Autoimmune Liver Disease, Liver Transplant Disorder, Autoimmune Hepatitis, Primary Sclerosing Cholangitis, End Stage Liver DIsease, Cirrhosis, Liver
Conditions
Keywords
Autoimmune Liver Disease, Liver Transplant Disorder, Autoimmune Hepatitis, Primary Sclerosing Cholangitis, End Stage Liver DIsease, Cirrhosis, Liver
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)
Interventions
DRUGSiplizumab
Siplizumab is an anti-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.
Sponsors
ITB-Med LLC
Elizabeth C. Verna
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-Label Study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serious infection in the first month post-transplant, | 1 Month post-transplant | viral, bacterial or fungal infection that leads to readmission, prolonged hospitalization, reoperation, intensive care unit admission, graft loss or death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of graft loss or death | 12 month Post-transplant | Loss of liver allograft or incidence of mortality |
| Incidence of BPAR | 12 month Post-transplant | biopsy proven acute rejection within 12 Month post-transplant |
| Incidence of treated BPAR | 12 month Post-transplant | biopsy proven acute rejection that requires treatment within 12 Month post-transplant |
| Incidence of immune-mediated liver injury | 12 month Post-transplant | biopsy proven acute rejection (BPAR), or recurrent AILD |
| Incidence of development of donor specific antibodies (DSA) | 12 month Post-transplant | Donor specific antibodies within 12 Month Post-transplant |
| Incidence of recurrent AILD | 12 month Post-transplant | based upon histology for autoimmune hepatitis \[AIH\] and histology and/or imaging for primary sclerosing cholangitis \[PSC\] |
| Incidence of refractory BPAR | 12 month Post-transplant | biopsy proven acute rejection within 12 Month post-transplant that is not responsive to treatment |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Concentration of NK- cells | 12 month Post treatment | Change in Concentration of NK- cells (cells/uL) |
| Change in Concentration of B- cells | 12 month Post treatment | Change in Concentration of B- cells (cells/uL) |
| CD2 receptor occupancy by dose level and subject | 12 month Post-transplant | Measurement of CD2 receptor occupancy |
| Dynamics of T-cell subset recovery in the blood and allograft liver | 12 month Post-transplant | Measurement of T-cell subset in the blood and allograft liver |
| Peak plasma concentration (Cmax) after single dose of siplizumab | 12 hours Post-treatment | Cmax after single dose |
| The area under the curve (AUC) from time zero to the last measurable plasma concentration sampling time. | 84 Days Post-transplant | AUC based on plasma concentrations over 84 days post-treatment |
| Descriptive summary statistics by dosing level and visit/sampling time point | 12 month Post-transplant | the frequency of siplizumab concentrations below the lower-limit of quantification (LLOQ) |
| Summary statistics of pharmacokinetic (PK) of Siplizumab | 12 month Post-transplant | mean, standard deviation (SD), coefficient of variation (CV), median, minimum and maximum of siplizumab concentrations. |
| Change in Concentration T-Cells | 12 month Post treatment | Change in Concentration of T- cells (cells/uL) |
Countries
United States
Contacts
Primary ContactTheresa Lukose, PharmD
Backup ContactAmanda Alonso, MHA
Outcome results
None listed