Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04054310 |
| Other study ID # |
IIP137 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 5, 2020 |
| Est. completion date |
May 1, 2024 |
Study information
| Verified date |
September 2023 |
| Source |
Perspectum |
| Contact |
Bryn Horsington, BSc. |
| Phone |
01865655343 |
| Email |
bryn.horsington[@]perspectum.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
To evaluate, in patients with suspected NASH referred for liver biopsy, the diagnostic
performance of CT1 at discriminating those with NAS≥4 & F≥2 from those without.
Description:
NASH trials will often use the criteria proposed by the NASH Clinical Research Network
(NASH-CRN), the NAS scoring system, to classify patients as suitable for study enrolment. NAS
is a summation of the histology scores for fat (0-3), inflammation (0-3), and ballooning
(0-2) with a score of 4 or 5 or higher regarded as NASH. Whilst the score doesn't include
fibrosis, the rapidly evolving clinical trials landscape in NASH has seen a shift in emphasis
from drugs proposed to target liver fat to the targeting of fibrosis. This was due to
observations contrary to the previously held belief that fibrosis could not improve, and the
data to support fibrosis being predictive of clinical outcomes. As a result, many clinical
trials now require patients to have a NAS ≥4 or 5, with the regulatory accepted criteria
requirement for at least a score of 1 for inflammation and 1 for ballooning, and evidence of
fibrosis of stage 2 or more (scored using the Kleiner-Brunt (0-4) scale). The route by which
a liver biopsy is indicated for inclusion to a clinical trial is usually based on patient
presentation and clinical work-up. In the Primary care patient presents with clinical risk
factors for NASH like metabolic syndrome. Blood biomarkers will be checked and if raised
patient will be referred to the hepatology. In the secondary care patient might have a
transient elastography and if CAP is equal or more than 280 and LSM is equal or more than 7
kPa, patient will have biopsy.
However clinical risk factors are often not sensitive enough, and NASH trials often suffer
from high levels of screen fails at biopsy, meaning a large proportion are unnecessarily
biopsied. Screening strategies are becoming increasingly more popular in order to reduce the
number that fail screening and metrics derived from magnetic resonance imaging (MRI) such as
T1-mapping and PDFF are emerging as promising diagnostic screening biomarkers in NASH.
MRI exploits the magnetic properties of hydrogen nuclei protons within a determined magnetic
field. T1 mapping measures longitudinal relaxation time, a measure of how long it takes for
protons to re-equilibrate their spins to the magnetic field after being excited by a
radiofrequency pulse, and thus is an indicator of regional tissue water (proton) content. T1
mapping has shown promise as an effective biomarker of liver inflammation and fibrosis, as T1
relaxation time lengthens with increases in extracellular fluid (which may be caused by
fibrosis and/or inflammation). The presence of iron however, which can be accurately measured
from MRI-T2star (T2*) relaxation time, shortens the T1, and thus must be accounted for. An
algorithm has been created (Perspectum Diagnostics) that allows for the bias introduced by
elevated iron to be removed from the T1 measurements, yielding the iron corrected T1 (cT1).
Iron corrected T1 (cT1) has been shown to correlate with fibro-inflammatory disease and can
effectively stratify patients with NASH and cirrhosis (7).
MRI-PDFF is a ratio, expressed as a percentage, of the fraction of the MRI-visible protons
attributable to fat divided by all MRI-visible protons in that region of the liver
attributable to fat and water. Taking advantage of the chemical shift between fat and water,
pulse sequences including fast spin echo and gradient-recalled echo (GRE) sequences can be
used to acquire images at multiple echo times at which fat and water signals have different
phases relative to each other. PDFF has been shown to have excellent correlation between
histologically graded steatosis across the clinical range seen in NASH and high diagnostic
accuracy in stratification of all grades of liver steatosis, although it is weaker in the
presence of advanced fibrosis. Whilst PDFF does not correlate with other features of NASH, it
has been reported that NAFLD patients with grade one steatosis are more likely to have
characteristics of advanced liver disease such as fibrosis and ballooning, and changes in
hepatic steatosis may be correlated with changes in other histological endpoints. Thus whilst
some authors advise caution about using PDFF as a biomarker of NASH it has been well accepted
by the NASH community as a biomarker for both enrolment and as an endpoint in NASH clinical
trials (e.g. MOZART: NCT01766713; FLINT: NCT01265498).
Where cT1 appears to have an advantage over PDFF as a non-invasive biomarker for NASH, is in
detection of patients with both disease activity (ballooning and inflammation) and fibrosis
as cT1 has been reported to be correlated with ballooning, fibrosis and NAFLD activity score,
and has been shown to predict clinical outcomes. As such it is emerging as a promising
biomarker for both screening and as an endpoint in NASH clinical trials (NCT02421094;
NCT02912260) particularly those investigating mechanisms of action of fibro-inflammation, or
for distinguishing those with more advanced NASH with fibrosis. Both cT1 and PDFF can be
acquired as part of the LiverMultiScan™ (LMS) imaging protocol (Perspectum Diagnostics Ltd,
UK).
Based on the data reported in the literature, and from our preliminary analysis of N=109
biopsy-confirmed NAFL patients recruited from the two UK studies, both cT1 and PDFF appear to
have potential to become diagnostic biomarkers, that may have utility for clinical trial
population enrichment when used in conjunction with clinical risk factors. Specifically, for
PDFF to identify participants who are more likely to have histopathologic findings of
steatosis, and cT1 to identify participants who are more likely to have histopathologic
findings of NASH, and NASH with fibrosis.
The primary objective of this study is to evaluate cT1 (Corrected T1) as a diagnostic
biomarker that can be used, in conjunction with clinical risk factors, to identify patients
who are more likely to have liver histopathologic findings of non-alcoholic steatohepatitis
(NASH). Ideally, this biomarker should identify patients with a non-alcoholic fatty liver
disease activity score (NAS) ≥ 4 and liver fibrosis (NASH/CRN Brunt/Kleiner scale) ≥ stage 2
on histopathologic assessment.
Based on our observations from earlier trials, our hypothesis is that we expect cT1 to have
good diagnostic accuracy for discriminating those with NAS≥4 & F≥2 from those without
