Clinical trial NCT03161496: Impact of Biomarkers on Pharmacokinetics and Pharmacodynamics of Direct Oral Anticoagulants
Official title: Impact of Biomarkers on Pharmacokinetics and Pharmacodynamics of Direct Oral Anticoagulants
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Novel Oral Anticoagulants
NOACs
Rivaroxaban
Apixaban
Dabigatran
Pharmacokinetics
Pharmacodynamics
Pharmacogenomics
Accurate Medication
Lead sponsor: Peking University First Hospital
Sponsor class: OTHER
First posted: 2017-05-19
Enrollment: 1200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: (I)Chinese Healthy Volunteers：In accordance with the criteria of each bioequivalence trial of NOACs；150-200 cases for each drug (II)Chinese Patients：In accordance with anticoagulation indications of NOACs，never received NOACs in a month and intend to take NOACs or have received NOACs for more than one week continuously；200 cases for each drug

Brief summary: It is general that there are many factors for individual differences of drugs in clinical application, of which genetic factors accounted for more than 20%. Novel oral anticoagulants-NOACs (include rivaroxaban, apixaban, dabigatran and so on) have advantages of convenient use and no need of monitoring, compared with the traditional vitamin K antagonist. With lack of predicted biomarkers, especially the research data of Chinese, it has the important significance in studying individual differences of NOACs in the anticoagulant efficacy and safety, through the pharmacogenomics research.

The aim of this study is to determine the polymorphism of drug metabolizing enzymes, drug transporters and drug target genes in Chinese population. By detecting the gene polymorphism, we intend to study the pharmacokinetic/ pharmacodynamics/ pharmacogenomics (PK-PD-PG) correlation of NOACs and provide scientific basis for accurate medication guide for people to use NOACs.


Eligibility criteria: Inclusion Criteria:

(I)Chinese Healthy Volunteers

* In accordance with the inclusion criteria for each bioequivalence trial of NOACs;
* Sign informed consent of the research;
* Complete to collect indexes of pharmacodynamics and pharmacogenomics in the cycle with control drug.

(II)Chinese Patients

* In accordance with anticoagulation indications of NOACs, include prevention of thrombosis in non valvular atrial fibrillation, prevention and treatment of deep vein thrombosis / pulmonary embolism and prevention of thrombosis after knee / hip replacement;
* More than 18 years of age, male or female;
* Never received NOACs in a month and intend to take NOACs or have received NOACs for more than one week continuously;
* sign informed consent.

Exclusion Criteria:

(I)Chinese Healthy Volunteers

* In accordance with the exclusion criteria for each bioequivalence trial of NOACs;

(II)Chinese Patients

* With history of immunodeficiency disease, including positive HIV index;
* Positive Hepatitis B surface antigen (HBsAg) and HCV index;
* Combined therapy of CYP3A4 strong inhibitors and P-gp inhibitors (e.g., systemic pyrrole antifungal agents such as ketoconazole, itraconazole, voriconazole and posaconazole; human immunodeficiency virus (HIV) - protease inhibitors such as ritonavir), CYP3A4 strong inducers and P-gp inducers (e.g., rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's Wort, etc.) in 14 days before treatment with NOACs;
* Severe liver dysfunction and abnormal renal function;
* Include contraindications of NOACs, such as hypersensitivity, active bleeding, moderate or severe liver disease, previous history of intracranial hemorrhage, gastrointestinal hemorrhage in the past 6 months and major operation within 30 days.

Primary outcomes:
measure: Incidence of stroke or systemic embolic events (including TIA)
timeFrame: At 1 year
measure: Incidence of bleeding events
timeFrame: At 1 year
Secondary outcomes:
measure: Genotype detected by next generation sequencing
timeFrame: pre-dose of NOACs (rivaroxaban, apixaban, dabigatran)
measure: Level of anticoagulant activity assessed by anti-factor Xa activity
timeFrame: At baseline; at 3 hours, at 8 or 9 hours, at 12 hours for Chinese healthy volunteers, at 48 or 72 hours for Chinese patients
measure: Level of anticoagulant activity assessed by anti-factor IIa activity
timeFrame: At baseline; at 2 hours, at 4 hours, at 8 hours, at 12 hours for Chinese healthy volunteers, at 72 hours for Chinese patients
measure: Expression level of miRNA
timeFrame: At baseline; at 2 or 3 hours, at 4 hours (only for dabigatran), at 8 or 9 hours, at 12 hours for Chinese healthy volunteers, at 48 or 72 hours for Chinese patients.
measure: Expression level of LncRNA
timeFrame: At baseline; at 2 or 3 hours, at 4 hours (only for dabigatran), at 8 or 9 hours, at 12 hours for Chinese healthy volunteers, at 48 or 72 hours for Chinese patients.
measure: Incidence of stroke or systemic embolic events in the other observation times
timeFrame: At 1 month, 6 months and 2 years (according the actual duration of NOACs taken in patiens)
measure: Incidence of bleeding events in the other observation times
timeFrame: At 1 month, 6 months and 2 years (according the actual duration of NOACs taken in patiens)
Other outcomes:
Locations:
city: Hefei
country: China
facility: Anhui Provincial Hospital（The First Affiliated Hospital Of USTC）
state: Anhui
city: Beijing
country: China
facility: Peking University First Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing HuiLongGuan Hospital
state: Beijing
city: Chongqing
country: China
facility: The Second Affiliated Hospital Of Chongqing Medical University
state: Chongqing
city: Fuzhou
country: China
facility: Fujian Medical University Union Hospital
state: Fujian
city: Fuzhou
country: China
facility: 900 Hospital of the Joint Logistics Team (Original name: Fuzhou General Hospital of Nanjing Militray Command)
state: Fujian
city: Zhengzhou
country: China
facility: The 7th People's Hospital of Zhengzhou
state: Henan
city: Changsha
country: China
facility: The Third Hospital of Changsha
state: Hunan
city: Wuxi
country: China
facility: Wuxi People's Hospital
state: Jiangsu
city: Wuxi
country: China
facility: The Affiliated Hospital of Jiangnan University, or called Original Wuxi Third Hospital
state: Jiangsu
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University
state: Jiangxi
city: Shenyang
country: China
facility: the First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine
state: Liaoning
city: Hohhot
country: China
facility: The affiliated hospital of Inner Mongolia medical university
state: Neimenggu
city: Qingdao
country: China
facility: The Affiliated Hospital of Qingdao University
state: Shandong
city: Shanghai
country: China
facility: Shanghai Public Health Clinical Center
state: Shanghai
city: Shanghai
country: China
facility: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
state: Shanghai
Study officials:
References:
citation: Liu Z, Mu G, Xie Q, Zhang H, Jiang J, Xiang Q, Cui Y. Hemoclot Thrombin Inhibitor Assay and Expected Peak-Trough Levels of Dabigatran: A Multicenter Study. Front Cardiovasc Med. 2022 Jul 22;9:894888. doi: 10.3389/fcvm.2022.894888. eCollection 2022.