Clinical trial NCT05913596: The Safety and Efficacy of CD38 Monoclonal Antibody Monotherapy for CaAMR in Renal Transplantation
Official title: A Multicenter, Prospective, One-arm Clinical Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Antibody-mediated Rejection
Kidney Tranplant
Lead sponsor: First Affiliated Hospital of Zhejiang University
Sponsor class: OTHER
First posted: 2023-06-22
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Each patient received CD38 monoclonal antibody monotherapy
Primary purpose: TREATMENT

Brief summary: Renal transplantation is the best choice for the treatment of end-stage renal disease, but the long-term survival of the graft is still remains a challenge. Chronic antibody-mediated rejection (AMR) is the main factor affecting the long-term survival of the graft. There is still no effective treatment for chronic antibody-mediated rejection, even in the active phase (CaAMR). In recent years, new therapeutic drugs based on the generation of DSA and the mechanism of AMR, including protease inhibitor bortezomi, CD20 monoclonal antibody, C5 monoclonal antibody and IL-6 antibody, have not been able to effectively eliminate and inhibit the generation of DSA, nor have they been proved to have a definite effect on AMR.

CD38 is a type II transmembrane protein that is highly expressed on plasma cells and NK cells, which are considered to play a key role in the occurrence and development of AMR. Recently, a few cases have reported that CD38 monoclonal antibody combined plasma exchange and/or IVIG may be an effective strategy for the prevention and treatment of AMR, but the effectiveness and safety of daratumumab monotherapy on CaAMR were unknown. This is a multicenter, prospective, single arm clinical study. The study will enroll 15 renal transplant recipients with positive DSA and CaAMR confirmed by biopsy after renal transplantation. According to inclusion and exclusion criteria patients will be screened to participate in the trial.

Detailed description: After successful enrollment, the patient will receive daratumumab of 16mg/kg once every two weeks (0-22 weeks) for a total of 12 times, and continue to receive triple immunosuppressive therapy with prednisone, mycophenolic acid, tacrolimus (target valley concentration of 5-7ng/ml) or cyclosporine (target valley concentration of 100-200ng/ml). Peripheral blood samples were collected from 0 to 24 weeks (weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) for routine blood tests, liver and kidney function electrolytes, tacrolimus or cyclosporine trough concentrations, HLA antibody quantification (weeks 0, 4, 8, 12, 16, 20, and 24), infection indicators (weeks 0, 8, and 24), immune status assessments (weeks 0, 4, 8, 12, 16, 20, and 24), and biopsy of transplanted kidneys was performed at 24 weeks to assess pathological changes.

Eligibility criteria: Inclusion Criteria:

1. Voluntary signing of written informed consent
2. Age ≥ 18 years old
3. ≥ 180 days after living donor kidney or DD donor kidney transplantation
4. EGFR ≥ 30mL/min/1.73 m2 (CKD-EPI formula)
5. Pre stored and/or newborn DSA (HLA antibody)

Exclusion Criteria:

1. Patients participating in another clinical trial
2. Age less than 18 years old
3. Female subjects are pregnant or breastfeeding, or do not receive appropriate contraceptive measures
4. ABO incompatibility transplantation
5. Kidney transplantation biopsy combined with one of the following results:

   A. T-cell mediated rejection B. New or recurrent severe thrombotic microangiopathy C. Polyomavirus nephropathy
6. Receive anti acute rejection treatment within 3 months before screening
7. Have been treated with other immunomodulatory monoclonal/polyclonal antibodies (such as CD20 antibody, bortezomib, C5 monoclonal antibody, IL-6/IL-6R antibody) within 3 months
8. Total bilirubin\>2 times the upper normal limit, alanine aminotransferase and aspartate aminotransferase\>2.5 times the upper normal limit
9. Hemoglobin\<8 g/dL
10. Thrombocytopenia: Platelets\<100 × 109/L
11. Leukopenia: White blood cells\<3 × 109/L, neutropenia: neutrophils\<1.5 × 109/L
12. Hypogammaglobulinemia: Serum IgG\<400 mg/dL
13. Eliminate active viral, bacterial, or fungal infections
14. Excluding Active Malignant Diseases with Intensive Immunosuppressive Therapy
15. Latent or active tuberculosis
16. Inoculate live vaccine within 6 weeks after screening
17. History of alcohol or illicit drug abuse
18. Serious medical or mental illness that may affect participation in the study
19. Active hepatitis B virus infection

Primary outcomes:
measure: The change of donor specific antibody
timeFrame: 6 months
Secondary outcomes:
measure: The change of serum creatinine
timeFrame: 6 months
measure: The change of BANFF score
timeFrame: 6 months
measure: Incidence of treatment-related adverse events
timeFrame: 6 months
measure: The change of NK cell count in PBMC
timeFrame: 6 months
Other outcomes:
Locations:
city: Hangzhou
country: China
facility: 79# Qingchun Road
state: Zhejiang
Study officials:
affiliation: the First Affiliated Hospital of Medicine College, Zhejiang University
name: Jianyong Wu, MD
role: PRINCIPAL_INVESTIGATOR
References: