REmission in Membranous Nephropathy International Trial (REMIT)

Study Overview
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Brief Summary
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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.

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

Conditions
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Primary Membranous Nephropathy

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: Oral prednisolone and cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years. Able to provide informed consent. Primary Membranous Nephropathy (PMN) confirmed by: 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 if the clinician decides against a biopsy, the patient must be anti-PLA2R positive and must not have diabetes. 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 Serum albumin <30 g/L. Estimated glomerular filtration rate (eGFR) ≥40 ml/min/1.73m2. Treatment with immunosuppression is warranted, as determined by the treating physician. Fully vaccinated against COVID-19 according to local practice/recommendation. Exclusion Criteria: Resistant to rituximab or have had >2 g of rituximab in the past. Resistant to cyclophosphamide or have had a cumulative >20 g of cyclophosphamide in the past. More than 3 years since PMN diagnosis. Proteinuria must not have decreased by >50% over 6 months whilst taking ACE-i/ARB. Patients with human immunodeficiency virus (HIV) infection, active hepatitis B or C infection, or other active infections. Patients with secondary membranous nephropathy Screening for malignancy must be considered especially in cases who are anti-PLA2R negative. Patients whose kidney biopsy shows concomitant features of diabetic nephropathy. Kidney transplant recipients. Pregnancy or breastfeeding. Women of childbearing age not willing to use contraception. 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. Any disorder or condition, in the opinion of the investigator, might pose an unacceptable risk to participant's safety and well-being. Inability to understand or comply with the requirements of the study. Incapable of recognizing the nature, significance, and scope of the clinical trial or giving consent are excluded, even if they have a legal representative. 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. 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. 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. Use of SGLT2-i and GLP-1 agonist within 90 days prior to randomisation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Obinutuzumab<br> | Drug: Obinutuzumab<br>* 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.<br>|
| Active Comparator: Oral prednisolone and cyclophosphamide<br> | Drug: Oral prednisolone and cyclophosphamide<br>* 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<br>|

What is the study measuring?
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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 |