The Safety and Efficacy of CD38 Monoclonal Antibody Monotherapy for CaAMR in Renal Transplantation

Antibody-mediated Rejection Clinical Trial

Official title:

A Multicenter, Prospective, One-arm Clinical Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05913596
• Other study ID #: IIT20220103C-R1
• Status: Recruiting
• Phase: N/A
• Start date: May 23, 2023
• Est. completion date: August 30, 2024

Study information

• Verified date: March 2023
• Source: First Affiliated Hospital of Zhejiang University
• Contact: Jianyong Wu, MD
• Phone: 86-571-87236189
• Email: wujianyong1964[@]zju.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 15
• Est. completion date: August 30, 2024
• Est. primary completion date: April 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Antibody-mediated Rejection
• Kidney Tranplant

Intervention

Drug:
• Daratumumab
After successful enrollment, the patient will receive daratumumab of 16mg/kg once every two weeks (0-22 weeks) for a total of 12 times. 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.

Locations

Country	Name	City	State
China	79# Qingchun Road	Hangzhou	Zhejiang

Sponsors (1)

Lead Sponsor	Collaborator
First Affiliated Hospital of Zhejiang University

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The change of donor specific antibody	Donor specific antibody changed 30% based on luminex HLA testing	6 months
Secondary	The change of serum creatinine	Creatinine changed by 30% compared to before treatment or returned to baseline level	6 months
Secondary	The change of BANFF score	The change of BANFF score, including c, g, ptc score	6 months
Secondary	Incidence of treatment-related adverse events	Adverse event monitoring, assessment of labs, monitoring of viral PCRs	6 months
Secondary	The change of NK cell count in PBMC	The change of NK cell count in PBMC collected at multiple time points throughout the study	6 months