Severe Acute Decompensated Alcoholic Hepatitis
Conditions
Brief summary
The purpose of this randomised, double-blind, placebo-controlled, phase II study is to assess the efficacy and safety of orally administered DS102 in adult patients with acute decompensated alcoholic hepatitis
Interventions
DRUG1000mg DS102 (BID)
Participants assigned to the open label pilot phase received 1000mg DS102 (BID)for 28 days.
Sponsors
Afimmune
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female patients aged 18 years and older 2. Total bilirubin of ≥ 5 mg/dl (85μmol/l) 3. Patients with definite or probable AH 4. MELD ≥18 at baseline visit 5. MDF ≥32 at baseline visit 6. AST ≥50 U/L 7. AST':ALT ratio \> 1.5 8. Female patients, or female partners of male patients, of child bearing potential must use highly effective birth control methods or have a sterilised partner for the duration of the study. Highly effective birth control methods are defined as methods that can achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include intrauterine device or sexual abstinence. Note: A woman is considered of child bearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy Note: Hormonal contraceptives are contraindicated in patients with severe hepatic diseases and are not acceptable as a birth control method in this study Note: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject 9. Patient and/or legally authorised representative must provide informed consent 10. Able to swallow the provided study medication 11. Not eligible for liver transplant during this hospitalisation
Exclusion criteria
1. Pregnant or lactating females. 2. Spontaneous liver function improvement defined by decrease of bilirubin level and MDF of \>10% within 5 days of hospital admission 3. Grade 4 hepatic encephalopathy (West Haven Criteria) 4. Type 1 hepatorenal syndrome (HRS) or a serum creatinine \>2 x ULN or the requirement for haemodialysis 5. History of hypersensitivity to any substance in DS102 capsules or placebo capsules. 6. Alcohol abstinence of \>6 weeks prior to screening 7. Duration of clinically apparent jaundice \>3 months prior to baseline 8. Other causes of liver disease including: 1. Evidence of chronic viral hepatitis (Hepatitis B DNA positive or HCV RNA positive) 2. Biliary obstruction 3. Hepatocellular carcinoma 4. Wilsons disease 5. Budd Chiari Syndrome 6. Non-alcoholic fatty liver disease 9. History of or active non-liver malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas). 10. Previous entry into the study 11. AST \>400 U/L or ALT \>270 U/L 12. Treatment with any experimental drug within 30 days prior to Day 0 visit (Baseline), or 5 half-lives (whichever is longer). 13. Patients who have used dietary supplements rich in omega-3 or omega-6 fatty acids in the four weeks prior to baseline. 14. Patients dependent on inotropic support (adrenaline or noradrenaline), including Terlipressin 15. Active variceal haemorrhage on this admission requiring more than 2 units of blood to maintain haemoglobin level within 48 hours 16. Presence of refractory ascites 17. Untreated or unresolved sepsis 18. Patients with cerebral haemorrhage, extensive retinal haemorrhage, acute myocardial infarction (within last 6 weeks) or severe cardiac arrhythmias (not including atrial fibrillation) 19. Known infection with HIV at screening. 20. Significant systemic or major illnesses other than liver disease that, in the opinion of the investigator, would preclude or interfere with treatment with DS102 and/or adequate follow up. 21. Previous liver transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and SUSARs. | Up to 28 days. | To evaluate the safety of orally administered DS102 in the treatment of adult patients with severe acute decompensated AH. |
| Descriptive Statistics for Plasma Total 15(S)-HEPE and Unesterified 15(S)-HEPE Pharmacokinetic Results for 1000 mg BD DS102 Administered Orally Twice-daily to Patients With Alcoholic Hepatitis | Up to 7 days | Descriptive Statistics for Plasma Total 15(S)-HEPE and Unesterified 15(S)-HEPE Pharmacokinetic Results for 1000 mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis. |
Countries
Georgia, United States
Participant flow
Recruitment details
This was a multicentre, double blind, placebo controlled, 2-arm parallel group comparison (Phase 2) study, preceded by an open label pilot phase, in which six patients were to receive open label treatment with 2000mg DS102 (1000mg BID) within 30 minutes after a meal for 28 days.
Pre-assignment details
A total of 126 participants were planned with actual enrolment in the study. 9 participants completed the open label pilot phase before the study was ended prematurely due to futility purposes.
Participants by arm
| Arm | Count |
|---|---|
| 1000mg DS102 (BID) Participants assigned to the open label pilot phase received 1000mg DS102 (BID)for 28 days. | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Other SAE and AE | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | 1000mg DS102 (BID) |
|---|---|
| Age, Continuous | 53.2 years STANDARD_DEVIATION 12.94 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 8 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 9 |
| other Total, other adverse events | 7 / 9 |
| serious Total, serious adverse events | 4 / 9 |
Outcome results
Primary
Descriptive Statistics for Plasma Total 15(S)-HEPE and Unesterified 15(S)-HEPE Pharmacokinetic Results for 1000 mg BD DS102 Administered Orally Twice-daily to Patients With Alcoholic Hepatitis
Descriptive Statistics for Plasma Total 15(S)-HEPE and Unesterified 15(S)-HEPE Pharmacokinetic Results for 1000 mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis.
Time frame: Up to 7 days
Population: The Full Analysis Set (FAS) included all patients who received at least one dose of investigational product. Patients were analysed according to the treatment they were assigned to, irrespective of what treatment they actually received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1000mg DS102 (BID) | Descriptive Statistics for Plasma Total 15(S)-HEPE and Unesterified 15(S)-HEPE Pharmacokinetic Results for 1000 mg BD DS102 Administered Orally Twice-daily to Patients With Alcoholic Hepatitis | Day 0 Unesterified 15(S)-HEPE | 542 ng/mL | Standard Deviation 399.4 |
| 1000mg DS102 (BID) | Descriptive Statistics for Plasma Total 15(S)-HEPE and Unesterified 15(S)-HEPE Pharmacokinetic Results for 1000 mg BD DS102 Administered Orally Twice-daily to Patients With Alcoholic Hepatitis | Day 7 Unesterified 15(S)-HEPE | 1060 ng/mL | Standard Deviation 1073 |
| 1000mg DS102 (BID) | Descriptive Statistics for Plasma Total 15(S)-HEPE and Unesterified 15(S)-HEPE Pharmacokinetic Results for 1000 mg BD DS102 Administered Orally Twice-daily to Patients With Alcoholic Hepatitis | Day 0 Total 15(S)-HEPE | 3110 ng/mL | Standard Deviation 3721 |
| 1000mg DS102 (BID) | Descriptive Statistics for Plasma Total 15(S)-HEPE and Unesterified 15(S)-HEPE Pharmacokinetic Results for 1000 mg BD DS102 Administered Orally Twice-daily to Patients With Alcoholic Hepatitis | Day 7 Total 15(S)-HEPE | 4470 ng/mL | Standard Deviation 3601 |
Primary
Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and SUSARs.
To evaluate the safety of orally administered DS102 in the treatment of adult patients with severe acute decompensated AH.
Time frame: Up to 28 days.
Population: The Full Analysis Set (FAS) included all patients who received at least one dose of investigational product. Patients were analysed according to the treatment they were assigned to, irrespective of what treatment they actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1000mg DS102 (BID) | Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and SUSARs. | Total Number of TEAEs | 7 Number of Events |
| 1000mg DS102 (BID) | Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and SUSARs. | Total Number of Serious TEAEs | 4 Number of Events |
| 1000mg DS102 (BID) | Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and SUSARs. | Total Number of Serious Treatment Related TEAEs | 1 Number of Events |
| 1000mg DS102 (BID) | Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and SUSARs. | Total Number of Treatment Related TEAEs | 1 Number of Events |
| 1000mg DS102 (BID) | Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and SUSARs. | Total Number of Not Treatment Related TEAEs | 6 Number of Events |