Primary objectiveTo evaluate the efficacy of BMS-986263 compared with placebo to improve liver fibrosis in participants with compensated cirrhosis due to NASHSecondary objectives1. To further assess the efficacy of BMS-986263 compared with placebo…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the efficacy of BMS-986263 compared with placebo to improve liver
fibrosis in participants with compensated cirrhosis due to NASH, by:
Proportion of participants who achieve >= 1 stage improvement in liver fibrosis
(NASH CRN Fibrosis Score), as determined by liver biopsy after 12 weeks of
treatment.
Secondary outcome
To further assess the efficacy of BMS-986263 compared with placebo to improve
liver fibrosis, as determined by liver biopsy, in participants with compensated
cirrhosis due to NASH, by:
* Proportion of participants with >= 1 stage improvement in liver fibrosis (NASH
CRN Fibrosis Score), with no worsening of NASH after 12 weeks of treatment
(worsening defined as an increase of the NAS by >= 1 point)
* Proportion of participants with >= 2 stage improvement in liver fibrosis (NASH
CRN Fibrosis Score) after 12 weeks of treatment Proportion of
* Proportion of participants with >= 1 stage improvement in liver fibrosis
(modified Ishak score) after 12 weeks of treatment
* Proportion of participants with >= 2 stage improvement in liver fibrosis
(modified Ishak score) after 12 weeks of treatment
* Change from baseline in CPA after 12 weeks of treatment
To assess the safety and tolerability of BMS-986263 in participants with
compensated cirrhosis due to NASH, by:
* Incidences of SAEs, AEs, clinical laboratory values, vital signs, physical
examination findings, and ECGs
* Change from baseline in BMD, as measured by DXA scan, at Follow-up Week 24
To assess the PK of BMS-986263 in participants with compensated cirrhosis due
to NASH
* Plasma concentrations of siRNA, DPD, HEDC, and S104 (components of BMS-986263
for injection)
Background summary
Study IM025017 aims to demonstrate the antifibrotic efficacy of BMS-986263,
using
a liver fibrosis histological endpoint, and the safety and tolerability of
BMS-986263, as assessed
by adverse events (AEs), serious adverse events (SAEs), laboratory results
(including assessment
of potential drug-induced liver injury), vital signs, physical examinations,
electrocardiograms
(ECGs), retinoid toxicity monitoring, infusion-related reaction monitoring, and
bone mineral
density (BMD) monitoring, in participants with nonalcoholic steatohepatitis
(NASH) and
compensated cirrhosis.
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of
chronic liver
disease in the world today. NASH, which is the more advanced form of NAFLD, is
defined as the
presence of hepatic steatosis and inflammation with hepatocyte injury
(ballooning), with or
without fibrosis. NASH is associated with increased mortality rates due to
cardiovascular-, liver-,
and cancer-related deaths. Currently, there are no approved drugs for the
treatment of NASH. With
the increasing prevalence of obesity and obesity-related diseases, NASH could
soon become the
leading indication for liver transplantation and the leading cause of
hepatocellular carcinoma
(HCC) globally.
NASH patients with cirrhosis have a particularly high unmet medical need for
effective therapies.
Among NASH patients, the stage of fibrosis is the strongest predictor of
disease-specific mortality,
and patients with cirrhosis are at the greatest risk for disease-related
morbidity and mortality.
Patients with cirrhosis are particularly at increased risk for poor clinical
outcomes, including
hepatic decompensation events and the need for liver transplant. It is
reasonable to assume that an
improvement in fibrosis would be predictive of clinical benefit, and a
reduction of fibrosis in
patients with compensated cirrhosis, if substantial, could lead to improvements
in liver function
and long-term clinical outcomes.
Study objective
Primary objective
To evaluate the efficacy of BMS-986263 compared with placebo to improve liver
fibrosis in participants with compensated cirrhosis due to NASH
Secondary objectives
1. To further assess the efficacy of BMS-986263 compared with placebo to
improve liver fibrosis, as determined by liver biopsy, in participants with
compensated cirrhosis due to NASH
2.To assess the safety and tolerability of BMS-986263 in participants with
compensated cirrhosis due to NASH
3. To assess the PK of BMS-986263 in participants with compensated cirrhosis
due to NASH
Study design
This is a randomized, double-blind, placebo-controlled, parallel-group,
multiple-dose Phase 2 study to evaluate the efficacy, safety, and tolerability
of BMS-986263 in adults with compensated cirrhosis due to NASH. The primary
study endpoint is the proportion of participants who achieve >= 1 stage
improvement in liver fibrosis (NASH CRN Fibrosis Score) on biopsy after 12
weeks of treatment.
The study includes:
* A screening period of up to 8 weeks
* A 12-week, double-blind treatment period, during which participants will
receive 1 of the following 3 treatments by intravenous (IV) infusion: 45 mg
BMS-986263 once every week (QW), 90 mg BMS-986263 QW, or placebo QW
* A follow-up period of 24 weeks, during which participants will not receive
investigational treatment
Participants meeting eligibility criteria during the screening period will
enter the treatment period and be randomized to receive 45 mg BMS-986263 QW, 90
mg BMS-986263 QW, or placebo QW by IV infusion in a double-blind manner for 12
weeks. Participants will be stratified at Randomization by the presence of
definite steatohepatitis on biopsy (yes versus no). At least 80% of
participants will be required to have definite steatohepatitis on the biopsy
used to confirm eligibility. Participants will receive study treatment via IV
administration for a total of 12 weeks. Liver biopsy will be performed at Week
12.
This study will utilize an external Data Monitoring Committee for the duration
of the study to assess safety data, and an external Independent Pathology
Review Committee to assess liver biopsies for eligibility and efficacy.
Intervention
Patients who have completed screening procedures (up to 56 days duration) and
met inclusion/exclusion criteria will be randomized on Day 1 of the treatment
period.
Patients will be randomized in a 1:1:1 ratio using interactive response
technology (IRT) to one of three treatments by intravenous (IV) infusion:
1. 45 mg BMS-986263 once every week
2. 90 mg BMS-986263 once every week
3. Placebo
Study burden and risks
As part of the trial, patients will be expected to attend multiple clinic
visits where they will undergo physical examinations, vital sign measurements,
blood tests for safety and efficacy assessment, pregnancy testing (for females
of child bearing potential), and monitoring for adverse events and serious
adverse events. Patients will be asked to complete questionnaires (CLDQ-NASH,
EQ-5D-5L, PGI-S-F and PGI-S-NS). Some visits require: CT/MRI scans, MRE scans,
ECGs, DXA scans and fibroscans. If there is no archival liver biopsy tissue
available or the sample was taken too long ago (>=12 months) patients will be
required to have a biopsy in order to participate. A liver biopsy is also
required at the end of the treatment period. Patients will be monitored for 12
weeks after treatment completion. The frequency of visits and number of
procedures carried out during this trial would be typically considered over and
above standard of care. The procedures are carried out by trained medical
professionals and every effort will be made to minimize any risks or discomfort
to the patient.
BMS will conduct rigorous safety monitoring to ensure patients safety by
regularly & systematically reviewing safety data; the reported safety events
will be closely followed-up.
Study medication and procedures related risks are outlined in the patient
information sheet in detail to ensure the patients are fully informed before
agreeing to take part in the study.
Orteliuslaan 1000
Urecht 3528 BD
NL
Orteliuslaan 1000
Urecht 3528 BD
NL
Listed location countries
Age
Inclusion criteria
*Male and female participants, ages >= 21 years to <= 75 years of age, inclusive,
at the time of screening;
*Liver biopsy performed within 12 months prior to the screening visit or
performed during the screening period. A liver biopsy performed prior to
informed consent form, if utilized for eligibility, must be available for
central pathology reading prior to Randomization.
i) Liver biopsy consistent with NASH Clinical Research Network (CRN)
Fibrosis
Score Stage 4, as assessed by central pathology reading.
ii) Liver biopsy must either be consistent with steatohepatitis, as
assessed by central
pathology reading, OR, for liver biopsies without definite steatohepatitis,
there should
be some evidence of steatosis and/or ballooning and the following definition of
NASH
cirrhosis must be fulfilled:
(1) Absence of other causes of liver disease AND either of the
following:
(a) At least 2 of the 3 following criteria:
(i) History of body mass index [BMI] >= 30 kg/m2
(ii) History of type 2 diabetes mellitus
(iii) History of hypertension AND/OR history of
dyslipidemia
OR
(b) Previous histologic readings of steatohepatitis (for
biopsies > 12 months prior to screening visit) AND either history of BMI >= 30
kg/m2 OR history
of type 2 diabetes mellitus.
NOTE: At least 80% of participants will be required to have definite
steatohepatitis on
the biopsy used to confirm eligibility.
Exclusion criteria
*Other active causes of liver disease (eg, alcoholic liver disease, hepatitis B
virus infection, chronic hepatitis C virus infection, autoimmune hepatitis,
primary biliary cholangitis, primary sclerosing cholangitis, drug-induced
hepatotoxicity, Wilson disease, homozygous α-1-
antitrypsin deficiency, iron overload [with blood iron saturation > 50%], or
hemochromatosis)
* Past or current evidence of hepatic decompensation (eg, ascites, variceal
bleeding, hepatic encephalopathy, or spontaneous bacterial peritonitis)
* Liver transplantation (past or planned)
* Child-Pugh Score > 6 at screening. Participants with a Child-Pugh Score > 6
with elevated total bilirubin and who have Gilbert Syndrome and direct
bilirubin <= the upper limit of normal (ULN) may be included after discussion
with the Medical Monitor
* Model for End-stage Liver Disease (MELD) score > 14 at screening.
Participants with a MELD Score > 14 with elevated total bilirubin and who have
Gilbert Syndrome and direct bilirubin <= the ULN may be included after
discussion with the Medical Monitor
* Evidence of HCC at screening based on (i) serum alpha-fetoprotein (AFP) > 20
ng/mL
(> 16.5 IU/mL) or (ii) Liver Reporting & Data System 3, 4, or 5 as determined
by historical computed tomography (CT)/magnetic resonance imaging (MRI) within
3 months prior to screening or from multiphasic CT/MRI of liver during screening
* The participant*s laboratory test results at screening include any of the
following:
* Albumin < 2.8 g/dL
* INR > 2.2
* Alanine aminotransferase value >= 5× the ULN
* Aspartate aminotransferase value >= 5× the ULN
* Total bilirubin > 3.0 mg/dL, unless participant has a diagnosis of Gilbert
Syndrome and direct bilirubin <= ULN
* Platelet count < 85,000/µL
* Hemoglobin A1c >= 9.0%
* Serum vitamin A (retinol) > ULN
* Inability to safely undergo a liver biopsy in the opinion of the
investigator.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-003932-22-NL |
| ClinicalTrials.gov | NCT04267393 |
| CCMO | NL81984.000.22 |