Clinical Care Pathway for Non-Alcoholic Fatty Liver Disease

(NCCP Trial)

Overseen By Kyler Godwin, PhD MPH BS

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: VA Office of Research and Development

Disqualifiers: Unstable leadership, Focus group participation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

32 Participants Needed

Trial Summary

What is the purpose of this trial?

Non-alcoholic fatty liver disease (NAFLD) is a new condition that has become the most common chronic liver disease in the world and a main cause of liver cirrhosis, liver failure and liver cancer. Obesity and diabetes, conditions that are very common among Veterans are the main risk factors for NAFLD. Therefore, the burden of NAFLD and its complications among Veterans is substantial. However, most VA patients with NAFLD are undiagnosed and untreated, and their care is not consistent with practice guidelines. The NAFLD Clinical Care Pathway (NCCP) intervention seeks to close this major gap in the care of Veterans by automatically identifying patients at risk of NAFLD, calculating their risk scores of having severe NAFLD, and educating the primary care providers on the diagnosis and treatment of NAFLD. This clinical trial will test the benefit of this NCCP intervention against usual care in increasing the rates of NAFLD diagnosis as well as referral to and enrollment in appropriate treatment. The study will also identify barriers and promotors of future NCCP implementation.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is resmetirom safe for humans?

Resmetirom has been shown to be safe and well tolerated in a 52-week clinical trial for non-alcoholic fatty liver disease, with common side effects including diarrhea and nausea at the start of treatment. ^{1 2 3 4 5}

What makes the NAFLD Clinical Care Pathway (Rezdiffra, resmetirom) treatment unique for non-alcoholic fatty liver disease?

The NAFLD Clinical Care Pathway is unique because it provides a structured approach to screening, diagnosing, and managing non-alcoholic fatty liver disease, focusing on accurate staging of liver fibrosis and integrating care across primary and secondary healthcare settings. This pathway emphasizes timely and evidence-based management, which is crucial for a condition that often shows no symptoms and lacks standard medication treatments. ^{6 7 8 9 10}

Research Team

Hashem B. El-Serag, MD MPH

Principal Investigator

Michael E. DeBakey VA Medical Center, Houston, TX

Eligibility Criteria

This trial is for individuals at risk of Non-alcoholic Fatty Liver Disease (NAFLD), which is often undiagnosed and untreated among Veterans. The study aims to improve diagnosis and treatment by using an automated system called NCCP to identify patients, assess their NAFLD severity, and guide primary care providers.

Inclusion Criteria

Patient Aligned Care Teams (PACT) at the Michael E. DeBakey VA Medical Center

Exclusion Criteria

PACTs with unstable leadership (i.e., pending departure, vacancy) at time of randomization

PACTs participating in the focus groups in Aim 1

PACTs who do not treat NAFLD

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Intervention

The NCCP intervention is applied, including e-trigger generation, FIB-4 score assessment, and provider education on NAFLD management

6 months

Every 3 months (e-trigger generation)

Follow-up

Participants are monitored for NAFLD diagnosis, risk stratification, and referrals to weight loss and hepatology services

6 months

6 and 12 months (data extraction from EHR)

Summative Evaluation

Evaluation to identify patient and provider characteristics associated with the effectiveness of NCCP and assess future implementation

12 months

Treatment Details

Interventions

• NAFLD Clinical Care Pathway

Trial Overview The intervention being tested is the NAFLD Clinical Care Pathway (NCCP), which uses electronic triggers (E-trigger) to automatically identify veterans at risk for severe NAFLD, calculate their risk scores, and educate healthcare providers on managing the condition.

Participant Groups

Group I: E-trigger Experimental Treatment 1 Intervention

The NCCP Intervention is made up of multiple components. The investigators will start by applying the e-trigger and assessing the FIB-4 score, and then will train and educate PACT personnel on managing patients with positive triggers, including making treatment recommendations in collaboration with an inter-professional team. The e-trigger will be generated every three months.

Group II: Usual care Active Control 1 Intervention

The control group will receive no additional training or education. PACTs will provide usual care.

NAFLD Clinical Care Pathway is already approved in United States for the following indications:

Approved in United States as Rezdiffra for:

• Non-alcoholic steatohepatitis (NASH)

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Findings from Research

In a 52-week phase 3 trial involving 1,143 adults with presumed NASH, resmetirom was found to be safe and well tolerated, with treatment-emergent adverse events occurring in similar rates compared to placebo.

Resmetirom significantly reduced hepatic fat, LDL-C, apoB, and triglycerides, indicating its potential efficacy in treating nonalcoholic steatohepatitis and supporting further clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Harrison, SA., Taub, R., Neff, GW., et al.[2023]

Current treatments for nonalcoholic fatty liver disease (NAFLD) are still not very effective, but weight loss remains a key target for therapy despite being difficult to achieve.

Several investigational drugs show promise for treating NASH, but concerns about long-term safety exist, particularly with vitamin E and other medications like pioglitazone and obeticholic acid, which have notable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment options for nonalcoholic steatohepatitis - a safety evaluation. Issa, D., Wattacheril, J., Sanyal, AJ.[2017]

In a 36-week study involving 125 patients with biopsy-confirmed NASH, resmetirom significantly reduced hepatic fat compared to placebo, with a 32.9% reduction at 12 weeks and 37.3% at 36 weeks, indicating its efficacy in treating NASH.

The treatment was generally safe, with most adverse events being mild or moderate; however, there was a higher incidence of mild diarrhea and nausea in patients taking resmetirom.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Harrison, SA., Bashir, MR., Guy, CD., et al.[2021]

In a network meta-analysis of 2,252 patients from 31 randomized controlled trials, GLP-1 agonists were found to significantly reduce intrahepatic steatosis (IHS) and liver enzyme levels compared to standard care, indicating their efficacy in treating non-alcoholic fatty liver disease (NAFLD).

While GLP-1 agonists showed the highest effectiveness in reducing liver fat and enzymes, they were also associated with a higher likelihood of adverse events compared to other anti-diabetic medications, highlighting the need for careful monitoring in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New anti-diabetic agents for the treatment of non-alcoholic fatty liver disease: a systematic review and network meta-analysis of randomized controlled trials. Kongmalai, T., Srinonprasert, V., Anothaisintawee, T., et al.[2023]

Non-alcoholic steatohepatitis (NASH) is a leading cause of liver failure and transplantation in the U.S., linked to conditions like obesity and type 2 diabetes, highlighting the urgent need for effective treatments.

Current first-line treatments focus on weight loss and lifestyle changes, but these may not work for patients with advanced liver disease, emphasizing the importance of ongoing drug development targeting NASH's underlying mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New drugs for NASH. Albhaisi, SAM., Sanyal, AJ.[2021]

A new primary care pathway for managing non-alcoholic fatty liver disease (NAFLD) that includes a specialist nurse-led clinic effectively discharged 70.8% of patients back to primary care, helping to alleviate the burden on secondary care services.

The pathway also improved screening for hepatitis B and C viruses and identified 17 new cases of alpha-1-antitrypsin deficiency, highlighting its potential to enhance overall patient care and early detection of related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of a primary to secondary care referral pathway and novel nurse-led one-stop clinic for patients with suspected non-alcoholic fatty liver disease. Fowell, AJ., Fancey, K., Gamble, K., et al.[2022]

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children, and its prevalence is rising due to challenges in diagnosis.

Currently, there are no effective medications for NAFLD, making management difficult for healthcare providers, which is why this paper offers guidelines for screening, diagnosis, and management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updates in non-alcoholic fatty liver disease (NAFLD). McNeice, K., Sandberg, K.[2021]

Nonalcoholic fatty liver disease (NAFLD) affects about 37% of US adults and is often asymptomatic, making early screening and accurate staging of fibrosis risk essential for effective management.

The American Gastroenterological Association has developed a Clinical Care Pathway to guide clinicians in the screening, diagnosis, and treatment of NAFLD, particularly for patients with significant fibrosis (stages F2-F4), ensuring evidence-based practices are accessible across various healthcare settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Care Pathway for the Risk Stratification and Management of Patients With Nonalcoholic Fatty Liver Disease. Kanwal, F., Shubrook, JH., Adams, LA., et al.[2022]

The NAFLD Care Pathway implemented at Kaiser Permanente San Diego led to increased participation in weight management programs, with 10.6% of patients engaging in such programs after referral, compared to only 3.8% before.

Patients who participated in weight management after referral experienced significant weight loss (-7.78 kg on average) and a greater reduction in ALT levels (-28.8 U/L), highlighting the pathway's effectiveness in promoting lifestyle changes and improving liver health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective analysis of a dedicated care pathway for nonalcoholic fatty liver disease in an integrated US healthcare system demonstrates support of weight management and improved ALT. Patton, H., Burchette, R., Tovar, S., et al.[2021]

The AGA clinical pathway for identifying adults with significant fibrosis in NAFLD shows a high negative predictive value (90%) for liver stiffness measurements (LSM) when combined with a low FIB-4 score, indicating it effectively rules out significant fibrosis in low-risk patients.

An alternative strategy that focuses on patients with a FIB-4 score of 1.3 or higher and diabetes could reduce unnecessary liver stiffness tests (VCTEs) from 14.5 million to 4.9 million while improving the positive predictive value from 13% to 33%, enhancing the pathway's efficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Performance of American Gastroenterological Association Clinical Care Pathway for the risk stratification of patients with nonalcoholic fatty liver disease in the US population. Udompap, P., Therneau, TM., Canning, RE., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Treatment options for nonalcoholic steatohepatitis - a safety evaluation. [2017]

3. England pubmed.ncbi.nlm.nih.gov

Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

New anti-diabetic agents for the treatment of non-alcoholic fatty liver disease: a systematic review and network meta-analysis of randomized controlled trials. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

New drugs for NASH. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Evaluation of a primary to secondary care referral pathway and novel nurse-led one-stop clinic for patients with suspected non-alcoholic fatty liver disease. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Updates in non-alcoholic fatty liver disease (NAFLD). [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Clinical Care Pathway for the Risk Stratification and Management of Patients With Nonalcoholic Fatty Liver Disease. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Retrospective analysis of a dedicated care pathway for nonalcoholic fatty liver disease in an integrated US healthcare system demonstrates support of weight management and improved ALT. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Performance of American Gastroenterological Association Clinical Care Pathway for the risk stratification of patients with nonalcoholic fatty liver disease in the US population. [2023]