The primary objective of this study is:-To evaluate whether selonsertib (SEL, previously known as GS- 4997) can cause fibrosis regression and reduce progression tocirrhosis and associated complications in subjects with NASH and bridging (F3)…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint at Week 48 includes the proportion of subjects
who achieve a >= 1-stage improvement in fibrosis (according to the NASH CRN
classification) without worsening of NASH (defined as a >= 1-point increase in
hepatocellular ballooning or lobular inflammation).
The clinical efficacy endpoint at Week 240 is event-free survival (EFS). EFS
will be assessed by time to the first clinical event including progression to
cirrhosis, liver decompensation events, liver transplantation, or all-cause
mortality.
Secondary outcome
Secondary Endpoints:
• Proportion of subjects who have progression to cirrhosis by Week 48;
• Proportion of subjects who have a >= 1-stage improvement in fibrosis without
worsening of NASH at Week 240;
• Proportion of subjects who have a >= 1-stage improvement in fibrosis at Week
48 and Week 240;
• Proportion of subjects who have NASH resolution without worsening of fibrosis
at Week 48 and Week 240.
Safety:
The safety of SEL in subjects with bridging fibrosis due to NASH will be
assessed during the study through the reporting of AEs, clinical laboratory
tests, vital sign assessments and concomitant medication usage.
An external Data Monitoring Committee (DMC) that consists of three
hepatologists and a PhD statistician will review the progress of the study.
They will convene after 50 subjects have completed the Week 4 visit and
approximately every 6 months thereafter to monitor the study for safety events.
Background summary
see section background of the protocol on page 19
Study objective
The primary objective of this study is:
-To evaluate whether selonsertib (SEL, previously known as GS- 4997) can cause
fibrosis regression and reduce progression to
cirrhosis and associated complications in subjects with NASH and bridging (F3)
fibrosis.
The secondary objective of this study is:
-To assess the safety and tolerability of SEL in subjects with NASH and
bridging (F3) fibrosis.
Study design
This is a Phase 3, randomized, double-blind, placebo-controlled study
evaluating the safety and efficacy of SEL in subjects with NASH and bridging
(F3) fibrosis.
Subjects meeting the study*s entry criteria will be randomly assigned in a
2:2:1 ratio to 1 of 3 treatment groups
Randomized Study Phase
Randomization will be stratified by the presence or absence of diabetes
mellitus (as determined by medical history or based on Screening lab values if
previously undiagnosed [i.e. hemoglobin A1c (HbA1c) >= 6.5% or fasting plasma
glucose >= 126 milligram/deciliter [mg/dL]) and by Enhanced Liver Fibrosis
(ELF*) score >= 9.76 or < 9.76 during Screening. Study drugs will be
administered for up to a total of 240 weeks.
A key primary objective of this study is to prevent progression to cirrhosis
and its complications.
Subjects who experience a confirmed hepatic clinical event prior to completing
the Week 240 Visit of the Randomized Phase will be offered the option to
rollover into an Open-Label (OL) Phase of the study. Each of the clinical
events (except histologic progression to cirrhosis, all-cause mortality and
liver transplantation) will require confirmation by a Hepatic Events
Adjudication Committee. All deaths will be reviewed by this committee to
determine if they are liver-related.
If a subject is clinically felt to have progressed to cirrhosis (e.g., based on
the presence of new esophageal varices, changes in biomarkers [including, but
not limited to, low serum albumin, high serum bilirubin, a low platelet count,
prolonged INR, or elevated liver stiffness], or development of other clinical
signs or symptoms of cirrhosis), the subject should undergo repeat liver biopsy
for confirmation of progression to cirrhosis (F4 fibrosis as assessed by the
central reader according to the NASH CRN classification) at the discretion of
the primary investigator (PI).
Once the clinical event (except histologic progression to cirrhosis, all cause
mortality and liver transplantation) is confirmed by the Hepatic Events
Adjudication Committee, the subject will no longer participate in the
Randomized Phase and will be offered the option to receive SEL 18 mg in the OL
Phase for a total treatment duration of 240 weeks inclusive of the Randomized
Phase. Rollover into the OL Phase of the study must occur within 60 days of
confirmation of the event. Subjects starting the OL Phase of the study will
complete the same study procedures as during the Randomized Phase of the study,
starting with the Day 1 visit with the exception of liver biopsy and intensive
PK substudy and the addition of ultrasound imaging at specified visits. Hepatic
clinical events will be adjudicated and deaths will be reviewed by the Hepatic
Events/DILI Adjudication Committee only during the Randomized Phase of the
study; potential DILI events and cardiovascular events including deaths will
continue to be adjudicated in the OL Phase by the Hepatic Events/DILI
Adjudication Committee and the Cardiovascular Events Adjudication Committee,
respectively.
Cardiovascular events including cardiovascular death, myocardial infarction,
stroke, hospitalization for unstable angina, hospitalization for cardiac
failure, and coronary revascularization will be adjudicated by an independent
Cardiovascular Events Adjudication Committee. Subjects experiencing a
cardiovascular event will continue in the Randomized Phase and not rollover
into the OL Phase. Cardiovascular events will be adjudicated during the
Randomized Phase and the OL Phase of the study.
Intervention
Treatment Group A: one SEL 6 mg tablet + one PTM SEL 18 mg tablet administered
orally once daily
Treatment Group B: one PTM SEL 6 mg tablet + one SEL 18 mg tablet administered
orally once daily
Treatment Group C: one PTM SEL 6 mg tablet + one PTM SEL 18 mg tablet
administered orally once daily
Study burden and risks
Selonsertib (SEL, formerly GS-4997) has been studied in 15 Phase 1 and 2
clinical studies involving more than 900 patients including patients and
healthy volunteers. In 2 Phase 2 studies including 122 patients with
Non-alcoholic Steatohepatitis (NASH) receiving SEL, most side effects reported
were mild. The phase 1 and 2 studies have shown that selonsertib was generally
well tolerated. The most common side effects occurring in 10% or greater of
these SEL treated patients were:
• Headache
• Nausea
In addition to treating patients with NASH, SEL has been given to 248 patients
with diabetic kidney disease (DKD) and 145 patients with pulmonary artery
hypertension (PAH). In these trials, common side effects occurring in >10% of
study patients receiving SEL included headache, nausea, diarrhea,
nasopharyngitis and upper respiratory infection (common cold), cough,
dizziness, shortness of breath and fatigue (feeling tired).
Selonsertib has also been given to 50 patients with severe alcoholic hepatitis
in conjunction with another medication called prednisolone (PRED). In these
patients, increased rates of severe infections (including rare infections like
brain infections) were seen when compared to the patients that did not receive
SEL. Other side effects occurring in 10% or greater of these patients included
ascites (fluid in abdomen), hepatic encephalopathy (mental status changes due
to liver failure), swelling in arms and legs, itching, constipation, low blood
sodium levels, low blood potassium levels, trouble sleeping, low blood
pressure, acute kidney injury, nausea, high white blood cells, sepsis (blood
infection) and upper abdominal pain.
Abnormal liver tests have been observed with SEL. If this happens to you, your
study doctor may request additional tests.
In animal studies, SEL has been associated with embryofetal toxicity
(malformations in fetuses and spontaneous abortions), and benign pituitary
tumors after long-term exposure to SEL at doses greater than the maximum human
dose.
Lakeside Drive 333
Foster City CA 94404
US
Lakeside Drive 333
Foster City CA 94404
US
Listed location countries
Age
Inclusion criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
1) Willing and able to give informed consent prior to any study specific procedures being performed
2) Liver biopsy consistent with NASH (defined as the presence of at least grade 1 steatosis, hepatocellular ballooning, and lobular inflammation according to the NAFLD Activity Score [NAS]) and bridging (F3 fibrosis) according to the NASH CRN classification, in the opinion of the central reader
a) A historical liver biopsy within 6 months of the Screening visit may be accepted as the Screening biopsy if the sample is deemed acceptable for interpretation by the central reader
b) If the subject is deemed ineligible for this study, the liver biopsy, if performed according to protocol specifications and is within 12 months of the Screening visit, may be used to determine eligibility for study GS-US-384-1944
3) Subject has the following laboratory parameters at the Screening visit, as determined by the central laboratory:
a) ALT <= 8 x ULN
b) CLcr >= 30 mL/min, as calculated by the Cockcroft-Gault equation
c) HbA1c <= 9.5% (or serum fructosamine <= 381 µmol if HbA1c is unable to be resulted)
d) Total bilirubin <= 1.3 x ULN (unless an alternate etiology such as Gilbert*s syndrome or hemolytic anemia is present)
e) INR <= 1.4, unless due to therapeutic anti-coagulation
f) Platelet count >= 100,000/µL
4) Body Mass Index (BMI) >= 18 kg/m2 at Screening
5) Males and non-pregnant, non-lactating females between 18 70 years of age; inclusive based on the date of the Screening visit
6) Females of childbearing potential (as defined in Appendix 3) must have a negative pregnancy test at Screening and Day 1
7) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 3
Exclusion criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Prior history of decompensated liver disease, including clinical ascites, HE, or variceal bleeding
2) CP score > 6, as determined at Screening, unless due to therapeutic anti-coagulation
3) MELD score > 12, as determined at Screening, unless due to therapeutic anti-coagulation
4) Chronic HBV infection (HBsAg positive)
5) Chronic HCV infection (HCV Ab and HCV RNA positive). Subjects cured of HCV infection less than 5 years prior to the Screening visit are not eligible
6) Other causes of liver disease including, but not limited to, alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (e.g., primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, iron overload, and alpha-1-antitryspin deficiency, based on medical history and/or centralized review of liver histology
7) History of liver transplantation
8) Current or history of HCC
9) Any weight reduction surgery in the 2 years prior to Screening or planned during the study (weight reduction surgery is disallowed during the study), and malabsorptive weight loss surgery (e.g., Roux-en-Y or distal gastric bypass) at any time prior to Screening
10) Weight loss > 10% within 6 months of Screening
11) HIV infection (HIV Ab and HIV ribonucleic acid [HIV RNA] positive)
12) Current alcohol consumption greater than 21 oz/week for males or 14 oz/week for females (1oz/30mL of alcohol is present in 1 12oz/360mL beer, 1 4oz/120mL glass of wine, and a 1 oz/30 mL measure of 40 proof alcohol)
13) Positive urine drug screen for amphetamines, cocaine or opiates (i.e. heroin, morphine) at Screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening may be included in the study. Subjects with a positive urine drug screen due to prescription opioid based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator
14) Unstable cardiovascular disease as defined by any of the following:
a) Unstable angina, myocardial infarction, coronary artery bypass graft surgery or coronary angioplasty within 6 months prior to Screening
b) Transient ischemic attack or cerebrovascular accident within 6 months prior to Screening
c) Symptomatic obstructive valvular heart disease or hypertrophic cardiomyopathy
d) Symptomatic congestive heart failure
e) Uncontrolled or recurrent ventricular tachycardia or other arrhythmia requiring an automatic implantable cardioverter defibrillator (AICD). Stable, controlled atrial fibrillation is allowed.
15) Use of any prohibited concomitant medication as described in Section 5.4. Subjects on Vitamin E must be on a stable dose for at least 6 months prior to the diagnostic liver biopsy and subjects on antidiabetic medications must be on a stable dose for at least 3 months prior to diagnostic liver biopsy
16) History of a malignancy within 5 years of Screening with the following exceptions:
a) Adequately treated carcinoma in situ of the cervix
b) Adequately treated basal or squamous cell cancer or other localized non-melanoma skin cancer
17) Unable to safely undergo a liver biopsy
18) Participation in another investigational study of a drug or device within 30 days or within 5 half-lives of the prior investigational agent (whichever is longer) prior to Screening
19) Concurrent participation in another therapeutic clinical study
20) Known hypersensitivity to SEL, the metabolites, or formulation excipient
21) Any laboratory abnormality or condition that, in the investigator*s opinion, could adversely affect the safety of the subject or impair the assessment of study results
22) Presence of any condition that could, in the opinion of the investigator, compromise the subject*s ability to participate in the study, including a history of substance abuse or a psychiatric condition requiring hospitalization or emergency room visit within 2 years of Screening
23) Unavailable for follow-up assessment or concern for subject*s compliance with the protocol procedures
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 | EUCTR2016-004374-18-NL |
| ClinicalTrials.gov | NCT03053050 |
| CCMO | NL60996.042.17 |