Multi-omics Study of Clinical Endpoints in CHD (OmiDETCHD)

Multi-omics Study of the Individual Differences of Drug Efficacy and Toxicity in Patients With Coronary Heart Disease

This study aimed to explore underlying mechanisms of individual differences in drugs for coronary heart disease treatment and its association with adverse consequences. It will enroll approximately 4000 coronal heart disease patients aged between 18 and 80 years in mainland China and follow-up for at least 1 years. Questionnaires, anthropometric measures, laboratory tests, and biomaterials will be collected . The principal clinical outcomes of the study consist of ischemia attack , cardiac death, renal injury,and myotoxic activity.

Study Overview

• Status: Unknown
• Conditions: Coronary Heart Disease
• Intervention / Treatment: Other: risk factors of adverse cardiovascular events; Other: multi-omics target discovery; Other: validation; Other: Predictive mathematical models

Detailed Description

The study is a multicenter prospective cohort study, aimed to explore underlying mechanisms of individual differences in drugs for coronary heart disease treatment and its association with adverse consequences.The genomic genotype, DNA methylation and metabolome of 1000 patients with coronary heart disease were determined using illumina high-density genotyping chip, high-throughput sequencing and high-resolution mass spectrometry. Blood exposures of statins and metoprolol and its metabolites was determined by UPLC-MS/MS.

The biological network using cross-omics analysis was reconstructed to identify potential causative key genes, bacteria, and endogenous metabolite targets that cause differences in individual responses. A machine identification algorithm selecting clinical factors and multi-omics targets was used to establish a predictive mathematical model.

A multi-center clinical cohort of 3000 coronal heart disease patients was used to verify the effects of various levels of omic targets on drug blood exposures, efficacy and toxic side effects. A comprehensive model based on multi-target combination of individualized drugs was constructed, and the predictive effect was clinically analyzed.

• Study Type: Observational
• Enrollment (Anticipated): 4000

Contacts and Locations

• Study Contact: Name: Shilong Zhong, Ph.D; Phone Number: 51157 862083827812; Email: zhongsl@hotmail.com
• Study Contact Backup: Name: Juer Liu, master; Phone Number: 51157 13430267895; Email: liujesysu@163.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Recruiting
      • Guangdong General Hospital
      • Contact: Shilong Zhong, Ph.D; Phone Number: 8618620819696; Email: zhongsl@hotmail.com
    • Guangzhou, Guangdong, China, 510080
      • Recruiting
      • The First Affiliated Hospital of Sun Yat-sen University
      • Contact: Chen Liu, MD, PhD; Phone Number: 8615013270269; Email: chenliu81@hotmail.com
  • Hunan
    • Changsha, Hunan, China, 410008
      • Recruiting
      • Xiangya Hospital Central South University
      • Contact: Qilin Ma, MD; Phone Number: 86731-84327203; Email: mqilin2004@163.com
  • Shanghai
    • Shanghai, Shanghai, China, 200233
      • Recruiting
      • Renji Hospital Affiliated to Shanghai Jiaotong University
      • Contact: Linghong Shen, MD, PhD; Phone Number: 8613916495713; Email: drshenlinghong@126.com
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Recruiting
      • West China Hospital, Sichuan University
      • Contact: Liang Ouyang, PhD; Phone Number: 8613880674611; Email: ouyangliang@scu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Chinese Han patients with coronary artery disease who have ingested metoprolol and statins were prospectively recruited from Guangdong General Hospital, Shanghai Jiao Tong University, Central South University, Sun Yat-sen University and Sichuan University.

Description

Inclusion Criteria:

• age: 18-80 years
• Chinese Han patients with coronary artery disease
• inpatients undergoing coronary angiography or percutaneous coronary intervention

Exclusion Criteria:

• renal insufficiency (defined as serum creatinine concentration > 2 times the upper limit of normal [230 μmol/L], renal transplantation or dialysis)
• hepatic insufficiency (defined as serum transaminase concentration > 2 times the upper limit of normal [80 U/L], or a diagnosis of cirrhosis)
• pre-existing bleeding disorders
• being pregnant or lactating
• advanced cancer or haemodialysis
• history of thyroid problems, and use of antithyroid drugs or thyroid hormone medication
• incomplete information about cardiovascular events during follow-up

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Discovery cohort; 1000 cases of coronary heart disease follow-up cohort was used for multi-omics target discovery.During the follow-up period, the information about the occurrence and risk factors of adverse cardiovascular events will be collected.	Other: risk factors of adverse cardiovascular events; During the follow-up period,general information(age, sex, BMI, blood pressure, the history of drink and smoke, medical history, etc).Blood biochemistry parameters（Lipid, hsCRP levels, etc）and other laboratory examination parameters will be collected; Other: multi-omics target discovery; Genome-wide genotype , DNA methylation and metabolomes were determined using illumina high-density genotyping chips, high-throughput sequencing, and high-resolution mass spectrometry respectly. Blood exposure of statins and metoprolol and its metabolites was determined by UPLC-MS/MS.
Validation corhort; 3000 coronary heart disease follow-up cohorts was used for validating the results from the discovery corhort. During the follow-up period, the occurrence and risk factors of adverse cardiovascular events.Predictive mathematical models based on multi-omics combination will be constructed finally.	Other: risk factors of adverse cardiovascular events; During the follow-up period,general information(age, sex, BMI, blood pressure, the history of drink and smoke, medical history, etc).Blood biochemistry parameters（Lipid, hsCRP levels, etc）and other laboratory examination parameters will be collected; Other: validation; The genome-wide genotype of patients with coronary heart disease was detected using the illumina chip. The methylation level of the functional region was detected by the target region enrichment methylation sequencing method. Intestinal flora differences were detected using 16SrDNA high-throughput sequencing.; Other: Predictive mathematical models; Machine learning algorithms such as multiple linear regression or Bayesian classification are used to optimize clinical factors and multi-group targets to establish predictive mathematical models.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	All-cause death	from date of baseline examination until the date of first documented death,up to 48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MACE	MACE was defined as the occurrence of cardiac death, nonfatal myocardial infarctions, coronary revascularisation and cerebral infraction.	from date of baseline examination until the date of first documented cardiovascular events,up to 48 months
Bleeding	Bleeding was the six-month incidence of combined alarming, internal, and nuisance bleeding events defined according to Serebruany et al15. Alarming bleeding included bleeding requiring a transfusion, intracranial bleeding, and life-threatening bleeding. Internal bleeding included haematoma, epistaxis, blood loss from the mouth, vagina, melaena, eye bleed, haematuria, and haematemesis. Nuisance bleeding included easy bruising, bleeding from small cuts, petechiae, and ecchymosis.	from date of baseline examination until the date of first documented bleeding,up to 48 months
Statin-induced myopathy (SIM)	The definition of SIM from statin treatment was based on the patients' subjective sense of muscular pain as well as CK elevations. These muscular side effects included myalgia (muscle pain/ache without serum CK elevations), other muscle-related symptoms such as weakness, cramps, spasms, soreness and twitching, CK elevations without physical symptoms, myositis or other muscle symptoms with CK elevations, and rhabdomyolysis.	from date of baseline examination until the date of first documented SIM,up to 48 months
CI-AKI	CI-AKI was diagnosed if a patient had an absolute increase in serum creatinine (sCr) concentration ≥ 0.3 mg/dl (26.4 μmol/L) from baseline or a relative increase ≥ 50 % in sCr concentration for more than 6 h within 48 h after surgery	more than 6 h within 48 h after Coronary Angiography

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
SYNTAX score	It is mainly used for the treatment of left main coronary artery lesions and/or three-vessel lesions.Patients with a score of ≥33 are recommended for CABG. Patients with a score between 23 and 32 can choose either PCI or CABG. Patients with a score of ≤22 are recommended for PCI and CABG.	more than 6 h within 48 h after Coronary Angiography

Collaborators and Investigators

• Sponsor: Guangdong Provincial People's Hospital
• Collaborators: Xiangya Hospital of Central South University; First Affiliated Hospital, Sun Yat-Sen University; RenJi Hospital; West China Hospital
• Investigators: Principal Investigator: Shilong Zhong, Ph.D, Guangdong Provincial People'S Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2017
• Primary Completion (Anticipated): December 31, 2019
• Study Completion (Anticipated): December 31, 2020

Study Registration Dates

• First Submitted: January 5, 2019
• First Submitted That Met QC Criteria: January 5, 2019
• First Posted (Actual): January 9, 2019

Study Record Updates

• Last Update Posted (Actual): February 12, 2019
• Last Update Submitted That Met QC Criteria: February 11, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: microbiome; metabolome; epigenome; genome; multi-omics targets; individual drug use
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
• Other Study ID Numbers: 2017YFC0909301

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No