Chiglitazar in combination with anti-inflammatory and hepatoprotective therapy for the treatment of MASH associated with T2DM: a prospective, multicentre, randomised, double-blind, placebo-controlled study protocol

Abstract

Introduction

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is the hepatic manifestation of the metabolic syndrome. When it co-occurs with type 2 diabetes (T2DM), it presents a significant therapeutic challenge due to a higher risk of fibrosis progression and adverse outcomes. While new treatments for MASH are emerging, their efficacy in the T2DM subpopulation remains an unmet need. Chiglitazar is a novel peroxisome proliferator-activated receptor pan-agonist that regulates key pathways in lipid metabolism, glucose homeostasis and inflammation. This trial aims to evaluate the efficacy and safety of chiglitazar as a combination therapy for patients with MASH and T2DM.

Methods and analysis

This is a prospective, multicentre, randomised, double-blind, placebo-controlled study. This trial will enrol 300 adult patients aged 18–75 years with biopsy-confirmed MASH and fibrosis stage F1 or higher. Participants will be randomised (1:1) to receive either chiglitazar 48 mg daily or a matching placebo. All participants will also receive background therapy consisting of vitamin E (100 mg three times a day) and polyene phosphatidyl choline (456 mg three times a day). The treatment duration is 78 weeks. The primary efficacy endpoint is resolution of steatohepatitis with no worsening of liver fibrosis. Key secondary endpoints include improvement in liver fibrosis by at least one stage and changes in metabolic and liver safety biomarkers.

Ethics and dissemination

Ethical approval has been obtained from the Shanghai Punan Hospital of Pudong New District Ethics Committee (Punan Branch of Renji Hospital Ethics Committee, Shanghai Jiaotong University School of Medicine). KY2025-066. The findings will be disseminated through publication in peer-reviewed journals and presentations at scientific conferences.

Trial registration number

NCT07303803.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This is a multicentre design with a relatively large sample size of 300 patients, and the liver biopsy specimens were used to evaluate the end points, which is a golden standard in such clinical study.

• An interim analysis will be conducted by an Independent Data Monitoring Committee for futility assessment and potential sample size re-estimation, enhancing the trial’s rigour and ethical conduct.

• This is a longer-term study for about 78 weeks; the safety of long-term medication can be better confirmed.

• The use of standardised background therapy to all participants ensures a consistent baseline of care across the study population.

• The use of a placebo comparator, instead of an active drug control, precludes direct efficacy comparison with existing approved metabolic dysfunction-associated steatohepatitis therapies.

Introduction

Non-alcoholic fatty liver disease (NAFLD) has recently been reclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), which is defined by the presence of hepatic steatosis in the context of at least one metabolic risk factor.¹ A more severe and progressive form of MASLD is metabolic dysfunction-associated steatohepatitis (MASH), which is characterised by inflammation and hepatocyte injury and can lead to fibrosis, cirrhosis, and hepatocellular carcinoma.² The global prevalence of MASLD is estimated at 32.4%, with a significantly higher burden among individuals with type 2 diabetes mellitus (T2DM), where the prevalence of MASH reaches 37.3%.^{3 4}

Insulin resistance (IR) is a central pathophysiological driver of both MASH and T2DM, creating a bidirectional relationship in which each condition exacerbates the other’s progression.⁵ Patients with T2DM exhibit a more aggressive MASH phenotype, with a faster rate of fibrosis progression—approximately one stage every 4.3 years.⁶ As fibrosis stage is the most significant predictor of liver-related mortality, effective therapies for this high-risk population are urgently needed.⁷

Currently, the therapeutic landscape for MASH is limited. While resmetirom, a thyroid hormone receptor-beta agonist, and semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), have been approved for MASH, significant gaps remain. For instance, subgroup analyses of GLP-1RA phase 3 trials did not demonstrate a significant improvement in liver fibrosis among patients with T2DM, a critical focus for improving long-term prognosis.⁸ Some palliative treatments such as vitamin E or polyene phosphatidyl choline were recommended for MASH patients in clinical practice in China.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that play a pivotal role in regulating metabolic homeostasis, inflammation and fibrosis, and they may have a beneficial effect in MASH.⁹ As an ideal drug for MASH, Pan-PPAR agonists hold the potential to intervene in several core processes within its pathogenesis. First, they can shift adipose from the liver to subcutaneous regions. PPARγ can auto-regulate its expression in cooperation with C/CAAT enhancer binding proteins, which are the primary drivers of adipocyte gene induction during terminal differentiation.¹⁰ Second, PPARs play an important role in energy metabolism, increasing fatty acid β-oxidation, restoring healthy lipid metabolism within hepatocytes.¹¹ Third, all three PPAR subtypes can inhibit inflammatory gene expression, especially by attenuating nuclear factor NF-κB-driven inflammatory cytokine and chemokine production.^{11 12} Finally, the PPARγ signalling pathways alleviate ER stress by inducing the expression of Nogo-B receptor and reducing the expression of protein kinase R-like endoplasmic reticulum kinase and inositol-requiring enzyme 1 signalling pathway.¹³

Chiglitazar is a novel PPAR pan-agonist approved by the National Medical Products Administration (NMPA) in China for glycaemic control in adults with T2DM.¹⁴ As a moderate and balanced agonist of all three PPAR subtypes, chiglitazar has been shown to improve glycaemic control and insulin sensitivity.14,16 A preceding phase 2 trial demonstrated that chiglitazar significantly reduced liver fat content in patients with MASLD.¹⁷ However, the trial duration was short, underscoring the need for larger and longer-term studies.

This study protocol describes a clinical trial designed to investigate the efficacy and safety of chiglitazar 48 mg/day administered for 78 weeks in patients with biopsy-proven MASH and significant fibrosis who also have T2DM.

Methods and analysis

Trial design

This trial is designed as a randomised, double-blind, placebo-controlled study, in order to investigate the efficacy and safety of chiglitazar in T2DM participants with MASH and fibrosis stage 1 or higher.

The study period is planned from January 2026 to December 2030. Patient enrolment is expected to be completed by June 2028, and all follow-up will be finished by December 2030. The study protocol is described in online supplemental file 1. As part of the screening process, a pre-screening is used to decrease the histological screen failure rate. The participants are required to have the liver stiffness measurement (LSM) by Fibroscan, meet the results of controlled attenuation parameter (controlled attenuation parameter CAP))≥ 238 dB/m and LSM≥ 8.5 kPa. After filling the pre-screening, several central laboratory tests, clinical assessments and liver biopsy are performed to evaluate the eligibility of participants. The screening period lasts approximately 1 month per patient. Participants are randomised 1:1 to receive chiglitazar 48 mg/day or placebo, both with added vitamin E 100 mg/three times a day and polyene phosphatidyl choline 456 mg/three times a day as background therapy. All treatments are administered daily for 78 weeks (figure 1). Liver biopsy will be performed at baseline and 78 weeks after the intervention, and the data will be evaluated by a blinded independent statistician.

Figure 1. Study design. MASH, metabolic dysfunction-associated steatohepatitis; T2DM, type 2 diabetes mellitus.

Objectives and endpoints

The primary objective is to prove that treatment with chiglitazar improves liver disease compared with placebo in T2DM participants with MASH and fibrosis stage 1 or over. The primary end point was resolution of steatohepatitis and no worsening of liver fibrosis at week 78, secondary end point was improvement in liver fibrosis and no worsening of steatohepatitis at week 78. Resolution of steatohepatitis is defined as either a reduction in NAFLD activity score (NAS) score of at least 2 points or a post-treatment NAS score of 3 points or less; a minimum 1-point improvement in score for ballooning or inflammation. Fibrosis is graded on the NASH Clinical Research Network (CRN) fibrosis scale from 0 to 4, and ≥ 1 grade improvement is defined as an improvement in fibrosis. Other secondary endpoints will determine the laboratory indicators as well as changes in CAP score and LSM (table 1).

Table 1. Study endpoints.

Primary endpoint	Secondary endpoints
Efficacy endpoint	Efficacy endpoint	Safety endpoint
Resolution of steatohepatitis and no worsening of liver fibrosis (The definition was based on the following criteria: either a reduction in NAS score of at least 2 points or a post-treatment NAS score of 3 points or less; a minimum 1-point improvement in score for ballooning or inflammation).	1. An improvement in liver fibrosis by≥1 stage (NASH CRN fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for steatosis, inflammation or ballooning). 2. Resolution of steatohepatitis and improvement in liver fibrosis. 3. Worsening in steatohepatitis. 4. Change in body weight, body mass index and abdominal circumference from baseline. 5. Amount and rate of change in alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase, creatinine, blood urea nitrogen, estimated glomerular filtration rate, haemoglobin A1c, platelets, homeostasis model assessment of insulin resistance, HDL-C, non-HDL-C, low-density lipoprotein-cholesterol/HDL-C ratio and triglycerides from baseline. 6. Change in CAP values assessed by transient elastography from baseline (Fibroscan). 7. Changes in liver stiffness values assessed by transient elastography from baseline (Fibroscan).	Occurrence rate of adverse events

CAP, controlled attenuation parameter; CRN, Clinical Research Network; HDL-C, high-density lipoprotein cholesterol; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis.

Rationale for treatment by using chiglitazar

Chiglitazar is a novel PPAR pan-agonist, currently approved by the NMPA for improving glycaemic control in adults with T2DM, either alone or in combination with metformin hydrochloride. In a recent clinical study of chiglitazar for the treatment of MASLD based on magnetic resonance imaging-proton density fat fraction (MRI-PDFF) assessment, 48 mg/day and 64 mg/day of chiglitazar for 18 weeks significantly improved steatohepatitis in the treatment group, and the therapeutic effect was more pronounced in the higher dose group.¹⁷ The dosage of chiglitazar is set based on this information, and the treatment period was set at 78 weeks, as long-term administration will allow us to evaluate efficacy and safety more significantly.

In this study, patients will be randomised in a 1:1 ratio to receive chiglitazar (48 mg/day) or placebo.

Rationale for standardised management of MASH

In a clinical study of vitamin E in the treatment of MASH based on liver biopsy assessment, 300 mg/day of vitamin E for 96 weeks resulted in a significant decrease in NAS scores and a significant decrease in the LSM value of Fibroscan in the treatment group compared with the placebo group, but the stage of fibrosis assessed by liver biopsy did not improve significantly.¹⁸

Polyene phosphatidyl choline is a commonly used hepatoprotective drug that plays an important role in maintaining cell membrane fluidity and function, and may reduce liver injury and promote hepatic recovery by restoring oxidative homeostasis and ameliorating inflammation.¹⁹

These two drugs are included to ensure that all participants receive standardised background therapy.

Drug supply

To ensure successful blinding, this study used placebo-controlled. Chiglitazar and placebo were manufactured by Chengdu Chipscreen Pharmaceutical. Physicians offer these drugs to patients freely.

Sample size estimation

The target number of participants in the study was 300 (150 patients in the chiglitazar group and 150 patients in the placebo group).

The estimation of sample size was derived from a two-group comparison of the proportions of patients satisfying the primary outcome. The sample size calculations were performed using PASS 2025 software. The expected proportions improved of about 0.629 in the chiglitazar group, and based on the Chinese NAFLD Clinical Research Network (CNAFLD CRN) study, about 0.293 in the placebo group.¹⁸ With an α level of two-sided type I error of 0.05 and a β level of type II error of 0.2, the minimum number for each group was 100 using the above estimations. Considering a 20% missing data rate and 0.15 superiority margin yielded approximately 125 patients per group or a total of 250 patients. In practice, to further ensure the validity of the trial data, we plan to enrol 150 patients in each of the treatment and control groups, totalling 300 participants in the study.

Eligibility criteria

Participants deemed eligible for inclusion in the study must satisfy the following criteria: They must be aged between 18 and 75 years; HbA1c≤9.5% at screening in patients with diagnosed T2DM; and they must have histological evidence of steatohepatitis and fibrosis stage 1 or higher, as per the NASH CRN classification, have a NAS score of at least 4, with a minimum of 1 point for lobular inflammation and hepatocyte ballooning. These criteria are to be determined by a central pathologist, based on a baseline liver biopsy evaluation. The exclusion criteria include participants with specific causes of chronic liver disease other than NAFLD, such as suspected alcohol consumption higher than 20 g/day for women and 40 g/day for men, or test positive for hepatitis B surface antigen, or hepatitis C virus RNA at screening. Treatment‐related exclusion criteria include using GLP‐1RAs and thiazolidinediones (TZDs) for 90 days prior to screening. If participants have a history of liver biopsies taken 6 months prior to screening, treatment must be at a stable dose from the time of biopsy until screening. The whole inclusion and exclusion criteria can be found in table 2.

Table 2. Patient inclusion and exclusion criteria.

Inclusion criteria

Exclusion criteria

1. Men and women aged at least 18 years and under 75 years (inclusive) at the time of obtaining consent. 2. Participants must be diagnosed as T2DM and HbA1c≤9.5% at the time of screening. 3. Participants must take Fibroscan examination with the result of CAP≥238 dB/m and LSM＞8.5 kPa. 4. Diagnosis of MASH by liver biopsy, with NAFLD Activity Score (NAS)≥4 with ≥1 point for each component and fibrosis stage 1 or more according to the NASH Clinical Research Network (CRN) scoring system (or liver biopsy not more than 6 months prior to screening). 5. Stable body weight (≤10% body weight change) for at least 3 months. 6. Possess good understanding and behaviour and be able to take the medication daily as required by the trial. 7. Willing to sign the informed consent.

1. Alcohol consumption>20 g ethyl alcohol/day for women and>40 g ethyl alcohol/day for men. 2. Evidence of other forms of chronic liver disease: Alcoholic liver disease. Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg) or hepatitis B DNA. Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA or positive hepatitis C antibody (anti-HCV). Evidence of autoimmune liver disease as defined by compatible liver histology. Current drug-induced liver disease as defined on the basis of typical exposure and history. Suspected or proven liver cancer. Any other type of liver disease other than MASH. 3. Uncontrolled T2DM defined as HbA1c>9.5% at the time of screening or type 1 diabetes mellitus (T1DM). 4. Patients with T2DM who have a history of diabetic ketoacidosis, proliferative diabetic retinopathy, diabetic maculopathy or severe non-proliferative diabetic retinopathy that requires acute treatment. 5. Any of the following cardiovascular conditions within 6 months prior to screening: Acute myocardial infarction (MI). Cerebrovascular accident (stroke). Unstable angina, Hospitalisation due to congestive heart failure (CHF). New York Heart Association Functional Classification IV CHF. 6. History of an active or untreated malignancy or are in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years. 7. Uncontrolled hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg). 8. Renal impairment measured as estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2. 9. Known clinically significant gastric emptying abnormality (eg, severe diabetic gastroparesis or gastric outlet obstruction) or chronically take drugs that directly affect gastrointestinal motility. 10. Have a known self or family history (first-degree relative) of multiple endocrine neoplasia type 2A or type 2B, thyroid C-cell hyperplasia, or medullary thyroid carcinoma (MTC). 11. Evidence of untreated hypothyroidism or hyperthyroidism based on clinical or laboratory evaluation. 12. A transplanted organ (corneal transplants allowed) or awaiting an organ transplant. 13. Women of childbearing potential: positive pregnancy test during screening or at randomisation or unwillingness to use an effective form of birth control during the trial (at least include one barrier contraceptive method) and breastfeeding. 14. Use of drugs associated with hepatic steatosis (eg, amiodarone, methotrexate, tamoxifen) for more than 2 weeks in the 3 months prior to screening. 15. Current use of medication is associated with weight gain, except when on stable dose for at least 3 months prior to screening and remaining on stable dose during the study. 16. Receiving or having received (within 3 months of screening) chronic (>2 weeks) systemic glucocorticoid therapy. 17. Use of medications or alternative remedies (within 3 months prior to screening; prescribed or over-the-counter) intended to promote weight loss. 18. Use of treatment targeting MASH for more than 2 weeks in the 3 months prior to screening (GLP-1 receptor agonists, TZD analogues or PPAR pan agonists). 19. Any other condition which in the opinion of investigator would impede compliance or hinder completion of the study.

CAP, controlled attenuation parameter; GLP-1, glucagon‐like peptide‐1; LSM, liver stiffness measurement; MASH, Metabolic dysfunction-associated steatohepatitis; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione.

Randomisation and masking

Randomisation will be stratified by baseline liver fibrosis stage (F1, F2, F3 or F4) according to the NASH CRN classification. A block randomisation method with a fixed block size (variable block sizes may be used to reduce predictability) will be employed to assign participants to the chiglitazar or placebo group in a 1:1 ratio. The randomisation list and corresponding allocation codes will be generated by an independent unblinded statistician using SAS V.9.4 or higher. The randomisation blind code will include the randomisation number, treatment allocation, and drug kit number.

To ensure successful blinding, this study uses a placebo control. All investigational products (chiglitazar 48 mg and matching placebo) will be manufactured by Chengdu Chipscreen Pharmaceutical. The active drug and placebo will be identical and indistinguishable in appearance, shape, size, colour, odour, taste and packaging.

Drug kits will be individually packaged for each participant according to their randomly assigned treatment code (A or B). The outer packaging will only display the study name, participant number, visit point, dosage and expiration date, without any information revealing the actual treatment group.

This trial will use an Interactive Web Response System (IWRS) for central randomisation and drug dispensing. After eligibility is confirmed, the investigator will log into the IWRS to obtain the randomisation number and corresponding drug kit number sequentially based on the order of successful screening. The IWRS will then assign the participant to the appropriate treatment group and dispense the corresponding medication. Both the participants and the investigators (including outcome assessors and data analysts) will remain blinded to the treatment assignment until study completion, database lock and unblinding per the prespecified unblinding plan.

Safety evaluation process

An adverse event (AE) is an unintended medical occurrence that happens in a subject undergoing a clinical study of the study drug. AEs are not necessarily causally related to treatment. An AE can therefore be any unfavourable, unanticipated signs (including abnormal laboratory test results), symptoms or temporary disease condition, whether or not related to the investigational drug. The physicians will assess the severity of AEs.

A serious AE (SAE) refers to medication-related events that require hospitalisation, are disabling, life-threatening or fatal or result in congenital malformations during treatment. Any SAE must be immediately reported to the hospital director and study drug supplier.

Follow-up visit

Participants will return for follow-up visits at 2, 6, 13, 26, 39, 52, 65 and 78 weeks after randomisation. The details of various data obtained at each of these follow-up visits are shown in table 3.

Table 3. Schedule for observations, tests and assessments.

Period item	Screen period		Treatment period								follow-up period
Visit	1	2*	3	4	5	6	7	8	9	10	11
Week for treatment	−2~0	0	2	6	13	26	39	52	65	78	80
Visit window (days)		±3	±3	±7	±7	±7	±7	±7	±7	±7	±7
Informed consent	X
Inclusion/Exclusion	X	X
Randomisation		X
Demographic data	X
Medical history	X
Vital signs (BP, pulse rate and body temperature)	X	X	X	X	X	X	X	X	X	X	X
Physical examination	X	X	X	X	X	X	X	X	X	X	X
Height, weight, BMI, abdominal circumference†	X	X	X	X	X	X	X	X	X	X	X
Concomitant medications	X	X	X	X	X	X	X	X	X	X	X
Diet, physical activity coaching	X	X	X	X	X	X	X	X	X	X	X
Study drugs dispense and return		X	X	X	X	X	X	X	X	X
Treatment			X
Liver biopsy‡	X									X
Fibroscan examination	X		X	X	X	X	X	X	X	X	X
Virological examination§	X
Blood routine examination¶	X		X	X	X	X	X	X	X	X	X
Blood biochemistry**	X		X	X	X	X	X	X	X	X	X
Coagulation function test††	X									X
Blood lipid test‡‡	X		X		X	X	X	X	X	X
Diabetes indicators§§	X		X	X	X	X	X	X	X	X
HbA1c	X				X	X	X	X	X	X
Pregnancy test¶¶	X
ECGs	X									X
Ultrasonic test***	X			X	X	X	X	X	X	X

^*Participants with acceptable previous liver biopsy do not need to attend Visit 2.

^†BMI was calculated based on height and weight.

^‡Participants with an acceptable liver biopsy prior to screening do not need to have an additional screening liver biopsy. The liver biopsy should be taken before all other examinations.

^§Virological examinations include serum hepatitis B surface Ag, hepatitis B DNA and hepatitis C antibody (Ab) or hepatitis C RNA.

^¶Blood routine tests include C reactive protein, haemoglobin, white blood cell count, neutrophil ratio and count, lymphocyte ratio and count, monocyte ratio and count, neutral lymphocyte ratio and platelet count.

^**Blood biochemistry includes alanine aminotransferase, aspartate aminotransferase, albumin, prealbumin, total bilirubin, direct bilirubin, indirect bilirubin, alkaline phosphatase, glutamyl transpeptidase, creatinine, uric acid, urea and eGFR.

^††Coagulation function tests include prothrombin time, international normalised ratio (INR) and D-dimer.

^‡‡Blood lipid tests include triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein and non-high-density lipoprotein.

^§§Diabetes indicators include fasting blood glucose, fasting insulin and fasting C-peptide.

^¶¶Serum pregnancy test will be performed at Visit 1 for women of child-bearing potential.

^***Ultrasonic test include liver, biliary, pancreatic, splenic, carotid and bilateral lower limb vessels.

BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate.

Concomitant treatment

Contraindicated treatments:

1. PPAR agonist, include TZDs and lanifibranor.

2. Fibrates drugs.

Antidiabetic drugs other than those listed above can be added for patients with inadequate glycaemic control.

Statistical analysis

The full analysis set (FAS) was defined as all patients after randomisation, treated with study drug and with at least one post-baseline fibroscan efficacy data assessment.

Per-protocol set (PPS) as a subset of the FAS dataset of more adherent protocols; required to refer to the set of cases that meet the inclusion criteria, do not meet the exclusion criteria and complete the treatment protocol, no serious breaches of the protocol (including the entry criteria), good adherence (adherence between 80–120%) and completion of the fill-in elements specified in the case report form (CRF) (no missing key efficacy indicators) were analysed.

Continuous variables will be summarised using mean, SD, median, minimum, maximum, first quartile (Q1) and third quartile (Q3). Categorical variables will be summarised using counts and percentages.

Comparisons between groups will use appropriate methods based on variable type: continuous variables will be compared using two-sample t-tests (if normality and homogeneity of variance assumptions hold) or Wilcoxon rank-sum tests; categorical variables will be compared using χ² tests or Fisher’s exact test (if χ² test is not applicable); ranked data will be analysed using Wilcoxon rank-sum or Cochran–Mantel–Haenszel (CMH) tests.

The primary efficacy analysis will be based on both the FAS and PPS. Statistical description and inference will use appropriate methods based on data characteristics. The proportions will be described for each group and compared. The difference in proportions and its 95% CI will be calculated. Superiority will be concluded if the lower limit of the 95% CI for the difference is greater than the superiority margin. Subgroup analyses will be conducted for important factors such as randomisation stratification factor, baseline body mass index, amount of weight loss, baseline liver fat content and T2DM severity. Other exploratory subgroup analyses may be performed if deemed necessary by the research team.

Secondary efficacy analyses will be based on both the FAS and PPS. Statistical description and inference will use appropriate methods based on the characteristics of each endpoint.

The software used for statistical analyses was SAS 9.4 or higher version, and all statistical tests were performed using two-sided tests, and a p value of less than 0.05 would be considered statistically significant for the differences tested.

Safety end points

The occurrence rate of AEs was monitored during each patient visit, from visit 1 to the follow-up period (visit 8). All patients after randomisation, treated with the study drug and with at least one assessment of post-treatment safety data were defined as the safety analysis set.

Interim analysis

This study plans to conduct a pre-specified interim analysis, the primary objectives of which are futility analysis and sample size re-estimation based on the conditional power of the primary endpoint. This interim analysis is scheduled to commence on completion of the 78 week visit by 50% of participants, with primary endpoint data requiring confirmation and locking by the central pathology laboratory. The entire analysis process will be conducted by an Independent Data Monitoring Committee (IDMC) and will remain blinded to the study team and relevant personnel. No formal hypothesis testing for efficacy will be performed at the interim analysis and no alpha will be spent; thus, no additional multiplicity adjustment is required and the primary endpoint will be tested once at study completion at a two-sided significance level of 0.05.

Data management

Investigators shall enter data into the Electronic Data Capture system in a timely, complete, accurate and legible manner based on the original observations of the subjects. Paper data file will be stored in locked filing cabinets, with restricted access. Non-identifying information will be provided to an independent team of statisticians for analysis when data collection is complete.

The sponsor shall appoint Clinical Research Associate to perform monitoring duties before, during and after the trial. Monitors shall supervise the study to ensure compliance with the protocol. They shall verify that all CRFs are correctly and completely filled out and are consistent with the source documents. Any errors or omissions shall be promptly corrected by the investigator. Corrections must leave the original entry legible, and the correction must be signed and dated by the investigator.

An IDMC will be established by the Sponsor prior to the formal initiation of this study. This committee will periodically evaluate the progress of the clinical trial, including safety data and critical efficacy endpoints (eg, interim analysis results), and will advise the Sponsor on whether to continue, modify or terminate the trial. The IDMC shall have written operating procedures and shall maintain records of all its meetings. The IDMC charter will be held in the Investigator Site File.

Ethics and dissemination

This study will be conducted in compliance with the Declaration of Helsinki. The study protocol and relevant supporting data were approved on December 2025, by the Shanghai Punan Hospital of Pudong New District Ethics Committee. The study was registered at clinicaltrials.gov (NCT07303803). All participants will sign a written informed consent. Copies of the written informed consent can be found in online supplemental file 2. The results of this study will be submitted for publication in international peer-reviewed journals. Requests for data sharing should be directed to the corresponding author.

Patient and public involvement

Patients or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

Discussion

The aim of the study is to demonstrate that treatment with chiglitazar 48 mg/day improves liver histology compared with placebo in participants with MASH and T2DM.

Indeed, the hypothesis that MASH represents the hepatic manifestation of the metabolic syndrome has been advanced, with the identification of IR as a core pathogenetic mechanism.^{20 21} Substantial evidence confirms that T2DM is an important independent risk factor for advanced liver disease.⁷ The real-world study of 18 million European patients by Alexander M et al has also demonstrated that in NAFLD/NASH patients, the strongest correlation with cirrhosis or hepatocellular carcinoma is observed among patients with diabetes at baseline (HR: 2.3 (1.9–2.8)).²² Moreover, diabetes accelerates disease progression. While the prevalence of advanced fibrosis (F2–4) was found to be approximately 5%–7% in the general population, in patients with T2DM, this figure increased to 12–20%.^{7 23} Furthermore, higher fibrosis stages exponentially increased the risk of liver-related mortality compared with F0 (F3 vs F0: HR: 3.04 (1.94–4.78), p<0.001, F4 vs F0: HR: 6.53 (3.55–12.03), p<0.001).²⁴

Only two types of drugs have been approved for MASH currently. Resmetirom, a thyroid hormone receptor beta-selective agonist, was approved by the Food and Drug Administration (FDA) in March 2024.²⁵ The phase 3 study showed meaningful benefits in both low-dose and high-dose resmetirom on two major points of MASH, the steatohepatitis resolution and fibrosis improvement.²⁶ This conclusion remains significant even in patients with T2DM. However, it only proved 52-week histological outcome data, the effects on the pituitary-thyroid hormone axis remain unclear and long-term safety data require further investigation.²⁷ These limitations will restrict its widespread use in patients.

Another class of drugs, the GLP-1RA semaglutide, was approved by the FDA in August 2025 for the treatment of MASH. Although the resolution of steatohepatitis met the endpoint in patients with T2DM, the other major endpoint—improvement in liver fibrosis—did not reach statistical difference compare to placebo.⁸ Furthermore, higher therapeutic doses (2.4 mg/week) and common gastrointestinal side effects (nausea for 36.3%, diarrhoea for 26.9% and constipation for 22.3%) make long-term use difficult.²⁸

Given the above limitations of currently approved agents—particularly the unresolved long-term safety concerns of resmetirom and the lack of fibrosis improvement in patients with T2DM as well as tolerability issues with semaglutide, which remains a clear unmet need for alternative therapeutic options in this high-risk population. The present study is therefore designed as an exploratory, placebo-controlled trial to establish the absolute efficacy and safety of chiglitazar in patients with MASH and T2DM. A placebo control is methodologically appropriate for such an initial and early-stage confirmatory investigation, as it provides an unbiased estimate of the treatment effect while accounting for disease natural history and the impact of standardised background therapy.

The PPARs are of pivotal significance in the regulation of metabolism and inflammation. Consequently, they occupy a prominent role among the nuclear receptor transcription factors, given their function in regulating insulin resistance (IR), lipid and glucose metabolism, inflammation and fibrosis.⁹ Chiglitazar is an innovative pan-PPAR agonist that has been shown to simultaneously activate all three subtypes of the receptor (α, β/δ and γ), which means the use of chiglitazar could deliver the therapeutic benefit across all progression stages of MASH. The influence of PPARs in the liver involves a complex inter-organ crosstalk. In simple terms, PPARα increases fatty acid oxidation, exerts anti-inflammation effects through transrepression of pro-inflammatory target genes.^{29 30} PPARβ/δ increases glucose utilisation and de novo lipogenesis in the liver, and it also activates Kupffer cells which contributes to hepatic insulin sensitivity.^{31 32} PPARγ mostly influences liver fibrosis, maintaining hepatic stellate cells in a quiescent state and preventing hepatic fibrogenesis.³³ The phase 2 study of chiglitazar has already shown a significant reduction in liver fat content and improvement in markers of liver injury in patients with MASLD.¹⁷ Altogether, chiglitazar is a promising new therapeutic candidate for the treatment of MASH.

Due to the worse prognosis in patients with MASH associated with T2DM and the difficulty of improving liver fibrosis, we chose vitamin E and polyene phosphatidyl choline as combination therapy. Vitamin E is a natural antioxidant, with oxidative stress being one of the contributors in the process of MASH; therefore, it might be a promising treatment.³⁴ A clinical study showed that a 96-week intervention of vitamin E (300 mg/day) remarkably reduced liver steatosis, but the stage of liver fibrosis did not improve significantly.¹⁸

Polyene phosphatidyl choline is a major active ingredient of essential phospholipids, which could maintain membrane fluidity and function. It has been reported to repair damaged hepatic cell membranes and restore oxidative balance, thereby promoting liver function restoration.³⁵ A prospective study completed by Maev et al in Russia showed that using polyene phosphatidyl choline as an adjunctive therapy can improve the ultrasonographic features of NAFLD.³⁶ This proved that polyene phosphatidyl choline might be useful in inflammatory and metabolic diseases. However, no studies have used liver biopsy to evaluate its therapeutic effect.

All participants in both the treatment and control groups received vitamin E and polyene phosphatidyl choline as standardised background therapy. Therefore, any between-group difference in the primary endpoint can be ascribed to the add-on effect of chiglitazar. Moreover, in patients with MASH and type 2 diabetes, liver dysfunction is common and there is a usual clinical need for basic hepatoprotective support.³⁷ A standardised background therapy across both arms reduces confounding variables and enhances internal validity rather than obscuring the investigational drug’s effect. Finally, although vitamin E is recommended in some guidelines for non-diabetic MASH, its effect on fibrosis remains limited in the T2DM population. And polyene phosphatidyl choline is widely used as a hepatoprotective agent in Chinese clinical practice but lacks high-grade biopsy-proven evidence. Thus, while these two agents provide a certain level of background care, they cannot substitute for targeted therapy addressing the core pathogenesis of MASH. Chiglitazar, as a pan-PPAR agonist, may fill this therapeutic gap by improving IR, inflammation and fibrosis.

In conclusion, this trial is expected to provide critical evidence on the efficacy and safety of chiglitazar for treating MASH in patients with T2DM. If successful, the findings may establish a new targeted therapeutic option for this clinically challenging and high-risk patient population, potentially reducing the long-term burden of advanced liver disease, and will support the rationale for future head-to-head active-controlled trials comparing chiglitazar directly with existing MASH therapies.