Clinical trial NCT06582329: Effect of Alpha-1 Antitrypsin Supplementation on Alcohol-Associated Hepatitis
Official title: Effect of Alpha-1 Antitrypsin Supplementation on Alcohol-Associated Hepatitis - A Prospective Pilot Study
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Alcohol-Associated Hepatitis
Lead sponsor: Medical University Innsbruck
Sponsor class: OTHER
First posted: 2024-09-03
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Therapeutic exploratory trial:

the trial is designed as a prospective, single center, open label, randomized controlled pilot study
Primary purpose: TREATMENT

Brief summary: The trial is designed as a prospective, single center, open label, randomized controlled pilot study evaluating the effect of A1AT (Alpha 1 Antitrypsin) on inflammation in patients with severe AAH (alcohol-associated hepatitis).

The objective is to evaluate the safety and the effect of intravenous A1AT on the systemic inflammation in patients with severe AAH. The objectives also include the assessment of A1AT on clinical outcomes including the incidence of adverse events (AEs) and serious adverse events (SAEs) and the cytokine.

Detailed description: About 5-7 % of patients with alcohol-associated chronic liver disease transform into acute on chronic liver disease (ACLF) per year. In patients with underlying alcohol-associated liver disease (ALD) and active drinking, a sudden onset of jaundice, malaise, decompensated liver disease and coagulopathy i.e. alcohol-associated hepatitis (AAH) might develop. In its severe form, AAH is associated with development of ACLF and bacterial infections and this disease exhibits a high short-term mortality of 20 to 50% within 3 months. Treatment options are limited currently, for instance, the use of corticosteroids.

Alpha-1 Antitrypsin (A1AT) acts as an anti-inflammatory protein by inhibiting the generation of pro-inflammatory cytokines. The investigators recently showed protective effects of A1AT in a pre-clinical experimental model of ALD, resulting in decreased levels of pro-inflammatory cytokines, less steatosis and hepatic injury. The investigators also have recently found that cirrhotic patients with A1AT concentrations less than 120 mg/dL had a significantly increased risk for death/liver transplantation in a cohort of 130 patients with ALD cirrhosis. This finding was not only significant, but also independent of the MELD-Na score, indicating that in ALD A1AT is not only a marker of reduced hepatic synthetic function. Further, significantly higher ferritin and lower transferrin in the cohort of patients with low A1AT also indicate more severe inflammation. An interventional analysis in an established mouse model of ALD showed that A1AT supplementation mitigated inflammation and histological changes further indicating that low AAT (Alpha 1 Antitrypsin) is a driver and not the consequence of tissue damage in ALD. These data support the use of A1AT in humans with severe AAH.

As a pilot trial the study also aims to establish important preliminary data for future studies and design of larger trials aimed at formal evaluation of the effect of A1AT on clinical endpoints.

Eligibility criteria: Inclusion Criteria:

1. Male or female patient ≥18 years of age at time of consent.
2. Severe AAH (Maddrey's discriminant function score ≥ 32) at screening.
3. No ACLF or ACLF Grade 1 at screening.
4. Daily average intake of \>80 g (men)/\>60 g (women) ethanol during the past 3 months (patient reported).
5. Understands and agrees to comply with the study procedures and provides written informed consent as documented by signature.
6. Outpatient or hospitalized patient not being on the Intensive Care Unit (ICU) at screening.

   Inclusion criterion 7 only applies to women of childbearing potential (WOCBP)
7. Negative urine pregnancy test, not breastfeeding \& agreement to use highly-effective means of contraception during the study. Allowed are sexual abstinence, vasectomized partners (˃3 months previously-vasectomy has to be confirmed by two negative semen analyses) or the consistent and correct use of an approved contraceptive method in accordance with the product label, for example: Barrier method (such as condoms, diaphragm, or cervical cap) used in conjunction with spermicide; intrauterine device; prescription hormonal contraceptive taken or administered via oral (pill), transdermal (patch), subdermal, or intramuscular (IM) route Inclusion criterion 8 only applies to male patients
8. Male patients who are sexually active with female partners of childbearing potential must agree to use a condom with spermicide and to use one other approved method of highly effective contraception from the time of investigational product administration for at least 90 days after the dose of investigational product and must refrain from sperm donation from Screening through at least 90 days following the last dose of investigational product.
9. Ability to speak and read German to a level which allows fully comprehending the meaning of everything that is said and written.

Exclusion Criteria:

1. Uncontrolled Diabetes Mellitus type 1 or 2 (defined by HbA1c \> 10%).
2. Corticosteroid use contraindicated.
3. Viral hepatitis, autoimmune hepatitis, HIV infection, Wilson disease, hemochromatosis, toxic liver injury, Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC).
4. Participation in another interventional clinical study within 6 months prior to screening and/or during trial participation.
5. Presence of any active malignancy (other than non-melanoma skin cancer) which required treatment within the past 12 months.
6. Chronic kidney disease receiving dialysis.
7. Do Not Attempt Resuscitation (DNAR) order in place.
8. IgA deficiency (IgA level \<7mg/dL) or known intolerance to A1AT.
9. History of liver transplantation or currently listed for liver transplant.

Primary outcomes:
measure: Serum concentration of IL-6 (interleukin-6) assessed at Visit 2 (Day 8+/-1) in the intervention (A1AT in combination with standard-of-care) and control group (standard-of-care).
timeFrame: at visit 2
Secondary outcomes:
measure: Serum A1AT concentration assessed at visit 5 (Day 29+/-3)
timeFrame: at visit 5 (Day 29+/-3)
measure: Incidence of Adverse Events (AEs) from the baseline visit (Day 1) to end of study visit (Day 90+/-7)
timeFrame: up to 3 months
measure: Incidence of Serious Adverse Events (SAEs) from the baseline visit (Day 1) through to end of study visit (Day 90+/-7)
timeFrame: up to 3 months
measure: Chronic Liver Disease Questionnaire (CLDQ) overall and subscale scores.
timeFrame: up to 3 months
measure: CLDQ-D overall and subscale scores
timeFrame: up to 3 months
Other outcomes:
measure: Model for end-stage liver disease (MELD)
timeFrame: up to 3 months
measure: The MELD-sodium (MELD-Na)
timeFrame: up to 3 months
measure: Child-Pugh-Turcotte
timeFrame: up to 3 months
measure: CLIF (Chronic Liver Failure)-C-AD (acute decompensation)
timeFrame: up to 3 months
measure: CLIF-C-OF (organ function)
timeFrame: up to 3 months
measure: CLIF-SOFA (Sequential Organ Failure Assessment) score
timeFrame: up to 3 months
measure: Maddrey's discriminant function
timeFrame: up to 3 months
measure: Time to hospital discharge
timeFrame: up to 3 months
measure: Time to re-hospitalization
timeFrame: up to 3 months
measure: Time to ICU admission
timeFrame: up to 3 months
measure: Liver-specific survival and transplant-free survival at End of Study Visit
timeFrame: up to 3 months
measure: Serum concentrations of IL-6
timeFrame: up to 3 months
Locations:
city: Innsbruck
country: Austria
facility: Medical University Innsbruck
Study officials:
References: