Transplant Antibody-Mediated Rejection: Guiding Effective Treatments

NCT ID: NCT03994783

Last Updated: 2025-04-13

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-07-17
• Study Completion Date: 2023-01-09

Brief Summary

This trial evaluates the addition of rituximab to standard of care in the treatment of antibody-mediated rejection in kidney transplant patients. The trial will involve adults and children. Half of participants will receive standard of care (methylprednisolone, intravenous immunoglobulin and plasma exchange), while the other half will receive standard of care and rituximab.

Detailed Description

Chronic antibody-mediated rejection (cAMR) is the leading cause of kidney transplant failure. Fifty percent of kidney transplant patients who develop acute antibody-mediated rejection (aAMR) will develop evidence of cAMR within 1 year of the acute rejection episode. There is currently no evidence on how to treat aAMR.

The planned research is a randomised controlled trial, which compares an acceptable and commonly used therapy, which will be referred to as "standard of care", with an additional agent, rituximab, added to the "standard of care" treatment. The participants with be randomised in a 1:1 ratio.

"Standard of care" will include optimisation of the participant's baseline anti-rejection medications and therapy to remove the antibodies which have developed against the kidney transplant, which are causing the damage. This is called plasma exchange. The participants will also receive therapy to reduce inflammation and reduce their immune response to their kidney transplant. This will be achieved using corticosteroids and intravenous immunoglobulins, respectively. These therapies have been used to treat aAMR for many decades.

The intervention arm will consist of the "standard of care" treatment, with the addition of a drug called rituximab, which will be administered in 2 separate doses. Rituximab is itself an antibody, which binds to certain cells in the body involved in antibody production, called B cells. Following the administration of rituximab, the number of B cells is reduced, which affects antibody production. Rituximab is commonly used in transplantation for this indication, as well as for other conditions.

Participants in both arms will be followed up to determine if there is a difference in the time to transplant failure and/or transplant function.

Conditions

Kidney Transplant Rejection; Antibody-mediated Rejection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard of Care (SOC)

Intravenous Methylprednisolone (500 mg (600 mg/m2 for paediatric participants), n=3) Plasma Exchange (PEX) (60 ml/kg max 4 l (1 - 1.5 plasma volumes for paediatric participants), n=7) Intravenous Immunoglobulin (high dose: 2 g/kg total, or low dose: 100 mg/kg n=7 after each PEX, no dose adjustment for paediatric participants)

Group Type: ACTIVE_COMPARATOR

Methylprednisolone

Intervention Type: DRUG

Intravenous infusion of methylprednisolone

Intravenous Immunoglobulin

Intervention Type: DRUG

High dose (2 g/kg total) or Low dose (100 mg/kg, n=7)

Plasma Exchange

Intervention Type: PROCEDURE

Blood is removed from the patient and filtered to remove the plasma. Red and white blood cells and platelets are returned to the patient with replacement fluid.

Standard of Care plus Rituximab (SOCR)

Intravenous Methylprednisolone (500 mg (600 mg/m2 for paediatric participants), n=3) Plasma Exchange (PEX) (60 ml/kg max 4 l (1 - 1.5 plasma volumes for paediatric participants), n=7) Intravenous Immunoglobulin (high dose: 2 g/kg total, or low dose: 100 mg/kg n=7 after each PEX, no dose adjustment for paediatric participants) Rituximab (375 mg/m2 max 1 g (no dose adjustment for paediatric participants), n=2 14 days +/- 2 days apart)

Group Type: EXPERIMENTAL

Rituximab

Intervention Type: DRUG

2 intravenous infusions of rituximab or approved biosimilar given 14 days +/- 2 days apart.

Methylprednisolone

Intervention Type: DRUG

Intravenous infusion of methylprednisolone

Intravenous Immunoglobulin

Intervention Type: DRUG

High dose (2 g/kg total) or Low dose (100 mg/kg, n=7)

Plasma Exchange

Intervention Type: PROCEDURE

Blood is removed from the patient and filtered to remove the plasma. Red and white blood cells and platelets are returned to the patient with replacement fluid.

Interventions

Rituximab

2 intravenous infusions of rituximab or approved biosimilar given 14 days +/- 2 days apart.

Intervention Type: DRUG

Methylprednisolone

Intravenous infusion of methylprednisolone

Intervention Type: DRUG

Intravenous Immunoglobulin

High dose (2 g/kg total) or Low dose (100 mg/kg, n=7)

Intervention Type: DRUG

Plasma Exchange

Blood is removed from the patient and filtered to remove the plasma. Red and white blood cells and platelets are returned to the patient with replacement fluid.

Intervention Type: PROCEDURE

Other Intervention Names

Rituximab Biosimilar; Mabthera

Eligibility Criteria

Inclusion Criteria

• Willing and able to give written informed consent by patient aged 16 years and over; or by a parent or legal guardian for patients who are under 16 years old
• 5 years old or older
• A diagnosis of acute AMR as defined by:
• The presence of ≥1 donor specific antibodies (DSA)
• An adequate renal transplant biopsy with histological features consistent with active AMR with no evidence of chronicity as defined by the Banff histological classification of allograft pathology:
• If C4d positive (2 or 3):
• v score ≥1 and/or
• g score ≥1 and/or
• thrombotic microangiopathy and/or
• ptc score ≥1
• or if co-existent cellular rejection, a g score of ≥1 OR
• If C4d negative (0 or 1):
• microcirculation inflammatory score (g + ptc) ≥2
• or if co-existing cellular rejection, a g score ≥1 and (g + ptc) ≥2 AND
• Chronic glomerulopathy (cg) score 0 or 1a
• Tubulo-interstitial fibrosis <50% and glomerular obsolescence <50%

Exclusion Criteria

• Patients who have received an ABO incompatible transplant
• Patients who have received rituximab as part of induction or post-transplant for any other indications (e.g. recurrent focal and segmental glomerular sclerosis)
• Patients who have completed PEX treatment prior to the index biopsy on the suspicion of acute AMR in the absence of histology
• Have active infection including bacterial, viral (including CMV (cytomegalovirus) and EBV (Epstein-Barr virus)), fungal or tuberculosis, which in the investigator's opinion could affect the conduct of the trial
• Co-existing BK (BK virus) nephropathy
• Patients with hepatitis B (patients with prior exposure to hepatitis B may be enrolled at the discretion of the PI)
• Have active hepatitis C (patients may be included if a negative hepatitis C recombinant immunoblot assay is confirmed or have a negative hepatitis C virus RNA [qualitative] test)
• Have human immunodeficiency virus (HIV)
• Active malignancy, which would pose a contraindication to any of the trial interventions
• Patients with known allergy, intolerance or contraindication to treatments in the standard of care arm or rituximab as outlined in the Summaries of Product Characteristics (SmPCs)
• Clinically significant comorbidity
• Females must be either post-menopausal for at least 1 year, surgically sterile or, if of child-bearing potential, must not be pregnant or lactating. If sexually active, female participants must agree to use an acceptable method of birth control for 12 months post treatment with rituximab. Female participants must also agree not to breastfeed for 12 months post treatment with rituximab.

• Minimum Eligible Age: 5 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cambridge University Hospitals NHS Foundation Trust

OTHER

Sponsor Role: collaborator

National Institute for Health Research, United Kingdom

OTHER_GOV

Sponsor Role: collaborator

Kidney Cancer UK

OTHER

Sponsor Role: collaborator

Imperial College London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michelle Willicombe, MA MRCP MD

Role: PRINCIPAL_INVESTIGATOR

Imperial College London

Locations

Imperial College London

London, , United Kingdom

Countries

United Kingdom

Other Identifiers

2018-002882-20

Identifier Type: -

Identifier Source: org_study_id