A Study to Evaluate the Safety and Efficacy of Efruxifermin in Subjects with Non-Cirrhotic Nonalcoholic Steatohepatitis (NASH) And Fibrosis
Scientific Title of Study
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Efruxifermin in Subjects with Non-Cirrhotic Nonalcoholic Steatohepatitis (NASH) And Fibrosis
Trial Acronym
NIL
Secondary IDs if Any
Secondary ID
Identifier
AK-US-001-0105 Original dated 24-Apr-2023
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
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)
India 801, Neelkanth Corporate Park, Near Vidyavihar Station, Vidyavihar
West, Mumbai 400 086.
Mumbai (Suburban)
India Mumbai (Suburban) MAHARASHTRA 40008 India
Phone
912249781252
Fax
Email
medicalmonitor@klinera.com
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
912249781252
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
Akero Therapeutics, Inc.
Address
601 Gateway Blvd., Suite 350, South San Francisco, CA 94080, USA
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
KlinEra Global Services
801, Neelkanth Corporate Park, Near Vidyavihar Station, Vidyavihar West, Mumbai 400 086
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
Department of Gastroenterology, All India Institute of Medical Science, Rishikesh - 249203, Uttarkhand, India Dehradun UTTARANCHAL
7579067715
docgupta1976@gmail.com
Dr Shalimar
All India Institution of Medical Sciences (AIIMS)
All India Institution of Medical Sciences,
Room no. 127, First floor,
Old OT Block, AIIMS Ansari nagar, Delhi - 110029 New Delhi DELHI
9868397211
dr.shalimar@gmail.com
Dr Parshottam Koradia
BAPS Pramukh Swami Hospital,
BAPS Pramukh Swami Hospital,
Shri Pramukh Swami Maharaj Marg, Adajan, Surat - 395009 Gujarat, India Surat GUJARAT
9825312027
purushottam_koradia@yahoo.co.in
Dr P Shravan Kumar
Gandhi Medical College and Hospital
Gandhi Medical College and Hospital, In Patient Block, 5th Floor, Department of Gastroenterology, Musheerabad, Secunderabad - 500003, Telangana, India Hyderabad TELANGANA
9848011080
shravangastro@gmail.com
Dr Joy Varghese
Gleneagles Global Health city,
Gleneagles Global Health city,
439, Embassy Residency Rd, Sholinganallur, Cheran Nagar, Perumbakkam, Chennai - 600100, Tamil Nadu Chennai TAMIL NADU
Department of Medical Gastroenterology, Superspeciality block, Government Medical college PO, Thiruvanathpuram-695011, Kerala India Thiruvananthapuram KERALA
9847111824
kdas40@gmail.com
Dr Dawesh Yadav
IMS, Banaras Hindu University,Varanasi
Department of gastroenterology, IMS, Banaras Hindu University,Varanasi-221005, Uttar Pradesh, India Varanasi UTTAR PRADESH
8130856563
devesh.thedoc@gmail.com
Dr Shivkumar Sarin
Institute of Liver and Biliary Sciences, Hospital
Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi, Delhi-110070 South West DELHI
91-01146300000
sksarin@ilbs.in
Dr Kausik Das
IPGME&R and SSKM Hospital
IPGME&R and SSKM Hospital,
244, A.J.C Bose Road, Kolkata - 700020, West Bengal, India Kolkata WEST BENGAL
9433162770
kausikdasmail@gmail.com
Dr Abhijit Chowdhury
JCMLRI, Indian Institute of Liver and Digestive Sciences
Centre for clinical research, JCMLRI, Indian Institute of Liver and Digestive Sciences campus, Sitala east, Sonarpur, Kolkata - 700150, West Bengal, India Kolkata WEST BENGAL
9433045435
achowdhury2002@yahoo.co.in
Dr Dharmendra BL
K R Hospital Princess Krishnajammanni Super Speciality Hospital
K R Hospital Princess Krishnajammanni Super Speciality Hospital, 1st Cross Rd, Brindavan Extension 1st stage, Opp to ESI Hospital, Mysore, Karnataka- 570001 Mysore KARNATAKA
9844400382
Drdharmu21@gmail.com
Dr Kaushal Madan
Max Smart Super Speciality Hospital,
Max Smart Super Speciality Hospital,
Press Enclave Marg, Mandir Marg, Saket, New Delhi - 110017, Delhi, India New Delhi DELHI
9958787720
kaushal.madan@maxhealthcare.com
Dr Abhai Verma
Medanta Hospital,
Medanta Hospital,
Sector - A, Pocket - 1, Amar Shaheed Path, Golf City, Lucknow - 226030, Uttar Pradesh, India Lucknow UTTAR PRADESH
9839600727
abhai.verma@medanta.org
Dr Saubhik Ghosh
Medical College and Hospital,
Medical College and Hospital,
88 College Street, Kolkata - 700073, West Bengal, India Kolkata WEST BENGAL
8017585988
soubikpgi@gmail.com
Dr Shrikant Mukewar
Midas Hospital
Midas Hospital, 392, Behind Empress Palace Opp Singh Saab Dhaba Wardha Road, Parsodi, Nagpur - 441108 Nagpur MAHARASHTRA
7720033280
shrikant_mukewar@yahoo.com
Dr Ajay Kumar Duseja
Post Graduate Institute of Medical Education & Research
Samvedana Hospital,
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
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 MAHARASHTRA
9699044016
arunvaidyagastro@gmail.com
Dr Mayank Kabrawala
SIDS Hospital & Research centre
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,
Sir Gangaram Hospital, Rajinder Nagar, New Delhi - 110060, India New Delhi DELHI
7838582169
drshivamkhare01@gmail.com
Dr Gaurav Kumar Gupta
SMS Superspeciality Hospital
Department of Gastroenterology,
SMS Super Speciality Hospital,
Vivekanand Marg, C-Scheme,
Jaipur – 302004, Rajasthan, India Jaipur RAJASTHAN
9214027938
drgauravsms@gmail.com
Dr Mukesh Kalla
SR Kalla Memorial Gastro and General Hospital
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
Efruxifermin is a fusion protein, comprised of human IgG1Fc linked to modified, human Fibroblast Growth Factor 21 (FGF21). Efruxifermin will administered subcutaneously once a week for 96 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 96 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. Subjects who do not have a historical liver biopsy specimen that meets Inclusion Criteria 7 must meet either inclusion criterion 4a OR 4b prior to collection of a liver biopsy specimen during the Screening visit:
a. FibroScan® liver stiffness measurement (LSM) > 7.5 kPa, OR
b. Enhanced Liver Fibrosis (ELF) score greater than or equal to 7.7
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. Hemoglobin A1c (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 ULN;
e. Creatine kinase (CK) < 3 × upper limit of normal (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 values of ALT or AST 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. Biopsy-proven NASH. Must have had a liver biopsy obtained less than or equal to 180 days prior to screening with fibrosis stage 1, 2, or 3 and a non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of more than or equal to 4 with at least 1 point in each of the following components:
a. Steatosis (scored 0 to 3),
b. Ballooning degeneration (scored 0 to 2), and
c. Lobular inflammation (scored 0 to 3)
Note: F1 subjects will be limited to approximately 25% of the total study population. The remaining population will be approximately balanced between F2 and F3 subjects.
8.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) within 90 days prior to the collection date of the liver biopsy specimen used to assess subject eligibility through randomization. Dose adjustments (but not initiation or discontinuation) of metformin are permitted in the 90 days prior to the collection date of the liver biopsy specimen used to assess subject eligibility.
9. Willing and able to give written informed consent prior to any study specific procedures being performed.
10. Female subjects of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at baseline/Day 1.
11.Male and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception.
ExclusionCriteria
Details
1.Presence of cirrhosis on liver biopsy (fibrosis stage 4).
2.Weight loss > 10% within 90 days prior to the collection date of the liver biopsy specimen used to assess subject eligibility.
3.Type 1 diabetes.
4.Unstable Type 2 diabetes 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.
5.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.
6.Subjects with osteoporosis, defined as a T-score of less than or equal to -2.5 at the femoral neck, total hip, or lumbar spine based on a centrally read 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.
7.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
8.Any current or prior history of decompensated liver disease including ascites requiring medical management, hepatic encephalopathy (HE), or variceal bleeding.
9.Model for End-Stage Liver Disease (MELD) score > 12, 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 DNA by quantitative polymerase chain reaction (PCR) will be required.
12.Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV 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 centralized review of 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 electrocardiogram (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) mentioned in protocol 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.Unable to safely undergo a liver biopsy.
27.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.
28.Unavailable for follow-up assessment or concern for subject’s compliance with the protocol procedures.
29. Known hypersensitivity to the study drug, the metabolites, or formulation excipients.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Case Record Numbers
Blinding/Masking
Participant and Investigator Blinded
Primary Outcome
Outcome
TimePoints
Proportion of subjects with fibrosis stage 2 or 3 who achieve NASH resolution (defined as a NAS of 0–1 for inflammation & 0 for ballooning) AND greater than
or equal to 1 stage improvement in fibrosis (based on NASH CRN fibrosis score)
Week52
Secondary Outcome
Outcome
TimePoints
Proportion of subjects with fibrosis stage 2 or 3 who achieve NASH resolution (defined as a NAS of 0–1 for inflammation & 0 for ballooning) & no worsening of fibrosis (based on NASH CRN fibrosis score)
Proportion of subjects with fibrosis stage 2 or 3 who achieve greater than or equal to 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) & no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis)
Week 52
Target Sample Size
Total Sample Size="1000" Sample Size from India="100" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of Efruxifermin (EFX) in subjects with non-cirrhotic NASH and fibrosis stage 2 or 3 (F2 or F3). An additional cohort of subjects with non-cirrhotic NASH and fibrosis stage 1 (F1) will be enrolled and evaluated only for safety and noninvasive efficacy endpoints.
Approximately 1000 patients will be enrolled globally, out of which 100 patients will be enrolled in India with approx. 75 patients with Fibrosis stages F2-F3 while 25 patients with Fibrosis stage F1.
Subjects meeting the study’s eligibility criteria will be randomly assigned in a 1:1:1 ratio to 1 of 3 treatment groups (Placebo, Efruxifermin (28 mg) and Efruxifermin (50 mg)).
EFX will be provided in a prefilled, single-use, non-pyrogenic LyoJect 3S dual chamber syringe (DCS). Chamber one contains lyophilized dry EFX powder, and chamber two contains a nominal volume of 1.0 mL of water for injection (WFI) diluent. The two chambers are separated by a middle plunger stopper. Efruxifermin is presented as a white to off-white powder and the diluent is presented as a colorless to slightly yellow liquid. Placebo will be provided as a lyophilized powder in chamber one of the LyoJect 3S DCS with a nominal volume of 1.0 mL of diluent contained in chamber two.
Efruxifermin/Placebo will be administered subcutaneously, once a week for 96 weeks.
The primary endpoint analysis will occur after all F2/F3 subjects have completed the Primary Endpoint Treatment duration (i.e., completed 52 weeks of treatment or permanently discontinued from the study prior to Week 52). For evaluation of longer-term safety and efficacy, subjects will continue to receive their assigned treatment for up to a total of 96 weeks. The 30-day Follow-up visit will be completed 30 days following the last dose of study drug.
Study participation may last up to 112 weeks, including a 12-week screening period, 96-week treatment period, and a 30-day Follow-up visit.