Clinical trial NCT06455280: A Study of SIPLIZUMAB in AILD and LT Patients
Official title: A 12-Month, Open-Label Study Evaluating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Siplizumab As Induction Therapy in Patients with Autoimmune Liver Diseases Undergoing Liver Transplantation (SET-SAIL)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Autoimmune Liver Disease
Liver Transplant Disorder
Autoimmune Hepatitis
Primary Sclerosing Cholangitis
End Stage Liver DIsease
Cirrhosis, Liver
Keywords: Autoimmune Liver Disease
Liver Transplant Disorder
Autoimmune Hepatitis
Primary Sclerosing Cholangitis
End Stage Liver DIsease
Cirrhosis, Liver
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: ITB-Med LLC
First posted: 2024-06-12
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open-Label Study
Primary purpose: TREATMENT

Brief summary: There is a significant unmet need for safe and effective therapeutic approaches to prevent immune-mediated graft injury and its complications in liver transplant (LT) recipients with autoimmune liver disease (AILD) including autoimmune hepatitis and primary sclerosing cholangitis. Siplizumab is an anti-cluster of differentiation 2 (CD2) monoclonal antibody that has demonstrated a favorable safety profile of siplizumab in over 779 human subjects and has been shown to target memory T cells-a key driver in the immune processes surrounding rejection and autoimmunity post LT in AILD. The purpose of this pilot, open-label phase 1 study is to determine the safety of siplizumab for induction in patients with AILD undergoing LT.

Up to eight (8) subjects will receive siplizumab 0.6 mg/kg/dose on the day of transplant (Day 0) and Day 4 post-transplant, for a total of two doses.

All subjects will be followed in the study for 12 months post-LT.

Detailed description: The purpose of this study is to evaluate the safety of siplizumab when used as induction immunosuppression in patients with primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) undergoing liver transplantation. Induction immunosuppression drugs are very potent anti-rejection drugs that are given immediately after transplantation to prevent rejection. Siplizumab is investigational, meaning it has not yet been approved for market use for this disease condition by the United States Food and Drug Administration (FDA).

Adult patients (18 years of age and older) listed for LT with the specific AILD diagnoses of PSC or AIH

All subjects will receive 0.6 mg/kg/dose intravenously on the day of transplant (Day 0) intraoperatively and on post-transplant Day 4.

Participation in this study will last approximately 15 months (\~ 3 months on the LT waitlist, up to 12 months participation post-LT)

Eligibility criteria: Inclusion Criteria:

1. Able to provide informed consent
2. Age ≥ 18 years old
3. Clinical diagnosis of AIH and/or PSC
4. Listed for liver transplantation
5. Epstein-Barr virus (EBV) seropositive within 12 months of screening

Exclusion Criteria:

1. Presence or history of significant liver disease other than AIH or PSC, including viral hepatitis, alcohol-related liver disease and biopsy-proven non-alcoholic steatohepatitis
2. Prior transplant
3. Listed for multiorgan transplant
4. Acute liver failure
5. Known malignancy, including cholangiocarcinoma and hepatocellular carcinoma
6. Other investigational products in the last 30 days or 5 half lives
7. Pregnant/lactating or unwilling to use contraception
8. Leukopenia (WBC less than 2,000/mm3
9. Absolute lymphocyte count \< 200/mm3
10. Sero-positive for HIV-1
11. Hepatitis C Virus (HCV) antibody or RNA positive (within 6 months of screening)
12. HBsAg, hepatitis B virus (HBV) DNA or HBcAb positive (within 6 months of screening)
13. Alcohol use exceeding 30g/day for men or 20g/day for women, and/or known phosphatidylethanol (PETH) level \>80 in the 3 months prior to LT
14. Untreated latent TB infection as detected by QuantiFERON Gold Plus Interferon Gamma Release Assay (IGRA) (or current standard interferon gamma release assay for TB)
15. Receipt of any live-attenuated vaccine within 2 months of transplant.

ADDITIONAL exclusion criteria to be reviewed at the time of transplant

1. Renal failure with dialysis or with estimated glomerular filtration rate (eGFR) \< 30 at the time of LT
2. Model for end-stage liver disease (MELD)-Na score \>30
3. Donor features of Donation after Cardiac Death (DCD), HCV Ab or nucleic acid testing (NAT+), HBcAb or HBsAg+, or blood types A, B, and O incompatible organ

Primary outcomes:
measure: Serious infection in the first month post-transplant,
timeFrame: 1 Month post-transplant
Secondary outcomes:
measure: Incidence of immune-mediated liver injury
timeFrame: 12 month Post-transplant
measure: Incidence of graft loss or death
timeFrame: 12 month Post-transplant
measure: Incidence of BPAR
timeFrame: 12 month Post-transplant
measure: Incidence of treated BPAR
timeFrame: 12 month Post-transplant
measure: Incidence of refractory BPAR
timeFrame: 12 month Post-transplant
measure: Incidence of development of donor specific antibodies (DSA)
timeFrame: 12 month Post-transplant
measure: Incidence of recurrent AILD
timeFrame: 12 month Post-transplant
Other outcomes:
measure: Peak plasma concentration (Cmax) after single dose of siplizumab
timeFrame: 12 hours Post-treatment
measure: The area under the curve (AUC) from time zero to the last measurable plasma concentration sampling time.
timeFrame: 84 Days Post-transplant
measure: Descriptive summary statistics by dosing level and visit/sampling time point
timeFrame: 12 month Post-transplant
measure: Summary statistics of pharmacokinetic (PK) of Siplizumab
timeFrame: 12 month Post-transplant
measure: Change in Concentration T-Cells
timeFrame: 12 month Post treatment
measure: Change in Concentration of B- cells
timeFrame: 12 month Post treatment
measure: Change in Concentration of NK- cells
timeFrame: 12 month Post treatment
measure: CD2 receptor occupancy by dose level and subject
timeFrame: 12 month Post-transplant
measure: Dynamics of T-cell subset recovery in the blood and allograft liver
timeFrame: 12 month Post-transplant
Locations:
city: New York
country: United States
facility: Columbia University Irving Medical Center/NewYork-Presbyterian Hospital
state: New York
Study officials:
affiliation: Columbia University Irving Medical Center/ New York Presbyterian Hospital
name: Elizabeth Verna, MD
role: PRINCIPAL_INVESTIGATOR
References: