Transplant Antibody-Mediated Rejection: Guiding Effective Treatments

NCT03994783 | Terminated Phase 3 DMC

• 1 other identifier: 2018-002882-20
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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.

Conditions

Kidney Transplant Rejection; Antibody-mediated Rejection

Keywords

Rituximab; AMR

Outcome Measures

Primary Outcomes (1)

• Allograft Survival as assessed by statistical model

  Statistical model measuring allograft survival as defined as duration from the date of randomisation to the date of eGFR ≤15 mL/min/1.72 m2 (where the eGFR measurement is not due to an acute reversible cause, as determined by the PI, or a follow-up consecutive eGFR measurement of ≤15 mL/min/1.72 m2 is recorded (where the first date is recorded as the date of failure)), or the date of renal replacement therapy (date of starting maintenance dialysis dependency, retransplantation etc), whichever occurs first.

  4 years

Secondary Outcomes (9)

• Serum creatinine as assessed by blood test

  1, 3, 6 and 12 months, 2, 3 and 4 years

• Estimated glomerular filtration rate (eGFR) as assessed by blood test

  1, 3, 6 and 12 months, 2, 3 and 4 years

• Proteinuria as assessed by urine test

  1, 3, 6 and 12 months, 2, 3 and 4 years

• Change in donor specific antibodies as assessed by blood test

  3 and 12 months

• Change in positivity of donor specific antibodies as assessed by blood test

  3 and 12 months

Study Arms (2)

Standard of Care (SOC)

ACTIVE COMPARATOR

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)

Drug: Methylprednisolone; Drug: Intravenous Immunoglobulin; Procedure: Plasma Exchange

Standard of Care plus Rituximab (SOCR)

EXPERIMENTAL

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)

Drug: Rituximab; Drug: Methylprednisolone; Drug: Intravenous Immunoglobulin; Procedure: Plasma Exchange

Interventions

Rituximab DRUG

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

Also known as: Rituximab Biosimilar, Mabthera

Standard of Care plus Rituximab (SOCR)

Methylprednisolone DRUG

Intravenous infusion of methylprednisolone

Standard of Care (SOC); Standard of Care plus Rituximab (SOCR)

Intravenous Immunoglobulin DRUG

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

Standard of Care (SOC); Standard of Care plus Rituximab (SOCR)

Plasma Exchange 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 (SOC); Standard of Care plus Rituximab (SOCR)

Eligibility Criteria

• Age: 5 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Imperial College London: lead
• Cambridge University Hospitals NHS Foundation Trust: collaborator
• National Institute for Health Research, United Kingdom: collaborator
• Kidney Cancer UK: collaborator

Study Sites (1)

Imperial College London

London, United Kingdom

Location

MeSH Terms

Interventions

Rituximab; Methylprednisolone; Immunoglobulins, Intravenous; Plasma Exchange

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Immunoglobulin G; Immunoglobulin Isotypes; Blood Transfusion; Biological Therapy; Therapeutics; Plasmapheresis; Blood Component Removal; Sorption Detoxification; Extracorporeal Circulation; Surgical Procedures, Operative

Study Officials

• Michelle Willicombe, MA MRCP MD

  Imperial College London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 17, 2019
• First Posted: June 21, 2019
• Study Start: July 17, 2019
• Primary Completion: July 17, 2021
• Study Completion: January 9, 2023
• Last Updated: April 13, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)