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The Chiglitazar perturbed Human multi-Omics ProfilE (ChiHOPE) project

ABSTRACT: The Chiglitazar perturbed Human multi-Omics ProfilE (ChiHOPE) project aimed at benefiting precision medicine of type 2 diabetes with multi-omics profiling. Chiglitazar, also known as Carfloglitazar, is an orally administered, non-thiazolidinedione small-molecule agonist of the α, δ and γ subtypes of the peroxisome proliferator-activated receptors (PPARs) developed by Chipscreen Biosciences. Since October 2021, Chiglitazar has been approved in China for use as an adjunct to diet and exercise to improve glycemic control in adult patients with T2D, and is also in phase 2 clinical development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). We constructed the ChiHOPE cohort of 835 drug-naïve patients with T2D, who were consented for this companion multi-omics study and represented 65% of the 1,274 patients participating in the two randomized, double-blind, phase 3 trials of the insulin sensitizer chiglitazar. The placebo-controlled CMAP trial (NCT02121717, ClinicalTrials.gov) included 350 patients randomly assigned to receive low dose (32 mg/day, n = 106), high dose (48 mg/day, n = 106) chiglitazar and placebo (n = 138) for treatment. The Sitagliptin-controlled CMAS trial (NCT02173457, ClinicalTrials.gov) included 485 patients randomly assigned to receive low dose (n = 161), high dose (n = 161) chiglitazar and sitagliptin (n = 163) for treatment. Multi-omics datasets were generated from longitudinally collected blood samples of patients at baseline, treated for 12 weeks and 24 weeks during trials. Specifically, genomic and methylomic data were generated from whole blood samples (n = 834) at baseline, whereas miRNAomic, proteomic and metabolomic data were generated from plasma samples at different time points (n = 2,190). Stringent quality control (QC) procedures were implemented to generate high-quality multi-omics datasets. Here are Proteomics data provided.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yuanting Zheng

PROVIDER: PXD068273 | iProX | Thu Sep 11 00:00:00 BST 2025

REPOSITORIES: iProX

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Project description:TNF antagonists are routinely used in severe rheumatoid arthritis (RA) patients who failed conventional DMARD therapy. According to large clinical trials, the three available drugs (adalimumab, infliximab and etanercept) display similar effects in terms of efficacy, tolerability and side effects. These studies also indicate that about 25% of RA patients treated with TNF-antagonists do not display any significant clinical improvement. The aim of this study was to investigate global molecular patterns in synovial biopsies from RA patients obtained 12 weeks after initiation of adalimumab therapy. All patients had rheumatoid arthritis (RA), according to the American College of rheumatology criteria for the diagnosis of RA. They had active disease at the time of initiation of adalimumab therapy and were resistant to conventional therapy. They all had erosive changes imaged on conventional x-rays of the hands and/or feet. All patients were treated with disease-modifying antirheumatic drugs (DMARD’s), 23 with methotrexate (median dose 15 mg/week, range 7.5 – 20 mg/week), and 2 with leflunomide (20 mg/day); 18 of them were treated with low-dose steroids (prednisolone ≤ 7.5 mg/day). Six patients had been included in double-blind clinical trials before inclusion in the present study (1 in a Golimumab versus placebo trial, 3 in a MapKinase inhibitor versus placebo trial and 2 in a TACE-inhibitor versus placebo trial). These trials were stopped at least 3 months prior to initiation of TNF-blocking therapy. All drug dosages were stable from at least 3 months prior to initiation of TNF blocking therapy until completion of the study. No steroid injections were allowed during the duration of the study. Adalimumab therapy was initiated at a dosage of 40 mg subcutaneously every other week. Disease activity at baseline and 12 weeks after initiation of therapy (T12) was evaluated using DAS(28)-CRP (3- and 4-variables) scores, and response to therapy was assessed according to the EULAR response criteria that categorize patients in responders (good- or moderate-) and non- (or poor-) responders based on changes in DAS activity between T0 and T12 and absolute DAS values at T12. Synovial biopsies were obtained by needle-arthroscopy of knee of the patients at T12. The aim of the study was to compare gene expression profiles in synovial tissue of RA patients who responded versus not responded to adalimumab therapy.

Project description:The VISP trial (PI Jim Toole, M.D., Wake Forest University School of Medicine) was a multi-center, double-blind, randomized, controlled clinical trial that enrolled patients aged 35 or older with Hcy levels above the 25th percentile at screening and a non-disabling cerebral infarction (NDCI) within 120 days of randomization [Toole, 2002]. The trial was designed to determine if daily intake of a multivitamin tablet with high dose folic acid, vitamin B6 and vitamin B12 reduced recurrent cerebral infarction (primary endpoint), and nonfatal myocardial infarction (MI) or mortality (secondary endpoints). Subjects were randomly assigned to receive daily doses of the high-dose formulation (n=1,827), containing 25mg pyridoxine (B6), 0.4mg cobalamin (B12), and 2.5mg folic acid; or the low-dose formulation (n=1,853), containing 200mcg pyridoxine, 6mcg cobalamin and 20mcg folic acid. Enrollment in VISP began in August 1997, and was completed in December 2001, with 3,680 participants enrolled. Within the trial, 2,164 participants from 46 clinic sites provided DNA and agreed for it to be shared for use in a genetic subset study of VISP. This study is part of the Genomics and Randomized Trials Network (GARNET, <a href="http://www.garnetstudy.org" target="_blank">http://www.garnetstudy.org</a>) funded by the National Human Genome Research Institute (NHGRI). The overarching goal is to identify novel genetic factors that contribute to stroke through large-scale genome-wide association studies of treatment response in randomized clinical trials. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were performed at the GARNET Coordinating Center at the University of Washington. The data of the VISP trial have been released to dbGaP users in several segments: Version 1 (phs000343.v1.p1), consisted of n=4 phenotype datasets, and all raw, cleaned and imputed genotype data. Version 2 (phs000343.v2.p1) included n=14 additional phenotype datasets (plus pedigree, consent, and sample-mapping data), and increased the available data to a total of n=970 phenotype variables. Version 3 (phs000343.v3.p1), the current release, includes all n=36 phenotype datasets (plus pedigree, consent, and sample-mapping data), and increases the available data to a total of n=1918 phenotype variables. Toole, J. F. (2002). Vitamin intervention for stroke prevention. J Neurol Sci, 203-204, 121-4. PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/12417369" target="_blank">12417369</a>.

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The Chiglitazar perturbed Human multi-Omics ProfilE (ChiHOPE) project

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