Fibrosis, Non Alcoholic Steatohepatitis
Conditions
Brief summary
This is a randomized, placebo-controlled phase 1/2a study to investigate the safety and tolerability of Idebenone in patients 18 years of age or older with non-alcoholic steatohepatitis, with stage 1-3 fibrosis. As secondary end point target engagement and fibrosis improvement will be assessed.
Detailed description
This is a prospective phase 1/2a, randomized, double-blinded, placebo-controlled, single center study of safety and efficacy of oral idebenone in adults 18 years of age or older with non-alcoholic steatohepatitis (NASH). Following IRB approval and written informed consent, 45 participants will be enrolled in the study and randomized in a 1:2 ratio on REDCap data capturing software. Participants will be randomized to two groups and receive the following tablets: placebo, idebenone at escalating doses of 200mg by mouth (P.O.) once a day for 2 weeks, then 200 mg twice a day for 2 weeks, then 3 times per day for the remainder of the study (up to 48 weeks). Monitoring and safety evaluation will continue for 12 weeks after the final dose. The study will investigate the safety and tolerability as primary end point and assess target engagement and fibrosis improvement as secondary end points.
Interventions
DRUGIdebenone
Idebenone, initially 200mg by mouth (P.O.) once a day for 2 weeks, then 200 mg twice a day for 2 weeks, then 200 mg three times per day for the remainder of the study will be used.
DRUGPlacebo
Placebo to match Idebenone once a day for 2 weeks, then twice a day for 2 weeks, then three times per day for the remainder of the study will be used.
Sponsors
Stanford University
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\) Male or non-pregnant/ non-lactating women ≥ 18 years of age * 2\) Diagnosis of NASH: NAFLD activity score (NAS) of 4 or greater with a score of 1 for each of the following (steatosis scored 0-3, lobular inflammation scored 0-3, ballooning scored 0-2): * Steatosis * Lobular inflammation * Hepatocyte ballooning 3) Fibrosis (Ishak fibrosis score ≥1 on liver biopsy) within 6 months of enrollment with MELD\<10, or based on MRE
Exclusion criteria
* Presence of any other form of liver disease, including viral hepatitis, autoimmune hepatitis, alcoholic liver disease, genetic causes of chronic liver disease): * Subjects with other etiologies of chronic liver disease, such as chronic hepatitis B and C; autoimmune hepatitis; and inherited liver disease. * ALT\>300 U/l * Total serum bilirubin ≥ to 1.3 mg/dL (Gilbert's Syndrome patients excepted) * International Normalized Ratio (INR) ≥ 1.3 * MELD\>10 * Serum creatinine \>2.0mg/dl * Known alcohol abuse or alcohol use disorder: * \>20 g/day for women * \>30 g/day for men * Active substance abuse * Any medical condition that prevents MRE, MR-PDFF * Platelet count ≤100//mm3 * Decompensated cirrhosis * Hemoglobin \<11 g/dl in females or \<12 g/dl in males * Presence/history of HCC * History of liver transplantation * History of bariatric surgery * History of inflammatory bowel disease * History of cardiovascular disease, long QT syndrome. * Subjects who have participated in investigational drug trials and took any investigational drugs within 60 days prior to the first dose of Idebenone. History of receiving other investigations drug within 30 days prior to enrollment * Any concerns regarding compliance by enrolling physician
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 | 60 weeks | Number of Participants with Treatment-Related Adverse Events (Assessed by CTCAE v4.0), and number of participants with abnormal Physical exams and abnormal laboratory tests results are reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Magnetic Resonance Elastography (MRE) as a Measure of Change in Fibrosis Stage | Week 48 | MR elastography is a standard of care technique to assess liver stiffness, that is a highly accurate non-invasive method. MRE creates elastograms (stiffness maps) and data generated in kilopascals (kPa) are correlated to fibrosis stage. Change in stiffness values indicate change in fibrosis. \< 2.5 kPa: normal; 2.5 to 3.0 kPa: normal or inflammation; 3.0 to 3.5 kPa: stage 1-2 fibrosis; 3.5 to 4.0 kPa: stage 2-3 fibrosis; 4.0 to 5.0 kPa: stage 3-4 fibrosis; \> 5.0 kPa: Stage 4 fibrosis or cirrhosis. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORNatalie Torok, MD
Stanford University
Participant flow
Pre-assignment details
53 participants signed informed consent; 44 were allocated to treatment.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 57.8 years STANDARD_DEVIATION 1.6 |
| Age, Customized ≤ 60 years | 15 Participants |
| Age, Customized > 60 years | 21 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 36 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 29 | 0 / 15 |
| other Total, other adverse events | 9 / 29 | 4 / 15 |
| serious Total, serious adverse events | 1 / 29 | 0 / 15 |
Outcome results
None listed