REmission in Membranous Nephropathy International Trial (REMIT)

Phase 3

Not yet recruiting

• Conditions: Primary Membranous Nephropathy
• Interventions: Drug: Oral prednisolone and cyclophosphamide; Drug: Obinutuzumab

• Registration Number: NCT06120673
• Lead Sponsor: The University of Queensland

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-12-12
• Status Verified: 2023-09
• Study First Submitted QC: 2023-11-01
• Last Update Submitted: 2023-11-01
• Study First Posted: 2023-11-07
• Last Update Posted: 2023-11-07
• Study Start: 2024-07-31
• Primary Completion: 2028-01-31
• Study Completion: 2028-01-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 224

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Oral prednisolone and cyclophosphamide	Oral prednisolone and cyclophosphamide	-
Obinutuzumab	Obinutuzumab	-

Primary Outcome Measures

Name	Time	Method
A ranked composite measure based efficacy, safety and quality of life at 24 months	24 months	A ranked composite measure comprising of: 1. Efficacy (complete/partial remission) plus safety (type of adverse event) at 24 months; 2. Number of adverse events up to 24 months; 3. Quality of Life (EQ-5D) averaged over 24 months

Secondary Outcome Measures

Name	Time	Method
Number of participants in Partial Remission (PR)	At 6, 12, 18, 24 month	Number of participants who have proteinuria of between \>3.0 and 3.5 g/day and \>50% reduction from baseline proteinuria
Number of participants with a lack of response to PMN treatment	Up until 24 months	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
Number of participants who relapse after CR or PR	Up until 24 months	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
Quality of life scores (EQ-5D-5L)	at 3, 6, 9, 12, 15, 18, 24 months	Quality of life scores using EQ-5D-5L
Number of participants in Complete Remission (CR)	At 6, 12, 18, 24 month	Number of participants who have proteinuria of ≤3.0 g/day
Number of participants in CR and/or PR	At 6, 12, 18, 24 month	Number of participants who meet complete and/or partial PMN remission definition
Number of non-serious adverse events of special interest	Up until 24 months	Number of protocol defined non-serious events of special interest (related to PMN or the study interventions)
Number of serious adverse events	Up until 24 months	Number of protocol defined serious adverse events
eGRF slope	Up until 24 months	Change in eGFR slope
All cause deaths	Up until 24 months	Number of deaths of any cause
Time to first relapse	Up until 24 months	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
Number of treatment or PMN associated deaths	Up until 24 months	Number of deaths attributed directly or indirectly to a complication of PMN or the treatment for PMN
Number of participants who have immunological remission (for anti-PLA2R positive participants)	Up until 24 months	Number of participants who have their anti-PLA2R-Ab level drop below 2 RU/mL who are ≥14 RU/ml at baseline
Number of participants who have a requirement for rescue therapy	Up until 24 months	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.
Number of participants who exit the trial	Up until 24 months	Number participant who cease trial follow-up for any reason

Trial Locations

Locations (13)

Canberra Hospital; 🇦🇺 Garran, Australian Capital Territory, Australia

Royal Prince Alfred Hospital; 🇦🇺 Camperdown, New South Wales, Australia

Sunshine Coast University Hospital; 🇦🇺 Birtinya, Queensland, Australia

Royal Brisbane and Women's Hospital; 🇦🇺 Brisbane, Queensland, Australia

Bundaberg Hospital; 🇦🇺 Bundaberg, Queensland, Australia

Cairns Hospital; 🇦🇺 Cairns, Queensland, Australia

Logan Hospital; 🇦🇺 Logan, Queensland, Australia

Mackay Base Hospital; 🇦🇺 Mackay, Queensland, Australia

Rockhampton Hospital; 🇦🇺 Rockhampton, Queensland, Australia

Mater Hospital; 🇦🇺 South Brisbane, Queensland, Australia

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