Clinical trial NCT06120673: REmission in Membranous Nephropathy International Trial (REMIT)
Official title: International, Multi-centre Randomised Clinical Trial of Obinutuzumab Versus Corticosteroid and Cyclophosphamide in Primary Membranous Nephropathy (REMIT Trial).
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Primary Membranous Nephropathy
Lead sponsor: The University of Queensland
Sponsor class: OTHER
Collaborators: name: University of Adelaide
First posted: 2023-11-07
Enrollment: 224
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: REMIT is an investigator-initiated, international, multi-centre, prospective, randomised, open-label, parallel-group trial. A total of 224 adult participants with Primary Membranous Nephropathy (PMN) will be recruited from renal units from Australia, New Zealand Canada, Asia, Europe, United Kingdom, and other countries. Participants will be randomised to receive either corticosteroid and cyclophosphamide or obinutuzumab. The primary outcome is a ranked, composite measure based on (a) efficacy, defined as either complete or partial remission of PMN, (b) number of adverse events, and (c) quality of life.


Eligibility criteria: Inclusion Criteria:

1. Age ≥18 years.
2. Able to provide informed consent.
3. Primary Membranous Nephropathy (PMN) confirmed by:

   1. Kidney biopsy (anti-PLA2R negative patients are eligible for inclusion if PMN is confirmed on biopsy. Kidney biopsy is generally encouraged to confirm diagnosis of PMN) or
   2. if the clinician decides against a biopsy, the patient must be anti-PLA2R positive and must not have diabetes.
4. Proteinuria ≥4 g/24h despite supportive treatment for at least 6 months with maximally tolerated dose of ACE-i or ARB (dose to be stable for at least 4 weeks), confirmed at final screening before randomisation
5. Serum albumin \<30 g/L.
6. Estimated glomerular filtration rate (eGFR) ≥40 ml/min/1.73m2.
7. Treatment with immunosuppression is warranted, as determined by the treating physician.
8. Fully vaccinated against COVID-19 according to local practice/recommendation.

Exclusion Criteria:

1. Resistant to rituximab or have had \>2 g of rituximab in the past.
2. Resistant to cyclophosphamide or have had a cumulative \>20 g of cyclophosphamide in the past.
3. More than 3 years since PMN diagnosis.
4. Proteinuria must not have decreased by \>50% over 6 months whilst taking ACE-i/ARB.
5. Patients with human immunodeficiency virus (HIV) infection, active hepatitis B or C infection, or other active infections.
6. Patients with secondary membranous nephropathy
7. Screening for malignancy must be considered especially in cases who are anti-PLA2R negative.
8. Patients whose kidney biopsy shows concomitant features of diabetic nephropathy.
9. Kidney transplant recipients.
10. Pregnancy or breastfeeding.
11. Women of childbearing age not willing to use contraception.
12. Suspected or known hypersensitivity, allergy, and/or immunogenic reaction history to monoclonal antibodies, corticosteroid, cyclophosphamide, any of their ingredients, and any other drugs from these same pharmacotherapeutic groups.
13. Any disorder or condition, in the opinion of the investigator, might pose an unacceptable risk to participant's safety and well-being.
14. Inability to understand or comply with the requirements of the study.
15. Incapable of recognizing the nature, significance, and scope of the clinical trial or giving consent are excluded, even if they have a legal representative.
16. Use of an investigational agent \<30 days or within five half-lives of the investigational agents (whichever is longer), whose effect or toxicity may overlap with that of obinutuzumab, prednisolone, cyclophosphamide, or their metabolites.
17. Active Tuberculosis infection. Testing for latent disease may be performed at screening if required by local regulations or in accordance with local clinical practice. Latent disease after completion of appropriate treatment is not exclusionary.
18. Low peripheral B-cell count (as per local reference range) . B-cell count must be checked, particularly in those who have received rituximab, cyclophosphamide or both anytime in the past.
19. Use of SGLT2-i and GLP-1 agonist within 90 days prior to randomisation.

Primary outcomes:
measure: A ranked composite measure based efficacy, safety and quality of life at 24 months
timeFrame: 24 months
Secondary outcomes:
measure: Number of participants in Complete Remission (CR)
timeFrame: At 6, 12, 18, 24 month
measure: Number of participants in Partial Remission (PR)
timeFrame: At 6, 12, 18, 24 month
measure: Number of participants in CR and/or PR
timeFrame: At 6, 12, 18, 24 month
measure: Number of non-serious adverse events of special interest
timeFrame: Up until 24 months
measure: Number of serious adverse events
timeFrame: Up until 24 months
measure: Number of participants with a lack of response to PMN treatment
timeFrame: Up until 24 months
measure: Number of participants who relapse after CR or PR
timeFrame: Up until 24 months
measure: Time to first relapse
timeFrame: Up until 24 months
measure: Number of participants who have immunological remission (for anti-PLA2R positive participants)
timeFrame: Up until 24 months
measure: Number of participants who have a requirement for rescue therapy
timeFrame: Up until 24 months
measure: Number of participants who exit the trial
timeFrame: Up until 24 months
measure: Quality of life scores (EQ-5D-5L)
timeFrame: at 3, 6, 9, 12, 15, 18, 24 months
measure: eGRF slope
timeFrame: Up until 24 months
measure: Number of treatment or PMN associated deaths
timeFrame: Up until 24 months
measure: All cause deaths
timeFrame: Up until 24 months
Other outcomes:
measure: Number of participants in Complete Remission (CR)
timeFrame: At any point up until end of study (when last participant reaches 24 months - ~42 months)
measure: Number of participants in Partial Remission (PR)
timeFrame: At any point up until end of study (when last participant reaches 24 months - ~42 months)
measure: Number of participants in CR and/or PR
timeFrame: At any point up until end of study (when last participant reaches 24 months - ~42 months)
measure: Number of non-serious adverse events of special interest
timeFrame: At any point up until end of study (when last participant reaches 24 months - ~42 months)
measure: Number of serious adverse events
timeFrame: At any point up until end of study (when last participant reaches 24 months - ~42 months)
measure: Number of participants with a lack of response to PMN treatment
timeFrame: At any point up until end of study (when last participant reaches 24 months - ~42 months)
measure: Number of participants who have immunological remission (for anti-PLA2R positive participants)
timeFrame: At any point up until end of study (when last participant reaches 24 months - ~42 months)
measure: Requirement for dialysis or kidney transplant
timeFrame: At any point up until end of study (when last participant reaches 24 months - ~42 months)
measure: eGRF slope
timeFrame: At any point up until end of study (when last participant reaches 24 months - ~42 months)
measure: Number of participants with treatment or PMN associated death
timeFrame: At any point up until end of study (when last participant reaches 24 months - ~42 months)
measure: Number of participants with all cause death
timeFrame: At any point up until end of study (when last participant reaches 24 months - ~42 months)
Locations:
city: Garran
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Birtinya
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Bundaberg
country: Australia
facility: Bundaberg Hospital
state: Queensland
city: Cairns
country: Australia
facility: Cairns Hospital
state: Queensland
city: Logan
country: Australia
facility: Logan Hospital
state: Queensland
city: Mackay
country: Australia
facility: Mackay Base Hospital
state: Queensland
city: Rockhampton
country: Australia
facility: Rockhampton Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Mater Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
Study officials:
affiliation: The University of Adelaide
name: Chen Au Peh
role: STUDY_CHAIR
affiliation: Nepean Blue Mountains Local Health District
name: Bhadran Bose
role: STUDY_DIRECTOR
References: