REmission in Membranous Nephropathy International Trial (REMIT) (REMIT)

International, Multi-centre Randomised Clinical Trial of Obinutuzumab Versus Corticosteroid and Cyclophosphamide in Primary Membranous Nephropathy (REMIT Trial).

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Primary Membranous Nephropathy
• Intervention / Treatment: Drug: Obinutuzumab; Drug: Oral prednisolone and cyclophosphamide

• Study Type: Interventional
• Enrollment (Estimated): 224
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Peta-Anne Paul-Brent; Phone Number: +61411 397 776; Email: remit@uq.edu.au

Study Locations

• Australia
  • Australian Capital Territory
    • Garran, Australian Capital Territory, Australia
      • Canberra Hospital
      • Contact: Giles Walters, Dr
  • New South Wales
    • Camperdown, New South Wales, Australia
      • Royal Prince Alfred Hospital
      • Contact: Steve Chadban, Prof
  • Queensland
    • Birtinya, Queensland, Australia
      • Sunshine Coast University Hospital
      • Contact: Nicholas Gray, Dr
    • Brisbane, Queensland, Australia
      • Royal Brisbane and Women'S Hospital
      • Contact: Sharad Ratanjee, Dr
    • Bundaberg, Queensland, Australia
      • Bundaberg Hospital
      • Contact: Clyson Mutatiri, Dr
    • Cairns, Queensland, Australia
      • Cairns Hospital
      • Contact: Harris Abdul Makim, Dr
    • Logan, Queensland, Australia
      • Logan Hospital
      • Contact: Jeremy Frazier, Dr
    • Mackay, Queensland, Australia
      • Mackay Base Hospital
      • Contact: Roy Cherian, Dr
    • Rockhampton, Queensland, Australia
      • Rockhampton Hospital
      • Contact: Than Han, Dr
    • South Brisbane, Queensland, Australia
      • Mater Hospital
      • Contact: Michael Burke, Dr
    • Woolloongabba, Queensland, Australia
      • Princess Alexandra Hospital
      • Contact: Ross Francis, A/Prof
  • Tasmania
    • Hobart, Tasmania, Australia
      • Royal Hobart Hospital
      • Contact: Steven Y"ew, Dr
  • Western Australia
    • Murdoch, Western Australia, Australia
      • Fiona Stanley Hospital
      • Contact: Ramyasuda Swaninatha, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Obinutuzumab	Drug: Obinutuzumab; Participants will receive an intravenous infusion of 1,000mg Obinutuzumab at Weeks 0, 2, 24 and 26. Prior to the administration of obinutuzumab, the participant will receive pre-medications consisting of all three: IV methylprednisolone 80 mg,; Paracetamol 1,000 mg orally,; Either cetirizine 10 mg orally or diphenhydramine 50 mg orally. These pre-medications must be completed between 30 to 60 minutes prior to the obinutuzumab infusion.
Active Comparator: Oral prednisolone and cyclophosphamide	Drug: Oral prednisolone and cyclophosphamide; Participants will receive a combination of oral prednisolone and cyclophosphamide with 2 options (Option A and B). Option A: Cyclical prednisolone and cyclophosphamide with IV methylprednisolone; IV methylprednisolone 500-1000 mg will be given on days 1, 2 and 3 at the start of months 1, 3, and 5.; Oral prednisolone will be given at 0.5 mg/kg/day (max 50 mg/day) in months 1, 3, and 5.; Oral cyclophosphamide will be given in months 2, 4 and 6, adjusted by age and weight Option B: Concurrent prednisolone and cyclophosphamide without IV methylprednisolone; Oral prednisolone will be given to meet a cumulative dose equivalent to 0.5 mg/kg/day for 90 days (max 50 mg/day).; Oral cyclophosphamide will be given for 90 days, adjusted by age and weight

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A ranked composite measure based efficacy, safety and quality of life at 24 months	A ranked composite measure comprising of: Efficacy (complete/partial remission) plus safety (type of adverse event) at 24 months; Number of adverse events up to 24 months; Quality of Life (EQ-5D) averaged over 24 months	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants in Complete Remission (CR)	Number of participants who have proteinuria of ≤3.0 g/day	At 6, 12, 18, 24 month
Number of participants in Partial Remission (PR)	Number of participants who have proteinuria of between >3.0 and 3.5 g/day and >50% reduction from baseline proteinuria	At 6, 12, 18, 24 month
Number of participants in CR and/or PR	Number of participants who meet complete and/or partial PMN remission definition	At 6, 12, 18, 24 month
Number of non-serious adverse events of special interest	Number of protocol defined non-serious events of special interest (related to PMN or the study interventions)	Up until 24 months
Number of serious adverse events	Number of protocol defined serious adverse events	Up until 24 months
Number of participants with a lack of response to PMN treatment	Number of participants who have <50% reduction in proteinuria from baseline or worsening (increasing in value from baseline) proteinuria, and had not achieved either PR or CR	Up until 24 months
Number of participants who relapse after CR or PR	Number of participant who have a reappearance of proteinuria to >3.5 g/day at a ≥50% higher level than the lowest post-treatment value in participants who had previously achieved either PR or CR	Up until 24 months
Time to first relapse	The time to relapse is the time interval from the last point in time when the participant was in the best remission status (either PR or CR) to the first relapse	Up until 24 months
Number of participants who have immunological remission (for anti-PLA2R positive participants)	Number of participants who have their anti-PLA2R-Ab level drop below 2 RU/mL who are ≥14 RU/ml at baseline	Up until 24 months
Number of participants who have a requirement for rescue therapy	Number of participants who have a lack of response or relapse at 12 months, and rescue therapies such as obinutuzumab, calcineurin inhibitors, or additional corticosteroid and cyclophosphamide are used.	Up until 24 months
Number of participants who exit the trial	Number participant who cease trial follow-up for any reason	Up until 24 months
Quality of life scores (EQ-5D-5L)	Quality of life scores using EQ-5D-5L	at 3, 6, 9, 12, 15, 18, 24 months
eGRF slope	Change in eGFR slope	Up until 24 months
Number of treatment or PMN associated deaths	Number of deaths attributed directly or indirectly to a complication of PMN or the treatment for PMN	Up until 24 months
All cause deaths	Number of deaths of any cause	Up until 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants in Complete Remission (CR)	Number of participants who have proteinuria of ≤3.0 g/day	At any point up until end of study (when last participant reaches 24 months - ~42 months)
Number of participants in Partial Remission (PR)	Number of participants who have proteinuria of between >3.0 and 3.5 g/day and >50% reduction from baseline proteinuria with stable kidney function (eGFR remains >40 ml/min/1.73m2)	At any point up until end of study (when last participant reaches 24 months - ~42 months)
Number of participants in CR and/or PR	Number of participants who meet complete and/or partial PMN remission definition	At any point up until end of study (when last participant reaches 24 months - ~42 months)
Number of non-serious adverse events of special interest	Number of protocol defined non-serious events of special interest (related to PMN or the study interventions)	At any point up until end of study (when last participant reaches 24 months - ~42 months)
Number of serious adverse events	Number of protocol defined serious adverse events	At any point up until end of study (when last participant reaches 24 months - ~42 months)
Number of participants with a lack of response to PMN treatment	Number of participants who have <50% reduction in proteinuria from baseline or worsening (increasing in value from baseline) proteinuria, and had not achieved either PR or CR	At any point up until end of study (when last participant reaches 24 months - ~42 months)
Number of participants who have immunological remission (for anti-PLA2R positive participants)	Number of participants who have their anti-PLA2R-Ab level drop below 2 RU/mL who are ≥14 RU/ml at baseline	At any point up until end of study (when last participant reaches 24 months - ~42 months)
Requirement for dialysis or kidney transplant	Number of participants who require dialysis or a kidney transplant (Stage 5 kidney disease)	At any point up until end of study (when last participant reaches 24 months - ~42 months)
eGRF slope	Change in eGFR slope	At any point up until end of study (when last participant reaches 24 months - ~42 months)
Number of participants with treatment or PMN associated death	Number of deaths attributed directly or indirectly to a complication of PMN or the treatment for PMN	At any point up until end of study (when last participant reaches 24 months - ~42 months)
Number of participants with all cause death	Number of deaths of any cause	At any point up until end of study (when last participant reaches 24 months - ~42 months)

Collaborators and Investigators

• Sponsor: The University of Queensland
• Collaborators: University of Adelaide
• Investigators: Study Chair: Chen Au Peh, The University of Adelaide; Study Director: Bhadran Bose, Nepean Blue Mountains Local Health District

Study record dates

Study Major Dates

• Study Start (Estimated): July 31, 2024
• Primary Completion (Estimated): January 31, 2028
• Study Completion (Estimated): January 31, 2028

Study Registration Dates

• First Submitted: December 12, 2022
• First Submitted That Met QC Criteria: November 1, 2023
• First Posted (Actual): November 7, 2023

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 1, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Nephritis; Glomerulonephritis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Glomerulonephritis, Membranous; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Prednisolone; Cyclophosphamide; Obinutuzumab
• Other Study ID Numbers: AKTN 18.03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Data sets will be made available to researchers within the REMIT Study for analysis of sub-studies and country specific outcomes after the primary manuscript has been accepted for publication.

For researchers outside the REMIT study, individual participant data will be made available upon request to a Data Access Committee, a review board set up to assess proposals based on sound science, benefit-risk balancing and research team expertise.

Where data linkage has been used to estimate health care services utilisation, data sharing will be determined by the specific requirements of the data custodians. In some circumstances it may not be possible to share participant level data beyond the country in which it was collected. This will be addressed on a jurisdiction basis.

• IPD Sharing Time Frame: 2 years after publication of pre-specified analyses

IPD Sharing Access Criteria

Data sets will be made available to researchers within the REMIT Study for analysis of sub-studies and country specific outcomes after the primary manuscript has been accepted for publication.

For researchers outside the REMIT study, individual participant data will be made available upon request to a Data Access Committee, a review board set up to assess proposals based on sound science, benefit-risk balancing and research team expertise.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No