
Metabolic dysfunction-associated steatohepatitis (MASH) presents a complex challenge in clinical trials due to its multifaceted nature and requirements for proper diagnosis. Addressing screen failure in MASH clinical trials is crucial, as it ensures the efficacy and safety profiles of potential treatments are accurately assessed from the onset. At Worldwide Clinical Trials, we’re committed to leveraging our MASH experience and patient-centric approach to navigate these challenges and drive better outcomes.
Common Causes of Screen Failures in MASH/MASLD
Due to the prevalence of screen failures and early dropouts in MASH and metabolic dysfunction-associated steatotic liver disease (MASLD) clinical trials, it’s important to understand why these occur so frequently. Here are several common causes:
- Difficulties in Diagnosis: MASH/MASLD can be challenging to diagnose since there is no single test to confirm the disease, and liver enzymes alone are insufficient for diagnosis. Liver biopsy is the standard for grading and staging but is not consistently performed due to its invasive nature and prohibitive cost. Misdiagnoses can lead to patients being excluded from studies during screening.
- Complex Disease Progression: The spectrum of MASH/MASLD encompasses various stages, from steatosis to advanced liver fibrosis. Inaccurately identifying the disease stage can lead to screen failures.
- Existing Comorbidities: Many patients with MASH/MASLD have comorbid conditions such as insulin resistance, dyslipidemia, central obesity, and hypertension. The medications used to manage these conditions can interfere with trial protocols, leading to exclusions from clinical trials or early dropouts.
- Placebo-Controlled Study Designs: Due to on- and off-label medications (i.e., GLP-1 agonists, or SGLT2 inhibitors), placebo-controlled studies are often less attractive for patient recruitment and retention in developed markets.
- Patient Eligibility Criteria: Strict inclusion and exclusion criteria related to liver function, fibrosis stage, and metabolic conditions may disqualify many potential participants, resulting in higher screen failures.
4 Ways Worldwide Mitigates Screen Failures
1. Strategic Pre-Screening & Screening
Accurate pre-screening to identify eligible participants early and efficiently is fundamental in reducing screen failures and requires a robust understanding of the disease’s diagnostic criteria. The least expensive pre-screening procedure includes using biomarkers and composite scores, such as FIB4 index scoring and enhanced liver fibrosis (ELF) biomarker analysis. Other noninvasive diagnostic measurements include:
- Magnetic resonance elastography (MRE): Ultrasound-based transient elastography
- MRI-based proton density fat fraction (MRI-PDFF): Magnetic resonance imaging to estimate proton density fat fraction
- Vibration-controlled transient elastography (VCTE)
For patients with MASLD, FIB-4 testing, followed by VCTE or MRE, provides valuable insights into liver stiffness and fibrosis. Comprehensive workups are recommended for at-risk MASH patients, especially those with hepatic fibrosis. Utilizing cut-off values from tests such as NFS and FAST can further aid in precise patient screening.
2. Innovative Protocol Design
Tailored clinical trial protocols to minimize screen failures require incorporating flexible eligibility criteria and adjusting protocols based on patient population characteristics. By adapting protocols to the specific needs of MASH patients, we can enhance the accuracy of participant selection and improve trial outcomes.
Successful protocol adaptations in MASH trials often involve modifications based on real-world challenges encountered during the study. For example, adjusting the frequency of liver biopsies or incorporating alternative diagnostic methods can help reduce participant dropout rates and enhance overall study efficiency. One innovative trial design that can be used is a basket trial for proof-of-concept, which helps establish early evidence for treatment.
3. Use of Advanced Diagnostic Tools
Specialized liver imaging techniques are essential in accurately assessing liver condition and reducing screen failures. Some techniques include whole organ volume analysis and liver stiffness measurements to provide detailed insights into liver health. It’s also critical to provide skilled rater training to reduce inter-rater variability. Ideally, the same experienced operator familiar with the equipment will perform the initial and repeat scans or reviews when needed.
4. Patient Recruitment & Retention Optimization
One significant factor that helps decrease screen failures and early dropouts in MASH trials is effective patient recruitment and retention strategies. One way to optimize patient retention is to develop a robust understanding of the patient journey and design the clinical trial with the patient’s needs in mind.
At the beginning of a study, there should be an intentional effort to educate potential patients regarding the invasive requirements of MASH studies, including information about why a follow-up procedure is necessary to assess response to treatment . When invasive screening procedures are necessary, they should be accompanied by a meaningful endpoint. For example, Rezdiffra (resmetirom) was approved by the FDA in March 2024 for the treatment of MASH, evaluated based on the surrogate endpoint of the extent of liver inflammation and scarring. To gain full approval, the FDA required the sponsor to conduct a post-approval study to verify Rezdiffra’s clinical benefit.
Another way to boost patient retention is to offer considerable support throughout the study, especially during the post-biopsy period, to address any side effects like pain or bleeding and to answer all their questions. The MASH liver biopsies are often done off-site in radiology suites, and the post-procedure follow-up by clinical site staff may vary greatly.
It’s important to build effective communication early in the trial so clinical site staff are in close contact with the patient post-procedure to assess their need for clinical support, following local standards of care, which can help minimize screen failures and early dropouts. As required by ethics and regulatory committees, the most invasive procedure, often the liver biopsy, should come last, with less invasive methods used as part of eligibility criteria to screen patients prior to biopsy.
Building strong relationships with patient advocacy organizations can help educate patients about MASH and the clinical trial process, improving participant engagement and adherence. It’s also imperative to provide fair compensation for participation to better increase the likelihood of patient engagement.
A further area where many screen failures in potential subjects occur is when primary care providers prescribe participants with prohibited medications that have not been disclosed. Discussing prohibited medications early, particularly before a screening liver biopsy is obtained, can help mitigate screen failures. To overcome this barrier, Worldwide often implements a priori stratification for concomitant medications to optimize patient outcomes.
MASH Clinical Trials with Worldwide
At Worldwide, we emphasize a comprehensive, patient-centric approach in our MASH clinical trials. Our team’s expertise in MASH, combined with our commitment to minimizing screen failures and improving patient care, ensures we deliver high-quality results. If you’re interested in learning more about our services and how we can assist in your MASH clinical trials, contact us.