated 
with peritoneal dialysis 
Study type: Phase I pharmacokinetic study 
Sponsor: CHU Caen Normandie 
Population: 
 
ESRD subjects treated with peritoneal dialysis without indication for apixaban 
 
Healthy subjects with normal renal function 

Primary Objective 
To compare pharmacokinetic parameters (Cmax, AUC, half-life, total plasma clearance) 
between healthy subjects and ESRD subjects treated with peritoneal dialysis, in order to 
propose an appropriate dosing regimen for PD patients. 
Secondary Objectives 
 
To characterize renal and peritoneal clearance of apixaban in PD patients 
 
To compare pharmacodynamic parameters (anticoagulant activity) 
 
To assess apixaban tolerability 
 
7. ABSTRACT 
Direct oral anticoagulants (DOACs) include dabigatran, a direct thrombin inhibitor, and 
apixaban and rivaroxaban, which are factor Xa inhibitors. Several large randomized 
controlled trials have demonstrated that these agents are non-inferior to warfarin for stroke 
prevention in patients with atrial fibrillation. 
In dialysis patients, warfarin remains the recommended approach for stroke prevention. 
However, significant concerns exist regarding the use of vitamin K antagonists in peritoneal 
dialysis (PD) patients, including deterioration of residual renal function, vascular 
calcification, and the burden of INR monitoring. DOACs could represent an attractive 
alternative, yet they have not been studied in this population. 
Apixaban pharmacokinetics in PD patients have not yet been investigated. Since apixaban is 
partially renally excreted and poorly dialyzable, accumulation may occur in severe renal 
impairment. Currently, apixaban remains contraindicated in dialysis patients in Europe due to 
insufficient clinical experience. 
This study proposes to compare the pharmacokinetics of a single oral dose of 5 mg apixaban 
between 12 PD patients and 12 healthy subjects. Blood, urine (if residual diuresis), and 
peritoneal dialysis fluid samples will be collected over 72 hours. Coagulation parameters and 
anti-Xa activity will also be measured. 
The ultimate goal is to establish an appropriate dosing regimen for PD patients and to support 
future efficacy and safety studies. 
Keywords: apixaban – peritoneal dialysis – pharmacokinetics – DOACs 
8. SCIENTIFIC RATIONALE AND GENERAL 
DESCRIPTION OF THE STUDY 
Background 

While antithrombotic therapy is recommended for the primary prevention of stroke in patients 
with atrial fibrillation (AF), all clinical trials on which these recommendations are based have 
excluded patients treated with peritoneal dialysis (PD). 
Study Population 
Patients with end-stage renal disease (ESRD) treated with PD represent approximately 6.3% 
of the dialysis population. They constitute a niche population that is systematically 
underrepresented in clinical trials. This rare and high-risk population does not represent a 
priority target for pharmaceutical companies developing new drugs. 
In France, the National Health Insurance estimated the cost of chronic kidney disease at more 
than €4 billion, based on 61,000 patients receiving renal replacement therapy (dialysis and 
kidney transplantation), including approximately €200 million for around 3,700 patients 
currently treated with peritoneal dialysis. The human cost is particularly high in terms of 
morbidity and mortality, impact on patients’ quality of life, and consequences for caregivers 
and families. 
In patients with ESRD, atrial fibrillation has a higher prevalence than in the general 
population. ESRD patients treated with PD who have AF have a higher one-year mortality 
than those without AF and are at particularly high risk of stroke [1]. 
Clinical Recommendations 
The most recent 2015 recommendations from the International Society for Peritoneal Dialysis 
(ISPD) suggest the use of warfarin for stroke prevention in these patients and do not 
recommend direct oral anticoagulants (DOACs), due to the lack of data in PD patients, who 
have been systematically excluded from clinical trials [2]. 
Toxicity of Vitamin K Antagonists 
However, vitamin K antagonists (VKAs) may cause deterioration of renal function [3], 
whereas residual renal function is strongly associated with survival in PD patients. In 
addition, VKAs are suspected to promote vascular calcification in this population. Finally, 
DOACs could eliminate the need for INR monitoring in patients whose venous access is often 
compromised. DOACs could therefore represent an attractive alternative, which has not yet 
been studied in this population. 
Conflicting International Data in Renal Failure 
Currently, all DOACs are contraindicated in Europe in patients with a creatinine clearance 
<15 mL/min (dialysis or non-dialysis). However, apixaban has been approved by the U.S. 
Food and Drug Administration (FDA) for use in hemodialysis patients [4], based on a 
pharmacokinetic study comparing 8 hemodialysis patients with 8 subjects with normal renal 
function. In this study, the area under the plasma concentration–time curve (AUC₀–∞) of 
apixaban was increased by 36%. Despite this increase, the FDA recommends the standard 
dose of 5 mg twice daily [5]. A second pharmacokinetic study in 7 hemodialysis patients with 
chronic kidney disease recommended a reduced dose of 2.5 mg twice daily, having observed 
supratherapeutic plasma concentrations at the FDA-recommended dose [6]. 

Current Knowledge in Peritoneal Dialysis 
To our knowledge, no pharmacokinetic study of DOACs has been conducted in PD patients, 
nor has any such study been registered on ClinicalTrials.gov. Nephrologists are therefore 
awaiting data that would allow safe and controlled use of DOACs in this population. 
Very recently, while acknowledging that stroke prophylaxis in dialysis patients with atrial 
fibrillation remains an area of uncertainty, an expert consensus from a KDIGO Controversies 
Conference (2018) suggested that if dialysis patients require oral anticoagulation for atrial 
fibrillation, low-dose apixaban might be preferred over VKAs, based on observational study 
data [7]. 
Study Rationale 
We hypothesize that, compared with subjects with normal renal function, PD patients will 
exhibit altered pharmacokinetics due to the combination of reduced renal elimination and 
drug clearance through peritoneal dialysis, which differs from clearance by hemodialysis. 
The primary objective is to compare the pharmacokinetics of a single oral dose of 5 mg 
apixaban between ESRD patients treated with PD and subjects with normal renal function, in 
order to establish an appropriate dosing regimen for PD patients. 
All PD-treated subjects, whether receiving automated peritoneal dialysis (APD) or continuous 
ambulatory peritoneal dialysis (CAPD), will be managed exclusively with CAPD during the 
three-day hospitalization following apixaban administration. 
The results of this study are expected to: 
a) determine plasma pharmacokinetic parameters of apixaban in PD patients (AUC₀–∞, 
elimination half-life [T½], total plasma clearance [Cl]); 
b) determine renal and peritoneal clearance (urinary clearance, peritoneal clearance); 
c) ensure safety in both study groups through the administration of a single dose, thereby 
limiting toxic risk; 
d) predict drug accumulation in PD patients; 
e) propose an appropriate dosing regimen for this specific patient population. 
The results of this study would allow progression to future efficacy and safety studies in a 
larger population receiving a dose guided by the findings of the present study. 
 
9. STUDY OBJECTIVES 
9.1 Primary Objective 
 
To compare plasma pharmacokinetic parameters (Cmax, AUC, T½, and Cl) between 
subjects with normal renal function and ESRD subjects treated with peritoneal 
dialysis. 
9.2 Secondary Objectives 

 
To characterize residual renal clearance and peritoneal clearance in ESRD subjects 
treated with PD. 
 
To compare pharmacodynamic parameters (anticoagulant activity) between subjects 
with normal renal function and ESRD subjects treated with PD. 
 
To assess apixaban tolerability. 
 
10. EVALUATION CRITERIA 
10.1 Primary Endpoint 
 
Measurement of plasma apixaban concentrations at multiple time points until 
complete elimination of the drug: 
o Time zero (T0): prior to administration, to verify the absence of assay 
interference. 
o Blood sampling at T1h, T2h, T3h, T4h, T6h, T9h, T12h, T24h, T48h, and 
T72h. 
10.2 Secondary Endpoints 
 
Measurement of peritoneal and urinary apixaban concentrations at multiple time 
points until complete elimination: 
o 24-hour urine collection in all subjects for 3 consecutive days. 
o Dialysate samples in PD subjects, 4 times per day for 3 days (total of 12 
samples). 
 
Plasma measurements of anti-Xa activity, prothrombin time (PT), and activated partial 
thromboplastin time (aPTT) at T0, T3h, T9h, and T72h. 
 
Safety endpoint: systematic collection of adverse events of any grade (CTCAE v5.0) 
from the signing of informed consent until 72 hours post-dose, and beyond for any 
events potentially related to apixaban administration. 
 
11. STUDY METHODOLOGY 
The tested dose will be a single oral administration of 5 mg apixaban. 
To accelerate recruitment, the study will be conducted in two regional centers: CHU Caen 
Normandie and CHU Rouen. 
At CHU Caen Normandie 
Subjects Treated with Peritoneal Dialysis 
 
Screening visit: patients will be recruited by a nephrologist at CHU Caen Normandie; 
the visit will take place at the Clinical Research Center (CRC). 
 
Hospitalization from Day 0 to Day 3: patients will be hospitalized at the CRC in Caen. 
 
End-of-study visit: patients may be seen at the Clinical Investigation Unit (CUMR). 

Healthy Subjects 
 
Screening visit: healthy volunteers will be recruited and followed at the CRC in Caen 
by CRC physicians and matched by sex, age (±5 years), and body weight (±20%). 
 
Hospitalization on Day 0, follow-up visits for plasma sampling on Days 1, 2, and 3, 
and end-of-study visit at the CRC in Caen. 
At CHU Rouen 
Healthy Subjects 
 
Screening visit: healthy volunteers will be recruited and followed at the Clinical 
Investigation Center (CIC) in Rouen by CIC physicians and matched by sex, age (±5 
years), and body weight (±20%). 
 
Hospitalization on Day 0, follow-up visits for plasma sampling on Days 1, 2, and 3, 
and end-of-study visit at the CIC in Rouen. 
Study Discontinuation Rules 
The study will be immediately discontinued in the event of a serious adverse event potentially 
related to the study. After analysis, if no risk is ultimately identified, the study may resume 
following authorization from the competent authority. If a risk is identified, the study will be 
permanently discontinued. 
Criteria for Permanent Discontinuation of Subject Participation 
Subjects may withdraw from the study at any time and for any reason, or participation may be 
discontinued at the investigator’s discretion. 
Reasons for premature study withdrawal may include: 
 
Subject refusal to continue 
 
Withdrawal of consent 
 
Protocol violation requiring study withdrawal 
 
Severe toxicity 
 
Decision of the investigator 
 
Decision of the sponsor 
 
Participant non-compliance 
Follow-up Procedures for Withdrawn Subjects 
All withdrawals must be documented, and the investigator must specify the reason. The case 
report form will be completed up to the time of study withdrawal. 
In the event of premature study withdrawal, the investigative team will send the study 
withdrawal form to the Clinical Research Associate (ARC) of the CPRC (02 31 06 50 68). 
The following must be specified: 
 
Criteria and procedures for premature treatment discontinuation 

 
Criteria and procedures for exclusion or premature withdrawal from the study 
 
Medical management procedures in the event of premature treatment discontinuation 
 
Medical management procedures in the event of exclusion from the study 
 
Follow-up procedures for withdrawn subjects 
Consequences of Study Withdrawal 
Subjects will be considered evaluable only if they have participated through T72 on Day 3 of 
the study. 
Withdrawals occurring before T72 will be replaced. 
Management of Lost-to-Follow-Up Subjects 
In the event of loss to follow-up, the subject’s primary care physician, the municipality of 
residence, and the municipality of birth will be contacted. 
Description of Rules for Temporary or Permanent Discontinuation of All or 
Part of the Study 
The study will be discontinued in the event of an unfavorable benefit–risk balance during the 
trial, upon sponsor decision or at the request of the competent authorities. 
 
12. SELECTION AND EXCLUSION OF STUDY 
PARTICIPANTS 
Inclusion Criteria 
Subjects Treated with Peritoneal Dialysis 
 
Male or female aged 18 to 80 years 
 
ESRD patient treated with peritoneal dialysis for at least three months 
 
Body mass index (BMI): 18 < BMI < 40 kg/m² 
 
Acceptable comorbidities and medical history as assessed by the investigating 
nephrologist, with an estimated life expectancy >6 months 
 
Hemoglobin >10 g/L 
 
Ability to provide written informed consent 
 
Affiliation with the national social security system 
 
French-speaking subject 
OR 
Healthy Subjects with Normal Renal Function 
 
Male or female aged 18 to 80 years 
 
Body mass index (BMI): 18 < BMI < 40 kg/m² 

 
Subject determined to be in good health by a responsible physician, based on a 
medical evaluation including medical history, vital signs, physical examination, and 
clinical laboratory tests 
 
Estimated glomerular filtration rate (eGFR) >90 mL/min (assessed using the CKD-EPI 
formula) 
 
Ability to provide written informed consent 
 
Affiliation with the national social security system 
 
French-speaking subject 
Non-Inclusion Criteria 
 
Known hypersensitivity to apixaban 
 
History of major bleeding 
 
Contraindication to apixaban according to the Summary of Product Characteristics 
(SmPC) for Eliquis® (except for ESRD in renal failure participants) 
 
Contraindication to Physioneal® or Extraneal® (for renal failure participants) 
 
Indication for anticoagulant therapy 
 
Current anticoagulant treatment 
 
Use of NSAIDs at anti-inflammatory doses (>300 mg) 
 
Treatment with strong CYP3A4 and P-gp inhibitors (increased exposure): azole 
antifungals (ketoconazole, itraconazole, voriconazole), amiodarone, HIV protease 
inhibitors, diltiazem, naproxen 
 
Treatment with CYP3A4 and P-gp inducers (reduced exposure): rifampicin, 
antiepileptic drugs, St John’s wort 
 
Moderate (Child–Pugh B) or severe (Child–Pugh C) hepatic impairment 
 
Current or recent (within 14 days prior to study) antibiotic treatment 
 
Pregnant or breastfeeding women 
 
Known hypersensitivity to icodextrin 
 
Inability to tolerate an intraperitoneal volume of 2 liters 
Exclusion Criterion 
 
Healthy subject with an eGFR <90 mL/min (assessed using the CKD-EPI formula) 
after selection as a normal renal function participant. 
13. TREATMENTS ADMINISTERED TO 
PARTICIPANTS 
1. Description/Presentation of the Investigational Medicinal Product(s), 
Comparator(s), and Auxiliary Medicinal Products/Devices 
Investigational Medicinal Product 
Item
Description
International Nonproprietary Name (INN) / 
strength 
Apixaban 5 mg 
Trade name / strength
Eliquis® 5 mg

Item
Description
Pharmaceutical form
Film-coated tablet
Study dosage
5 mg as a single dose
Route/mode of administration
Oral
Storage conditions 
Room temperature – no special storage 
precautions 
Reference SmPC for ELIQUIS® 5 mg: 
http://ec.europa.eu/health/documents/community-
register/2018/20180531141190/anx_141190_fr.pdf 
Auxiliary Medicinal Products 
 
Auxiliary medicinal product 1
Auxiliary medicinal product 2
INN / strength 
See SmPC for solution composition 
See SmPC for solution 
composition 
Trade name / 
strength 
Physioneal 40 glucose (1.36% or 3.86%), 
double-bag system with screw (Luer) 
connection, 2 L 
Extraneal, double bags (PVC) 
with Luer screw connection, 2 L 
Pharmaceutical form Peritoneal dialysis solution
Peritoneal dialysis solution
Study dosage
2 L at 08:00, 12:00, and 16:00 for 3 days
From 20:00 to 08:00 for 3 days
Route/mode of 
administration 
Intraperitoneal 
Intraperitoneal 
Storage conditions 
Room temperature – do not store below 4°C Room temperature – do not 
store below 4°C 
Reference SmPCs: 
 
Physioneal 40 glucose 1.36% (isotonic): http://base-donnees-
publique.medicaments.gouv.fr/extrait.php?specid=61274635 
 
Physioneal 40 glucose 3.86% (hypertonic): http://base-donnees-
publique.medicaments.gouv.fr/extrait.php?specid=67998759 
 
Extraneal: http://agence-prd.ansm.sante.fr/php/ecodex/rcp/R0287620.htm 
 
2. Supply Chain of the Investigational Treatment(s) and Auxiliary 
Treatments/Devices 

2.1 Source of the Investigational Medicinal Product and Auxiliary Treatments/Devices 
Apixaban 5 mg (ELIQUIS®) required for the study will be purchased by the coordinating 
pharmacy of CHU Caen Normandie from Bristol-Myers Squibb. A batch release certificate 
and, where applicable, certificates of analysis will be required from the supplier for each 
batch ordered and received. 
Dialysis solutions and auxiliary devices will be provided by the participating centers and 
reimbursed by the sponsor. They will be used according to standard clinical practice in the 
care unit (CRC/CIC) where participants are included and treated. 
2.2 Packaging 
Apixaban 5 mg (ELIQUIS®) scored tablets in pre-cut blister packs will be repackaged into 
unit boxes (one apixaban tablet per box) by the coordinating pharmacy of CHU Caen 
Normandie, which will perform final batch release after repackaging and relabeling. 
2.3 Labeling 
Blister packs and unit boxes of apixaban 5 mg (ELIQUIS®) will be labeled in accordance 
with Article R.5121-16 of the French Public Health Code, the Order of May 24, 2006 
specifying medicinal product labeling content, and the recommendations of Annex 13 of the 
European Good Manufacturing Practices. 
2.4 Supply / Resupply 
Initial supply will be performed by the coordinating pharmacy of CHU Caen Normandie at 
site initiation. 
Resupply will be carried out if necessary by participating centers using the dedicated form 
provided by the sponsor. 
Each receipt of apixaban 5 mg (ELIQUIS®) will be recorded (quantity, batch number, and 
expiry date) in an appropriate accountability log under the responsibility of the investigator 
and pharmacist. 
2.5 Storage Conditions 
The investigational treatment must be stored by the pharmacy of each investigational center in 
its original packaging, protected from light, at room temperature, in a temperature-controlled 
and locked room. 
2.6 Dispensing 
Dispensing of the investigational treatment will be performed upon presentation of the study-
specific nominative prescription provided by the sponsor or the participating center. Each 
dispensing will be recorded in an appropriate accountability log under the responsibility of the 
investigator and pharmacist. Batch numbers and expiry dates of dispensed products will be 
documented to ensure traceability. 

2.7 Administration 
The single oral dose of apixaban 5 mg (ELIQUIS®) will be administered on Day 0 (D0) with 
water, after at least 2 hours of fasting. 
2.8 Returns and Destruction 
Used or unused investigational treatments must be returned to the hospital pharmacy of the 
participating center. Returned quantities will be recorded on a subject-specific accountability 
form. 
Used, unused, or expired investigational treatments will be destroyed on site after written 
approval from the sponsor. A destruction certificate will be issued by the pharmacist of the 
participating center. 
 
3. Management of Toxicities Related to the Investigational Medicinal Product 
or Its Administration (if applicable) 
Any toxicities related to apixaban 5 mg administration will be managed by the investigator or 
co-investigator responsible for the participant. 
 
4. List of Authorized and Prohibited Treatments and Substances 
4.1 Prohibited Treatments and Substances 
Prohibited treatments include other anticoagulants, such as unfractionated heparin, low-
molecular-weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, 
etc.), and oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.). 
Subjects receiving strong CYP3A4 and P-gp inhibitors (increased exposure) will not be 
included: azole antifungals (ketoconazole, itraconazole, voriconazole), amiodarone, HIV 
protease inhibitors, diltiazem, naproxen. 
Subjects receiving CYP3A4 and P-gp inducers (reduced exposure) will not be included: 
rifampicin, antiepileptics, St John’s wort. 
Smoking and grapefruit juice are prohibited during the study due to their effects on CYP3A4. 
4.2 Treatments Authorized with Precautions 
Precautions must be taken in subjects treated concomitantly with nonsteroidal anti-
inflammatory drugs (NSAIDs), including acetylsalicylic acid. In the ApiDP study, subjects 
receiving NSAIDs at anti-inflammatory doses are not included. 

4.3 Special Warnings and Precautions for Use 
Refer to the reference SmPC for apixaban 5 mg (ELIQUIS®). 
 
5. Methods for Monitoring Treatment Compliance 
Subject compliance will be assessed and documented during the on-site single administration 
of apixaban 5 mg (ELIQUIS®). 
 
14. PRACTICAL CONDUCT OF THE STUDY 
1. Inclusion of Subjects Undergoing Peritoneal Dialysis 
Screening visit (D−30 to D−5): 
During this medical visit conducted by the investigator nephrologist: 
1. Informed consent 
The investigator will inform the subject of the study objectives, constraints, and 
foreseeable risks, review the information sheet and consent form, and answer all 
questions prior to any assessment. If the subject agrees to participate, both the subject 
and investigator will sign and date the consent form in duplicate. One copy will be 
retained by the investigator for 15 years after study completion; the other will be 
provided to the subject. 
2. Verification of inclusion/non-inclusion criteria 
3. Collection of medical history and concomitant treatments 
 
Clinical examination including vital signs, weight, and height 
 
Blood tests 
 
Urine pregnancy test if applicable 
 
Verification of administrative documents required for compensation payment and 
national registry enrollment 
 
Scheduling of subsequent visits with the CRC in Caen and CIC in Rouen 
4. Registration in the VRB registry 
Day 0 (D0) = Hospitalization and Drug Administration – 
MONDAY (CRC or CIC) 
Morning 
Initiation of the standardized continuous ambulatory peritoneal dialysis (CAPD) protocol 
for the following 3 days. 
The patient arrives with a full abdomen, according to their usual peritoneal dialysis care 
protocol. 

Time 
08:00 
12:00 
16:00 
20:00 
D0 (Monday)
At home
Physioneal 2 L
Physioneal 2 L Extraneal 2 L
D1 (Tuesday)
Physioneal 2 L Physioneal 2 L
Physioneal 2 L Extraneal 2 L
D2 (Wednesday) Physioneal 2 L Physioneal 2 L
Physioneal 2 L Extraneal 2 L
D3 (Thursday)
Physioneal 2 L Return to standard regimen
Note: 
If the subject presents with fluid overload (assessed after the first 24 hours), the nephrologist 
may replace the morning dialysis bag with a hypertonic Physioneal solution to achieve 
ultrafiltration. 
 
Morning – Medical Visit 
Clinical examination and verification of the absence of drug–drug interactions. 
A catheter will be inserted for the various blood samplings. 
 
Absence of contraindications according to the Eliquis SmPC (except for end-stage 
renal disease in participants with renal failure) and absence of contraindications to 
Physioneal or Extraneal (for participants with renal failure) 
 
Healthy subjects: considered healthy by the investigator based on a medical 
evaluation including medical history, vital signs, physical examination, and clinical 
laboratory tests 
 
Renally impaired subjects: presenting comorbidities and medical history deemed 
acceptable by the investigator (estimated life expectancy > 6 months) 
Women of childbearing potential must have a negative urinary pregnancy test (β-hCG) on D0 
prior to apixaban administration. Women with amenorrhea > 12 months and follicle-
stimulating hormone (FSH) levels ≥ 40 IU/L are not considered of childbearing potential. For 
women with amenorrhea ≥ 2 years, FSH measurement is not required. 
 
Pre-dose (before apixaban administration) 
 
Blood sample for apixaban pharmacokinetics 
 
Blood sample for anticoagulant activity (anti-Xa), PT, and aPTT 
 
Peritoneal dialysis fluid sample 
 
Urine sample for apixaban assay 
 
12:00 (T0) 
Oral administration of apixaban 5 mg at 12:00 ± 1 hour. 
The apixaban tablet must be swallowed with a glass of water, 30 minutes before lunch, after 
drainage and at the beginning of Physioneal infusion. 

 
Initiation of 24-hour urine collection 
 
Pharmacokinetic Sampling Schedule 
 
T1h (±5 min): blood sample for apixaban PK 
 
T2h (±5 min): blood sample for apixaban PK 
 
T3h (±5 min): blood sample for apixaban PK 
o plus blood sample for anti-Xa activity, PT, and aPTT 
 
T4h (±5 min): blood sample for apixaban PK 
o start of afternoon bag infusion and sampling of drained dialysis fluid 
o peritoneal dialysis fluid sample for creatinine and urea kinetics 
 
T6h (±5 min): blood sample for apixaban PK 
 
T8h (±5 min): start of evening bag infusion and sampling of drained dialysis fluid 
o peritoneal dialysis fluid sample for creatinine and urea kinetics 
 
T9h (±5 min): blood sample for apixaban PK 
o plus blood sample for anti-Xa activity, PT, and aPTT 
 
T12h (±5 min) (around midnight): blood sample for apixaban PK 
 
Day 1 (D1) – TUESDAY 
 
T20h (around 08:00): start of morning bag infusion and sampling of drained dialysis 
fluid 
o peritoneal dialysis fluid sample for creatinine and urea kinetics 
 
T24h (±5 min) (around noon): blood sample for apixaban PK 
o start of midday bag infusion and sampling of drained dialysis fluid 
o measurement of 24-hour urine volume 
o urine sample for apixaban assay 
o urine + plasma + peritoneal dialysis fluid samples for creatinine and urea 
kinetics 
o measurement of renal urea clearance (UV/P urea) and creatinine clearance 
(UV/P creatinine) using blood sampling and 24-hour urine collection; 
estimation of renal function by averaging the two clearances (peritoneal 
dialysis subjects only) 
o initiation of a new 24-hour urine collection 
 
T28h (±5 min) (around 16:00): start of afternoon bag infusion and sampling of 
drained dialysis fluid 
 
T32h (±5 min) (around 20:00): start of evening bag infusion and sampling of drained 
dialysis fluid 
 
Day 2 (D2) – WEDNESDAY 
 
T44h (around 08:00): start of morning bag infusion and sampling of drained dialysis 
fluid 

 
T48h (±5 min): blood sample for apixaban PK 
o start of midday bag infusion and sampling of drained dialysis fluid 
o measurement of 24-hour urine volume and urine sampling 
o initiation of a new 24-hour urine collection 
 
T52h (around 16:00): start of afternoon bag infusion and sampling of drained dialysis 
fluid 
 
T56h (around 20:00): start of evening bag infusion and sampling of drained dialysis 
fluid 
 
Day 3 (D3) – THURSDAY (T72) AND DISCHARGE 
 
T68h (around 08:00): start of morning bag infusion and sampling of drained dialysis 
fluid 
 
T72h (±5 min) (around noon): blood sample for apixaban PK 
o measurement of 24-hour urine volume and urine sampling 
o end of urine collection 
o sampling of drained dialysis fluid and resumption of the subject’s personal 
peritoneal dialysis regimen 
o blood sample for anti-Xa activity, PT, and aPTT 
A medical visit will then be performed, followed by subject discharge. 
 
End-of-Study Visit at 1 Month (±10 days) 
Clinical examination, vital signs, collection of concomitant treatments and adverse events. 
 
2. Inclusion of Healthy Volunteers with Normal Renal 
Function (Group 2) 
The CRC of Caen or the CIC of Rouen will organize the recruitment of healthy volunteers 
matched to peritoneal dialysis patients (respectively at CHU Caen Normandie and CHU 
Rouen). 
Management will be identical to that of peritoneal dialysis patients, except for the absence of 
peritoneal dialysis fluid sampling. In addition, apixaban administration may occur as early as 
08:00. Pharmacokinetic sampling times will be adjusted accordingly. 
Evaluations 

Evaluation 
Screening (D-
30 to D-5) 
D0 D1 D2 D3
End-of-
Study 
Visit 
Informed consent
X
Eligibility verification
X
Clinical examination
X
X
X
Vital signs (BP, weight, height, BMI)
X
X
X
Pregnancy test (if applicable)
X
X
Laboratory tests
X
Creatinine clearance (CKD-EPI, healthy subjects) X
Dialysis subjects – Kt/V clearance (creatinine & 
urea, from 24h urine, plasma at D1, PD fluid first 
24h)
 
X X  
 
 
Oral apixaban 5 mg administration
X
Standardized peritoneal dialysis protocol (3 
Physioneal + 1 Extraneal/24h) – PD subjects
 
X X X X  
Blood collection for pharmacokinetics
X X X X
Blood collection for hemostasis tests + anti-Xa 
activity
 
X  
 
 
X 
24-hour urine collection
X X X
Urine collection for pharmacokinetics
X X X X
Dialysis fluid collection for pharmacokinetics
X X X X
Concomitant treatments
X
X X X X X
Adverse events
X
X X X X X
 
15. Sample Management 
All assays will be performed in batch at the end of the study. 
Day Time 
Plasma 
Dialysis fluid 
Urine 
Kt/V Clearance 
 
 
Apixaban 
assay
Anti-Xa activity, PT, 
aPTT
Apixaban 
assay
Creatinine, urea 
D0 Pre-
dose
X 
X 
X 
X 
1h
X
2h
X
3h
X
X
4h
X
X
X (PD fluid)
6h
X
8h
X
X (PD fluid)
9h
X
X
12h
X

Day Time 
Plasma 
Dialysis fluid 
Urine 
Kt/V Clearance 
D1 20h
X
X (PD fluid)
 
24h 
X 
 
X 
X (PD fluid + urine 24h + 
plasma)
28h
X
32h
X
D2 44h
X
48h
X
X
52h
X
56h
X
D3 68h
X
72h
X
X
X
X
Total samples: 
 
Plasma for apixaban: 11 
 
Plasma for anti-Xa, PT, aPTT: 4 
 
Dialysis fluid: 13 (PD subjects only) 
 
Urine: 4 (apixaban assay) 
 
Kt/V clearance: 4 
 
Sample Processing 
CHU Caen (CRC): 
 
Blood samples: centrifuge at 1900–2000 g for 11 min at 22°C, then freeze as 3 plasma 
aliquots for apixaban assay. 
 
Anti-Xa, PT, aPTT samples: 2 aliquots of 500 µL plasma after double centrifugation 
(2000–2500 g, 15–25°C, 11 min). 
 
PD fluid samples (PD subjects): 13 tubes, frozen as 3 aliquots for apixaban assay. 
 
Urine: 4 tubes frozen as 4 aliquots for apixaban assay; 4 tubes sent directly for 
creatinine and urea assay. 
CHU Rouen (CIC): 
 
CIC performs sampling and coordinates logistics with CRB Caen for processing. 
 
16. Data to Be Collected 
Screening Visit (D-30 to D-5): 
 
Date of informed consent 
 
Age, sex, weight, height, BMI 

 
Blood pressure 
 
Laboratory tests: CBC (including hemoglobin g/dL), electrolytes, liver function tests 
(AST, ALT, γ-GT, ALP) 
 
Creatinine clearance (CKD-EPI, healthy subjects only) 
 
Concomitant medications 
 
Pregnancy test if applicable 
 
Date of initiation of peritoneal dialysis 
 
Renal history for PD subjects, Charlson comorbidity score 
 
Eligibility verification 
Hospitalization (D0): 
 
Blood pressure, weight (for PD subjects: estimated empty abdominal weight based on 
full abdominal weight and Monday morning drained volume) 
 
Start of 24-hour urine collection 
 
Pregnancy test if applicable 
 
Time of apixaban administration 
 
Concomitant medications 
D0–D3: 
 
Plasma apixaban concentrations: T0, T1h, T2h, T3h, T4h, T6h, T9h, T12h, T24h, 
T48h, T72h 
 
PD fluid and urine apixaban concentrations: 24-hour urine ×3, PD fluid 4×/day ×3 
days = 12 samples (PD subjects only) 
 
PD fluid creatinine and urea (T4h, T8h, T20h, T24h) 
 
Plasma anti-Xa, PT, aPTT: T0, T3h, T9h, T72h 
 
PD subjects: renal clearance calculations (plasma and 24h urine creatinine and urea) 
 
Safety: systematic recording of adverse events (any grade, CTCAE v5.0) from 
informed consent until 72h post-dose and beyond if possibly related to apixaban 
End-of-Study Visit (1 month ± 10 days): 
 
Weight, blood pressure, concomitant medications, adverse events 
17. STATISTICAL METHODOLOGY 
This is an open-label, parallel-group study with a single oral administration. 
1. Planned Number of Participants 
 
12 end-stage renal disease (ESRD) patients treated with peritoneal dialysis (PD). 
 
12 healthy subjects with normal renal function, serving as the control group. Each 
control subject will be matched to a patient by age (±5 years), weight (±20%), and sex. 
Justification 
Assuming a 36% difference in AUC between the two groups (based on pharmacokinetic 
studies in hemodialysis patients), with a standard deviation of ±25%, a two-sided alpha of 5%, 
and a power of 90%, 11 evaluable subjects per group are required. To account for potential 

dropouts, 12 subjects per group will be included, resulting in a total of 24 subjects. One 
dropout per group is anticipated. 
Group 1 will consist of 12 ESRD patients on PD. 
Group 2 will consist of 12 healthy subjects, matched to Group 1 by age (±5 years), weight 
(±20%), and sex. 
The body weight of PD patients will be measured as dry weight (empty abdomen). 
2. Statistical Methods 
This is an open-label, parallel-group, single-dose study involving 24 subjects. 
Descriptive statistics will be used to summarize baseline characteristics and to present 
apixaban pharmacokinetic parameters. Continuous variables will be expressed as mean ± 
standard deviation (SD). The coefficient of variation (CV) will be calculated as SD divided by 
the mean and expressed as a percentage. 
The Wilcoxon rank-sum test will be used to compare pharmacokinetic parameters between 
groups. Pharmacokinetic and pharmacodynamic modeling will be performed using nonlinear 
mixed-effects models (SAS v9.0). 
Subjects will be considered evaluable only if they complete assessments through 72 hours 
post-dose (T72) on Day 3. Early withdrawals before T72 will be replaced. 
 
18. FEASIBILITY 
The University Center for Kidney Diseases follows 60 ESRD patients treated with PD, 
ensuring sufficient enrollment potential, with approximately half expected to meet the 
inclusion criteria. 
The Nephrology Department at CHU Rouen, in collaboration with ANIDER, follows 20 
ESRD patients treated with PD, also ensuring adequate enrollment potential, with about half 
likely to meet the inclusion criteria. 
 
19. ELECTRONIC DATA MANAGEMENT 
Data will be managed using Ennov Clinical software. 
 
20. RISK-BENEFIT ASSESSMENT FOR PARTICIPANTS 
Benefits 
No direct benefit is expected for study participants. The anticipated benefit is collective, 
contributing to scientific knowledge regarding apixaban pharmacokinetics in renal 
impairment. 

Risks 
The risks are related to the known adverse effects of apixaban, particularly in patients with 
renal impairment due to dose-dependent effects. The most common adverse events include 
bleeding, bruising, epistaxis, and hematoma. 
The risk is minimized by administering a single 5 mg dose. In controlled studies, oral 
administration of apixaban to healthy subjects at doses up to 50 mg/day for 3–7 days (25 mg 
twice daily for 7 days or 50 mg twice daily for 3 days) did not result in clinically significant 
adverse effects (Eliquis® SmPC). 
21. SAFETY ASSESSMENT 
Description of Safety Evaluation Parameters 
 
Clinical monitoring: Adverse events (AEs) will be closely monitored during the 3-
day hospitalization period. Participants will be evaluated by the investigator at Day 30. 
 
Laboratory assessments: Anticoagulant activity measured at 3 hours (T3h) and 72 
hours (T72h) post-dose will be analyzed by the investigator. 
 
22. ADVERSE EVENT REPORTING 
1. Definitions 
 
Adverse Event (AE): Any harmful occurrence in a subject participating in biomedical 
research, whether or not it is related to the study or investigational product. 
 
Serious Adverse Event (SAE): Any AE that: 
o Results in death, 
o Is life-threatening, 
o Requires hospitalization or prolongation of hospitalization, 
o Results in significant or persistent disability/incapacity, or a congenital 
anomaly, 
o Is considered serious by the investigator. 
A SAE related to the study becomes a Serious Adverse Reaction (SAR). 
 
Unexpected Serious Adverse Reaction (USAR): Any SAE related to the 
investigational medicinal product whose nature, severity, or outcome is not consistent 
with the Reference Safety Information (SmPC or Investigator’s Brochure). 
 
Expected Serious Adverse Reaction (ESAR): Defined in the protocol, Investigator’s 
Brochure, or study documents: 
o Any AE already listed in the most recent SmPC or Investigator’s Brochure, 
o Any serious AE expected from study procedures or methods. 
2. Description of ESARs 
Reference safety information for ELIQUIS 5 mg: most recent EPAR available on the EMA 
website, section 4.8. 
In the indication of non-valvular atrial fibrillation, the expected AEs are primarily bleeding 
events. 

Other expected effects include hypersensitivity (e.g., pruritus, anaphylactic reaction, 
angioedema) and syncope, occurring in <1% of patients receiving Eliquis®. 
 
23. PROCEDURES FOR RECORDING AND REPORTING AEs 
Investigator Responsibilities 
Detection and recording of AEs: 
All AEs must be actively sought, reported, recorded, managed, and evaluated from the date of 
informed consent until one month after study completion, and until resolution. AEs are 
collected: 
 
During scheduled clinical, laboratory, or other assessments and through systematic 
questioning by the investigator, 
 
Through spontaneous reporting by participants, who are instructed to contact the 
investigator in case of any AE. 
All AEs, regardless of severity (graded per CTCAE v5.0), will be recorded on AE case report 
forms. Each AE will be documented individually, with severity graded as: 
 
Mild (Grade 1): no interference with daily activity, 
 
Moderate (Grade 2): moderate interference with daily activity but acceptable, 
 
Severe (Grade 3): significant and unacceptable interference with daily activity, 
 
Life-threatening (Grade 4), 
 
Death (Grade 5). 
Reporting of SARs: 
The investigator must notify the sponsor without delay of all serious AEs, whether related to 
the study or not, expected or unexpected. 
 
Form: SARs are reported to the sponsor via fax to +33 2 31 06 35 09 (Clinical 
Research Pharmacovigilance Fax). 
Special case: healthy volunteer studies 
In case of a SAE potentially related to the study, the investigator must take urgent safety 
measures, suspend administration to all participants, and notify the sponsor immediately. 
The investigator must provide additional information regarding SAEs promptly and assess 
severity, intensity, and causality. All SAEs will be followed until complete resolution. 
Delayed AEs reasonably related to the investigational product or study must be reported 
without time limitation. 
Reporting period: 
SAEs must be reported from: 
 
Date of informed consent, 
 
Throughout the participant’s follow-up as per the study protocol, 
 
Up to 4 weeks after study completion, 

 
Beyond the follow-up period if reasonably related to the study or investigational 
product (e.g., delayed serious effects such as cancer or congenital anomalies). 
Sponsor Responsibilities 
Reporting unexpected SAEs: 
The sponsor evaluates causality between the SAE and the investigational product(s) or study 
procedures, determines expected vs. unexpected status, and reports all unexpected SAEs to 
EMA (EudraVigilance) and ANSM. 
Regulatory timelines: 
 
Immediately: fatal or life-threatening unexpected SAEs; additional relevant 
information must be reported within 8 days, 
 
Within 15 calendar days: other unexpected SAEs; additional information must be 
reported within 8 days. 
For healthy volunteer studies, all SAEs are reported immediately to ANSM. 
Reporting new safety information: 
Defined as any new data that may lead to reassessment of the benefit-risk profile, 
modification of product use, study conduct, study documents, or suspension/modification of 
the protocol. 
The sponsor reports new safety information without delay to ANSM and the Ethics 
Committee (CPP). 
Special consideration for first-in-human studies: 
For first-in-human studies or first use in healthy volunteers, any SAE constitutes new safety 
information. 
 
The sponsor suspends administration of the product pending safety measures, 
 
Implements urgent safety measures, 
 
Notifies ANSM, CPP, and ARS immediately. 
Annual Safety Report: 
On the anniversary of the trial authorization by ANSM, the sponsor prepares a safety report 
including: 
 
List of all SARs (expected and unexpected), 
 
List of all SAEs (related and unrelated), 
 
Concise critical analysis of subject safety. 
This report is submitted to ANSM and the relevant CPP within 60 days of the trial 
authorization anniversary. 
 
24. PARTICIPANT INVOLVEMENT 

 
Study procedures will occur at the Clinical Research Center of CHU Caen or the 
Clinical Investigation Center of Rouen. 
 
Pharmacokinetic and pharmacodynamic analyses will be conducted at CHU Caen. 
 
All participants must be beneficiaries of the French social security system. 
 
The investigator will verify participant involvement in other clinical trials to assess 
compatibility with the API-DP protocol. 
Compensation: €900. 
 
25. ACCESS TO DATA AND SOURCE DOCUMENTS 
Participant Information: 
In accordance with French data protection laws (Loi Informatique et Libertés, Law No. 2002-
303), participants have the right to access and correct their data at any time. Participation and 
consent procedures are documented in the participant’s medical record. Participants will be 
informed of overall study results at study completion. 
Access to source data: 
Authorized personnel from the sponsor (CHU Caen) will monitor CRFs and verify against 
source medical records. 
27. LEGAL AND ETHICAL CONSIDERATIONS 
1. Participant Information and Consent: 
Free, informed, and explicit consent will be obtained after the participant has been informed 
of the study’s objectives, procedures, duration, potential benefits, risks, and constraints, as 
well as the nature of the investigational product and the opinion provided by the Ethics 
Committee (CPP), and after adequate time for reflection. 
 
The information sheet will be given to the participant. 
 
The consent form will be dated and personally signed by the participant and by an 
investigator authorized for the protocol before any study-related procedures. 
 
Participation in the study will be documented in the participant’s medical record at the 
inclusion visit (date of inclusion and dates of study visits). 
For minors capable of expressing their will, a separate information sheet will be provided. 
Consent must be signed by both the holders of parental authority and the minor. 
Genetic analyses will require a specific information sheet and consent form. 
2. Ethics Committee Opinion and Regulatory Authority Submission: 
This study is considered “interventional research” under Article L.1121-1 of the French 
Public Health Code (Law No. 2012-300 of March 5, 2012, and implementing Decree No. 
2016-1537 of November 16, 2016). It will be submitted for review by a CPP. 
The CHU Caen Normandie, as the sponsor, will submit the protocol to the relevant 
Competent Authority (AC) and obtain authorization. 
The sponsor must provide insurance covering all participants and participating centers. 

3. Substantial Amendments: 
Any modification to the protocol or to the information and consent documents must be 
authorized by the CPP and ANSM. 
4. End-of-Trial Notification: 
The sponsor shall notify the end of the trial within: 
 
90 days after planned completion (last participant’s last visit), or 
 
15 days in case of premature termination. 
5. Final Study Report: 
The final report summarizes the study results. It must be submitted to ANSM within one year 
after trial completion (planned or premature, except for trials stopped due to non-enrollment). 
 
28. PARTICIPANT INFORMATION AND CONSENT 
Free, informed, and explicit consent will be obtained after providing the participant with all 
necessary information regarding the study objectives, procedures, duration, potential benefits, 
risks, constraints, the nature of the investigational product, and the CPP opinion, with 
sufficient time for reflection. 
 
Consent will be dated and signed by the participant and the responsible investigator 
before any study-related procedures. 
 
Participation will be documented in the medical record at the inclusion visit. 
For minors capable of expressing their will, a separate information sheet will be provided, and 
consent must be signed by both parents/guardians and the minor. 
Genetic analyses require a specific information sheet and consent form. 
 
29. ETHICS COMMITTEE REVIEW AND COMPETENT AUTHORITY 
NOTIFICATION 
 
Interventional research under Article L.1121-1 of the Public Health Code (Law No. 
2012-300, March 5, 2012, and Decree No. 2016-1537, Nov 16, 2016) requires CPP 
approval. 
 
The CHU Caen, as sponsor, will submit the protocol to the relevant Competent 
Authority (AC). 
 
The CPP must approve the protocol and informed consent form. 
 
Any amendment to the protocol or consent form must be submitted to the CPP and 
AC. 
 
The sponsor will maintain insurance for all participants and centers. 
1. Substantial Amendments: 
All protocol amendments must be authorized by the CPP and ANSM. 
2. End-of-Trial Notification: 

 
Planned completion: within 90 days of last participant visit. 
 
Premature termination: within 15 days. 
3. Final Study Report: 
The final report summarizes the study results and must be submitted within one year after 
trial completion, except for trials stopped due to non-enrollment. 
 
30. DATA HANDLING AND DOCUMENT RETENTION 
CHU Caen Normandie will comply with MR-001 methodology (Deliberation No. 2018-153, 
May 3, 2018) for processing personal health data collected during research, in accordance 
with consent. Declaration No.: 2012002-V0. 
This automated processing complies with the EU General Data Protection Regulation 
(GDPR) of April 27, 2016. The methodology covers all personal data processing in research. 
The coordinating investigator will conduct the study according to this methodology and retain 
source documents for 15 years, including: 
 
Ultrasound reports, 
 
Laboratory results, 
 
Clinical observations in patient medical records, etc. 
 
31. PUBLICATION POLICY 
Authorship must comply with ICMJE guidelines: each author must have contributed 
sufficiently to take responsibility for the content. Essential contributions: 
1. Study conception/methods and/or data analysis and interpretation, 
2. Drafting or critical revisions of the manuscript, 
3. Final approval of the published version. 
Author order (coordinating investigator, methodologist, principal investigators) reflects 
participation in the study (number of subjects included and evaluable) and significant 
contributions during study conduct. Funding sources will be disclosed. 
Ancillary study results may only be published with the agreement of the principal 
investigators and methodologist, and after publication of the main study. 
The coordinating investigator will sign the final clinical study report, confirming agreement 
with analyses, results, and conclusions. 
The study and its results are the exclusive property of CHU Caen, and investigators are 
bound by professional confidentiality. Results may be presented at conferences and published. 
Drafts of communications and publications will be reviewed with all participating 
investigators. 

 
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Kidney Disease and Atrial Fibrillation. Am J Nephrol. 2018;48(1):36-45. 
2. Wang AY, Brimble KS, Brunier G, et al. ISPD Cardiovascular and Metabolic 
Guidelines in Adult Peritoneal Dialysis Patients Part II - Management of Various 
Cardiovascular Complications. Perit Dial Int. 2015 Jul-Aug;35(4):388-96. 
3. Yao X, Tangri N, Gersh BJ, et al. Renal Outcomes in Anticoagulated Patients With 
Atrial Fibrillation. J Am Coll Cardiol. 2017 Nov 28;70(21):2621-2632. 
4. Chokesuwattanaskul R, Thongprayoon C, Tanawuttiwat T, et al. Safety and efficacy 
of apixaban versus warfarin in patients with end-stage renal disease: Meta-analysis. 
Pacing Clin Electrophysiol. 2018 Mar 25. 
5. Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and 
safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin 
Pharmacol. 2016 May;56(5):628-36. 
6. Mavrakanas TA, Samer CF, Nessim SJ, et al. Apixaban Pharmacokinetics at Steady 
State in Hemodialysis Patients. J Am Soc Nephrol. 2017 Mar 16. 
7. Kalra PA, Burlacu A, Ferro CJ, Covic A. Which anticoagulants should be used for 
stroke prevention in non-valvular atrial fibrillation and severe chronic kidney disease? 
Curr Opin Nephrol Hypertens. 2018 Jul 16.