SIPLIZUMAB in AILD and LT

Cirrhosis, Liver Clinical Trial

— SET-SAIL  

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)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06455280
• Other study ID #: AAAU7303
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: June 1, 2024
• Est. completion date: March 31, 2026

Study information

• Verified date: June 2024
• Source: Columbia University
• Contact: Theresa Lukose, PharmD
• Phone: 212-305-3839
• Email: tt2103[@]cumc.columbia.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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-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.

Description:

The purpose of this study is to evaluate the safety of siplizumab when used as induction immunosuppression in patients with PSC or 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)

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 8
• Est. completion date: March 31, 2026
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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. 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. HCV antibody or RNA positive (within 6 months of screening)

12. HBsAg, 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 PETH level >80 in the 3 months prior to LT

14. Untreated latent TB infection as detected by QuantiFERON Gold Plus 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 eGFR < 30 at the time of LT

2. MELD-Na score >30

3. Donor features of Donation after Cardiac Death (DCD), HCV Ab or NAT+, HBcAb or HBsAg+, or ABO incompatible organ

Related Conditions & MeSH terms

• Autoimmune Hepatitis
• Autoimmune Liver Disease
• Cholangitis
• Cholangitis, Sclerosing
• Cirrhosis, Liver
• End Stage Liver DIsease
• Fibrosis
• Hepatitis
• Hepatitis, Autoimmune
• Liver Cirrhosis
• Liver Diseases
• Liver Transplant Disorder
• Primary Sclerosing Cholangitis

Intervention

Drug:
• Siplizumab
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.

Locations

Country	Name	City	State
United States	Columbia University Irving Medical Center/NewYork-Presbyterian Hospital	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Elizabeth C. Verna	ITB-Med LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Peak plasma concentration (Cmax) after single dose of siplizumab	Cmax after single dose	12 hours Post-treatment
Other	The area under the curve (AUC) from time zero to the last measurable plasma concentration sampling time.	AUC based on plasma concentrations over 84 days post-treatment	84 Days Post-transplant
Other	Descriptive summary statistics by dosing level and visit/sampling time point	the frequency of siplizumab concentrations below the lower-limit of quantification (LLOQ)	12 month Post-transplant
Other	Summary statistics of PK of Siplizumab	mean, standard deviation (SD), coefficient of variation (CV), median, minimum and maximum of siplizumab concentrations.	12 month Post-transplant
Other	Change in peripheral immunophenotype	Measurement of subsets of T-, B- and NK-cells	12 month Post treatment
Other	CD2 receptor occupancy by dose level and subject	Measurement of CD2 receptor occupancy	12 month Post-transplant
Other	Dynamics of T-cell subset recovery in the blood and allograft liver	Measurement of T-cell subset in the blood and allograft liver	12 month Post-transplant
Primary	Serious infection in the first month post-transplant,	viral, bacterial or fungal infection that leads to readmission, prolonged hospitalization, reoperation, intensive care unit admission, graft loss or death.	1 Month post-transplant
Secondary	Incidence of immune-mediated liver injury	biopsy proven acute rejection [BPAR], or recurrent AILD	12 month Post-transplant
Secondary	Incidence of graft loss or death	Loss of liver allograft or incidence of mortality	12 month Post-transplant
Secondary	Incidence of BPAR	biopsy proven acute rejection within 12 Month post-transplant	12 month Post-transplant
Secondary	Incidence of treated BPAR	biopsy proven acute rejection that requires treatment within 12 Month post-transplant	12 month Post-transplant
Secondary	Incidence of refractory BPAR	biopsy proven acute rejection within 12 Month post-transplant that is not responsive to treatment	12 month Post-transplant
Secondary	Incidence of development of donor specific antibodies (DSA)	Donor specific antibodies within 12 Month Post-transplant	12 month Post-transplant
Secondary	Incidence of recurrent AILD	based upon histology for autoimmune hepatitis [AIH] and histology and/or imaging for primary sclerosing cholangitis [PSC]	12 month Post-transplant

External Links

•   Gugenheim, J., et al., Delayed rejection of heart allografts in hypersensitized rats by extracorporeal donorspecific liver hemoperfusion. Transplantation, 1986. 41(3): p. 398-400.
•   Kwong, A., et al., OPTN/SRTR 2018 Annual Data Report: Liver. Am J Transplant, 2020. 20 Suppl s1: p. 193- 299.
•   Qian, J., et al., Studies on the induction of tolerance to alloantigens. I. The abrogation of potentials for delayed-type-hypersensitivity response to alloantigens by portal venous inoculation with allogeneic cells. J Immunol, 1985. 134(6): p. 3656-61.