Clinical trial NCT03994783: Transplant Antibody-Mediated Rejection: Guiding Effective Treatments
Official title: A Multicentre Randomised Controlled Trial to Assess the Efficacy of Adding Rituximab to Standard of Care in Treating Acute Antibody-mediated Rejection in Kidney Transplantation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Kidney Transplant Rejection
Antibody-mediated Rejection
Keywords: Rituximab
AMR
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: Cambridge University Hospitals NHS Foundation Trust
name: National Institute for Health Research, United Kingdom
name: Kidney Cancer UK
First posted: 2019-06-21
Enrollment: 3
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Allograft Survival as assessed by statistical model
timeFrame: 4 years
Secondary outcomes:
measure: Serum creatinine as assessed by blood test
timeFrame: 1, 3, 6 and 12 months, 2, 3 and 4 years
measure: Estimated glomerular filtration rate (eGFR) as assessed by blood test
timeFrame: 1, 3, 6 and 12 months, 2, 3 and 4 years
measure: Proteinuria as assessed by urine test
timeFrame: 1, 3, 6 and 12 months, 2, 3 and 4 years
measure: Change in donor specific antibodies as assessed by blood test
timeFrame: 3 and 12 months
measure: Change in positivity of donor specific antibodies as assessed by blood test
timeFrame: 3 and 12 months
measure: Change in mean fluorescence index of donor specific antibodies as assessed by blood test
timeFrame: 3 and 12 months
measure: Incidence rate of adverse event as assessed by questionnaire
timeFrame: 4 years
measure: Health-related quality of life (QoL) as assessed by EuroQoL EQ-5D-5L/EQ-5D-Y questionnaire
timeFrame: 3 months, 1, 2, 3 and 4 years
measure: Cost effectiveness economic analysis
timeFrame: 4 years
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Imperial College London
Study officials:
affiliation: Imperial College London
name: Michelle Willicombe, MA MRCP MD
role: PRINCIPAL_INVESTIGATOR
References: