A clinical study to evaluate the safety and efficacy of efruxifermin in subjects with Nonalcoholic Steatohepatitis or Nonalcoholic Fatty Liver Disease.
Scientific Title of Study
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Efruxifermin in Subjects with Non-Invasively Diagnosed Nonalcoholic Steatohepatitis (NASH)/Nonalcoholic Fatty Liver Disease (NAFLD)
Trial Acronym
NIL
Secondary IDs if Any
Secondary ID
Identifier
AK-US-001-0107 Version number "Original" dated 04-May-2023
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Designation
Affiliation
Address
Phone
Fax
Email
Details of Contact Person Scientific Query
Name
Dr Sawan Bopanna
Designation
Medical Monitor
Affiliation
Klinera Global Services
Address
801, Neelkanth Corporate Park, Near Vidyavihar Station, Vidyavihar West, Mumbai 400 086
Mumbai (Suburban) MAHARASHTRA 400086 India
Phone
91249781252
Fax
Email
medicalmonitor@klinera.com
Details of Contact Person Public Query
Name
Rajeev Singh
Designation
Senior Project Manager
Affiliation
Klinera Global Services
Address
801, Neelkanth Corporate Park, Near Vidyavihar Station, Vidyavihar West, Mumbai 400 086.
Mumbai (Suburban) MAHARASHTRA 400086 India
Phone
912249781252
Fax
Email
rsingh@klinera.com
Source of Monetary or Material Support
Akero Therapeutics, Inc. 601 Gateway Blvd., Suite 350 South San Francisco, CA 94080
Primary Sponsor
Name
Ms Klinera Global Services
Address
801, Neelkanth Corporate Park, Opp Vidyavihar Station, Vidyavihar (West) Vidyavihar (India) - 400086
Type of Sponsor
Contract research organization
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
Argentina Australia Canada France Germany India Israel Italy Malaysia Mexico Poland Republic of Korea Spain Switzerland Taiwan Turkey United Kingdom United States of America
B-27, 88-G, New Colony, Ravindrapuri, Varanasi - 221005, Uttar Pradesh, India Varanasi UTTAR PRADESH
8573888800
hemantg26@yahoo.com
Dr Amit Goel
Sanjay Gandhi Postgraduate Institute of Medical Sciences
Department of Hepatology, Lucknow-226014, Uttar Pradesh, India Lucknow UTTAR PRADESH
9936275741
agoel.ag@gmail.com
Dr Arun Vaidya
Seth G.S Medical College and KEM Hospital,Parel
Department of Gastroenterology,MS Building, 9th Floor, Ward 32A, Parel, Mumbai-400012 Mumbai (Suburban) MAHARASHTRA
9699044016
arunvaidyagastro@gmail.com
Dr Mayank Kabrawala
SIDS Hospital & Research centre
A unit of SIDS health care private limited,
Off ring road, Near shell petrol pump, Ring road-sosyo circle lane, Surat-395002, Gujarat, India Surat GUJARAT
9825130363
mayankkabrawala@hotmail.com
Dr Shivam Khare
Sir Ganga Ram Hospital
Institute of Liver, Gastroenterology & Pancreatico Biliary Sciences,
Rajinder Nagar, New Delhi - 110060, India New Delhi DELHI
7838582169
drshivamkhare01@gmail.com
Dr Gaurav Kumar Gupta
SMS Super Speciality Hospital
Department of Gastroenterology,
Vivekanand Marg, C-Scheme,
Jaipur – 302004, Rajasthan, India Jaipur RAJASTHAN
9214027938
drgauravsms@gmail.com
Dr Mukesh Kalla
SR Kalla Memorial Gastro and General Hospital
78-79, Dhuleshwar Garden, behind HSBC bank, Sardar Patel Marg, C-Scheme, Jaipur - 302001, Rajasthan, India Jaipur RAJASTHAN
Institutional Ethics Committee, Post Graduate Institute of Medical Education and Research
Approved
Institutional Ethics Committee, Sanjay Gandhi Postgraduate Institute of Medical Sciences
Submittted/Under Review
Institutional Ethics Committee, VGM Hospital-Institute of Gastroenterology
Approved
IPGME&R Research Oversight Committee, IPGME&R,
Approved
Max Healthcare Ethics Committee
Approved
Samvedna hospital ethics committee
Approved
Sir Ganga Ram Hospital Ethic Committee
Approved
SR Kalla Memorial Ethical Committee for Human Research
Approved
Sterling Ethics Committee-Baroda
Approved
Surat Institute of digestive sciences Ethics Committee
Approved
Regulatory Clearance Status from DCGI
Status
No Objection Certificate
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: K74||Fibrosis and cirrhosis of liver,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Efruxifermin (EFX) 50 mg
Efruxifermin is a fusion protein, comprised of human IgG1Fc linked
to modified human Fibroblast Growth Factor 21 (FGF21).
Efruxifermin will be administered subcutaneously
once a week for 52 weeks
Comparator Agent
Placebo to match Efruxifermin (EFX)
Efruxifermin (EFX) Placebo is
composed of lyophilized EFX
Placebo formulation which is
closely match the visual
appearance and solution
properties of the active drug
product. Efruxifermin (EFX)
Placebo will administered
subcutaneously once a week for
52 weeks
Inclusion Criteria
Age From
18.00 Year(s)
Age To
75.00 Year(s)
Gender
Both
Details
1.Males and non-pregnant, non-lactating females between 18–75 years of age, inclusive, on the day of signing informed consent.
2.Previous history or presence of T2D (as determined by medical history or based on screening lab values if previously undiagnosed [i.e. HbA1c greater than or equal to 6.5%]) or 2 out of 4 components of metabolic syndrome (obesity, dyslipidemia, elevated blood pressure, elevated fasting glucose).
3.Body-mass index (BMI) greater than or equal to 25.0 kg/m2
4.Suspected or confirmed diagnosis of NASH/NAFLD or non-invasively diagnosed NASH/NAFLD, identified based on ONE of the following:
a. Recent liver biopsy (obtained within 365 days prior to screening) documenting definite NASH or presumed NASH with evidence of metabolic disease and no other etiology for liver disease
b.Recent median liver fat greater than or equal to 8.0% as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF)
Note: Historical MRI-PDFF must have been obtained within 180 days prior to Screening, unless subject consented to the Optional MRI-PDFF/cT1 substudy
c.Recent Corrected T1 (cT1) greater than or equal to 840 ms as assessed by LiverMultiScan®
Note: Historical cT1 must have been obtained within 180 days prior to Screening, unless subject consented to the Optional MRI-PDFF/cT1 substudy
d.FibroScan® liver stiffness measurement (LSM) greater than or equal to 7.5 kilopascals (kPa) AND Controlled Attenuation Parameter (CAP) greater than or equal to 280 dB.m-1 at Screening
e.ELF score greater than or equal to 7.7
Note: If a historical value for an ELF test performed less than or equal to 90 days prior to the Screening visit is available, then the screening ELF score does not need to be repeated
f. Recent mean liver stiffness greater than or equal to 2.5 kPa as assessed by magnetic resonance elastography (MRE)
Note: Historical MRE must have been obtained within 180 days prior to Screening
5.Central laboratory tests at screening that meet all of the following criteria:
a.Estimated glomerular filtration rate (eGFR) greater than or equal to 15 mL/min, as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI);
b.HbA1c less than or equal to 9.5%;
c.International Normalized Ratio (INR) < 1.3, unless due to therapeutic anticoagulation;
d.Total bilirubin < 1.3 mg/dL and direct bilirubin less than or equal to 0.5 mg/dL. For subjects with Gilbert’s syndrome or hemolytic anemia, total bilirubin may be elevated if direct bilirubin less than or equal to upper limit of normal (ULN);
e.Creatine kinase (CK) < 3 × ULN;
f.Platelet count greater than or equal to 100,000/µL;
g.Triglyceride (TG) level less than or equal to 500 mg/dL;
h.Aspartate aminotransferase (AST) > 17 for females and > 20 for males, AST less than or equal to 5 × ULN;
i. Alanine aminotransferase (ALT) less than or equal to 5 × ULN;
j.Alkaline phosphatase (ALP) < 2 × ULN;
k.25-Hydroxy Vitamin D greater than or equal to 20 ng/mL
Note: Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion
6.Documented stability of ALT and AST levels, as evidenced by no significant worsening of ALT and AST values at pre-baseline relative to screening values and the following parameters:
a. If the screening and pre-baseline ALT and AST values are both less than or equal to 1.5 × ULN, there is no limit to the difference between the values
b.If at least 1 of the screening or pre-baseline ALT or AST values is > 1.5 × ULN and shows worsening at pre-baseline, the percent increase must be less than or equal to 50%
Note: Subjects must have ALT and AST repeated during the screening period (Pre-Baseline visit) at minimum 28 days between blood draws to confirm either criterion 6a or 6b above. Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion
7.Subjects on Vitamin E greater than or equal to 800 IU/day, antidiabetic, weight loss, or lipid-modifying medication(s) must be on a stable dose (defined as
no significant change in prescription efficacy, initiation of medication, or medication discontinuation) for at least 90 days prior to screening through randomization. Dose adjustments (but not initiation or discontinuation) of metformin are permitted in the 90 days prior to screening
8.Willing and able to give written informed consent prior to any study specific procedures being performed
9.Female subjects of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at baseline/Day 1
10.Male and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in protocol.
11.For Optional MRI-PDFF/cT1 Substudy Only: Screening MRI-PDFF median liver fat and cT1 assessments must meet both 11a AND 11b based on centrally read LiverMultiScan® assessment:
a.MRI-PDFF median liver fat greater than or equal to 8.0%
b.cT1 greater than or equal to 840 ms
12.For Open-Label Rollover Subjects Only: Subjects rolling over from the placebo arm of AK-US-001-0101, AK-US-001-0102, or AK-US-001-0103 must meet Inclusion Criteria 5 and 6 only
ExclusionCriteria
Details
1.Weight loss > 10% in the 90 days prior to screening
2.Type 1 diabetes
3.Unstable T2D defined as:
a.Insulin dose adjustment > 35% within 30 days prior to screening through randomization,
b.Any prior history of diabetic ketoacidosis and/or hyperglycemic hyperosmolar state
4.Hypoglycemia unawareness, hospitalization due to hypoglycemia, or history of severe hypoglycemia (hypoglycemia requiring outside assistance to regain normal neurologic status) within 90 days prior to screening
5.Subjects with osteoporosis, defined as a T-score of less than or equal to minus 2.5 at the femoral neck, total hip, or lumbar spine based on a centrally read
dual-energy X-ray absorptiometry (DXA) scan performed during screening
Note: A historical DXA scan performed within 90 days prior to screening may be accepted as the screening DXA scan. The historical scan must have been performed on a scanner previously qualified by the central imaging vendor that is available for use at post-baseline visits
6.Poorly controlled hypertension (systolic blood pressure > 160 mm Hg, or diastolic blood pressure > 100 mm Hg) at the Screening visit or Pre-Baseline visit
Note: Vital signs for eligibility assessment may be repeated one time at the Investigator’s discretion
7.Any current or prior history of decompensated liver disease including ascites requiring medical management, hepatic encephalopathy (HE), or variceal bleeding
8.Model for End-Stage Liver Disease (MELD) score > 12, unless due to therapeutic anticoagulation or Gilbert’s syndrome
9.Child-Pugh score > 6 (Class B or C), unless due to therapeutic anticoagulation or Gilbert’s syndrome
10.History of pancreatitis
11.Chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive) or acute hepatitis A infection (hepatitis A immunoglobulin M [IgM] antibody positive). For subjects with positive hepatitis B core antibody (HBcAb), HBV deoxyribonucleic acid (DNA) by quantitative polymerase chain reaction (PCR) will be required
12.Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV ribonucleic acid [RNA] positive). Subjects cured of HCV infection less than 2 years prior to the Screening visit (based on date of RNA PCR negative confirmation following conclusion of treatment) are not eligible
13.Prior (less than 2 years prior to screening) or planned (during the study period) bariatric surgery (e.g., gastroplasty, Roux-en-Y gastric bypass) or reversal or removal of intragastric balloon. Surgery failure less than 2 years prior to screening is also exclusionary
14.Other causes of liver disease based on medical history and/or liver histology and/or central laboratory results, including but not limited to: alcoholic liver disease, autoimmune disorders (e.g., primary biliary cholangitis [PBC], primary sclerosing cholangitis
[PSC], autoimmune hepatitis), drug induced hepatotoxicity, Wilson disease, or clinically significant iron overload
15.History of liver transplantation
16.Current or prior history of hepatocellular carcinoma (HCC)
17.Current diagnosis of Cushing’s syndrome
18.History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening
Note: Significant alcohol consumption is defined as an average exceeding 1 ethanol containing drink/day in female subjects and 2 ethanol containing drinks/day in male subjects.
19.Human immunodeficiency virus (HIV) infection
20.Uncontrolled cardiac arrhythmia or confirmed QT interval corrected using Fridericia’s formula (QTcF) > 450 msec for males and > 470 msec for females at the screening ECG assessment; Subjects with cardiac pacemakers and elevated QTcF (> 450 msec for males and > 470 msec for females) may be allowed to participate if, in the Investigator’s opinion, the subject’s cardiac function is stable
Note: ECG for eligibility assessment may be repeated one time at the Investigator’s discretion
21.Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or stroke within 90 days prior to screening
22.Life expectancy of less than 2 years
23.Use of any investigational medication within 30 days or 5 half-lives, whichever is longer, prior to screening or concurrent participation in another therapeutic clinical study
24.Use of any prohibited medication(s) including any prior exposure to EFX
25.Positive urine drug screen for amphetamines, cocaine, or opiates (e.g., heroin, morphine) at screening. Subjects with a positive urine drug screen due to prescription medication (e.g., opiates, methylphenidate) are eligible if the prescription and diagnosis are reviewed and approved by the Investigator. Subjects on stable methadone or buprenorphine maintenance treatment for at least 180 days prior to screening may be included in the study
26.Presence of any laboratory abnormality or significant systemic or major illnesses (other than liver disease) that, in the opinion of the
Investigator, compromises the subject’s ability to safely participate in and complete the study including, but not limited to:
a.Pulmonary disease, heart failure, renal failure, organ transplantation, serious psychiatric disease, malignancy, history of substance abuse and/or a psychiatric condition requiring hospitalization and/or emergency room visit within 180 days of screening
27.Unavailable for follow-up assessment or concern for subject’s compliance with the protocol procedures
28.Known hypersensitivity to the study drug, the metabolites, or formulation excipients
29.For Optional MRI-PDFF/cT1 Substudy Only: Subjects who have contraindications to magnetic resonance (MR) imaging (e.g., unmanageable claustrophobia, certain metal implants, or unable to fit within MR scanner due to girth)
30.For Optional Fecal Substudy Only: History or presence of Inflammatory Bowel Disease or Inflammatory Bowel Syndrome
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Case Record Numbers
Blinding/Masking
Participant and Investigator Blinded
Primary Outcome
Outcome
TimePoints
Safety & tolerability will be assessed through
the reporting of extent of exposure, AEs, and
clinical assessments
52 Weeks
Secondary Outcome
Outcome
TimePoints
Change from baseline in FAST Score
• Change from baseline in ELF score and
components (TIMP-1, HA, PIIINP), Pro-C3,
and liver stiffness assessed by FibroScan®
52 Weeks
Target Sample Size
Total Sample Size="480" Sample Size from India="60" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
AK-US-001-0107 is a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Efruxifermin in Subjects with Non-Invasively Diagnosed Nonalcoholic Steatohepatitis (NASH)/Nonalcoholic Fatty Liver Disease (NAFLD)
The trial will be conducted in 60 subjects in India across 25 sites in India. The duration of the trial is 52 weeks. The drug is administered once weekly subcutaneous Injection. The drug will be assigned 1:2 ratio, which means 1 out of 3 subjects will receive the Placebo and 2 out of 3 subjects will receive the drug.