Renal Allograft Tolerance Through Mixed Chimerism - SMC/MGH

Renal Failure Clinical Trial

Official title:

Renal Allograft Tolerance Through Mixed Chimerism - SMC/MGH

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04540380
• Other study ID #: Tolerance SMC-MGH
• Status: Recruiting
• Phase: Phase 1
• Start date: September 1, 2021
• Est. completion date: June 2025

Study information

• Verified date: June 2024
• Source: Massachusetts General Hospital
• Contact: Tatsuo Kawai, MD PhD
• Phone: 617-726-0289
• Email: tkawai[@]mgh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal is to investigate the safety of the conditioning regimen, and its ability to induce donor/recipient lymphohematopoietic chimerism without Chimerism Transition Syndrome (CTS), which may result in donor-specific unresponsiveness (tolerance) to the renal allograft in the absence of maintenance immunosuppression.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: June 2025
• Est. primary completion date: January 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Male or female 18-65 years of age.

• Candidate for a living-donor renal allograft from an HLA mismatched donor

• Subjects with chronic kidney disease stage or ESRD who are treated with either hemodialysis or peritoneal dialysis.

• First transplant.

• Use of FDA-approved methods of contraception

• Ability to understand and provide informed consent.

• Negative COVID at screening and 2 days before procedure

Exclusion Criteria:

• ABO blood group-incompatible renal allograft.

• Participant with a (non DSA) PRA > 20% within 6 months prior to transplant

• Persistent Leukopenia (WBC less than 2,000/mm3) or thrombocytopenia (<100,000/mm3).

• Seropositivity for HIV-1, hepatitis B core antigen, or hepatitis C virus (confirmed by hepatitis C virus RNA); or positivity for hepatitis B surface antigen.

• Active infection

• Left ventricular ejection fraction < 40% as determined by TTE or clinical evidence of heart failure

• Forced expiratory volume FEV1 or DLCO < 50% of predicted.

• Lactation or pregnancy

• History of cancer (following the American Transplant Society Guidelines)

• Underlying renal disease etiology with a high risk of disease recurrence in the transplanted kidney (such as focal segmental glomerulosclerosis).

• Prior dose-limiting radiation therapy

• Known genetic disease or family history that may result in greater sensitivity to the effects of irradiation, or a physical deformity that would preclude adequate shielding or appropriate dosing during the irradiation component of the conditioning regimen

• Enrollment in other investigational drug studies within 30 days prior to enrollment

• Abnormal (>2 times lab normal) values for (a) liver function chemistries (ALT, AST, AP), (b) bilirubin, (c) coagulation studies (PT, PTT).

• Allergy or sensitivity to any component of Siplizumab, Fludarabine, Cyclophosphamide, tacrolimus, DMSO, MMF or rituximab.

• The presence of any medical condition that the investigator deems incompatible with participation in the trial.

• Subjects who have non-insulin dependent diabetes (NIDDM) without good blood glucose control (HbA1c<7). Subject with severe retinopathy, gastroparesis, or severe neuropathy which prevent subject's normal independent daily activities will be excluded from the study

Related Conditions & MeSH terms

• Renal Failure
• Renal Insufficiency

Intervention

Drug:
• Rituximab, Fludarabine, Cyclophosphamide, Thymic irradiation and Siplizumab
Conditioning regimen .Patients will receive Rituximab, Fludarabine, Cyclophosphamide, Thymic irradiation and Thymoglobulin

Procedure:
• Combined bone marrow and kidney transplant
Recipients will receive a conditioning regimen that includes rituximab on study days -7 and -2, fludarabine 10mg/m2/day on days -6 to -3 (4 doses), cyclophosphamide (22.5mg/kg/day) on days -5 and -4, followed by local thymic irradiation (7 Gy) on day -1 and Siplizumabon days -1, 0, and +1. Combined kidney and bone marrow transplant will be performed on study day 0. Methylprednisolone will be started at 250 mg/day on day 0 and tapered to prednisone 20mg by day 10 after which it will be continued until day 20. Prophylaxis will be provided for hemorrhagic cystitis, PCP, fungal infection, CMV, and perioperative infection. All patients who require any blood transfusion will receive only leukocyte-depleted and irradiated blood products for a period of at least 52 weeks following transplantation. The proportion of patients successfully weaned off immunosuppression without chimerism transition syndrome (CTS) will be assessed.

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Massachusetts General Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Transient Chimerism		36 months after immunosuppression withdrawal
Primary	Incidence of Chimerism Transition Syndrome		36 months after immunosuppression withdrawal
Primary	Incidence of tolerance induction		36 months after immunosuppression withdrawal