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Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO)

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ClinicalTrials.gov Identifier: NCT03018535
Recruitment Status : Recruiting
First Posted : January 12, 2017
Last Update Posted : January 12, 2017
Sponsor:
Collaborators:
University of Bari
Azienda Ospedaliera Brotzu
University of Messina
University of Milan
Universita di Verona
University of Chieti
University of Bologna
Azienda Sanitaria Locale Roma E
Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi
Regione Piemonte
University of Modena and Reggio Emilia
University of Pisa
University of Milano Bicocca
Humanitas Hospital, Italy
Azienda Ospedaliera Universitaria Policlinico
Fondazione Salvatore Maugeri
University of Bern
University of Alberta
Istituto Giannina Gaslini
Information provided by (Responsible Party):
Francesco Scolari, Azienda Ospedaliera Spedali Civili di Brescia

Brief Summary:

Idiopathic Membranous nephropathy (IMN) is an auto-immune glomerular disease. Recent studies suggest that circulating auto-antibodies against the podocyte surface antigens phospholipase A2 receptor1 (PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A) cause the disease in the majority of the patients. Additional autoantibodies, directed to podocyte neo-expressed cytoplasm proteins have been described, including aldose reductase (AR), Mn-superoxide dismutase (SOD2) and alpha-enolase (alpha-ENO).

The commonest presentation of IMN is nephrotic syndrome. Data from placebo arms of interventional studies show that 30-40% of the untreated patients with persistent nephrotic syndrome (NS) progress to end-stage renal disease (ESRD).

The best-validated treatment regimen of IMN is combination therapy with steroids and cyclophosphamide, capable to induce remission of protenuria in two-third of the patients.

Despite this evidence of efficacy, there are concerns about the use of cyclophosphamide, since it may be associated with adverse events, including bone marrow suppression, gonadal toxicity, infections and oncogenic effects. Thus, the availability of alternative therapies highly effective but with a greater safety profile is desirable.

Given the key role of IgG antibodies in IMN, B cell depletion may favourably impact the glomerular disease. The anti-CD20 monoclonal antibody Rituximab is a selective B cell depleting agent. There is evidence that Rituximab is effective in the treatment of other diseases in which B cells play a key role, such as ANCA-related vasculitis. Observational studies in IMN provided encouraging data; in addition, the drug seems well tolerated.

Head-to-head comparisons between Rituximab and steroid plus ciclophosphamide in randomized clinical trials are missing.

The investigators propose this study in order to test, in a randomized controlled trial, the hypothesis that Rituximab is more effective than cyclical steroid/alkylating-agent therapy in inducing remission in patients with IMN and NS undergoing the initial treatment. In addition, the levels of the above-mentioned pathogenetic autoantibodies will be measured at baseline and during treatment. Finally, the study will compare the safety profile of steroid plus cyclophosphamide and Rituximab by evaluating the rate and severity of adverse events


Condition or disease Intervention/treatment Phase
Glomerulonephritis, Membranous Drug: Rituximab Drug: Methylprednisolone Drug: Cyclophosphamide Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Controlled Trial of Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy
Study Start Date : January 2012
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: RITUXIMAB
1 g. IV of Rituximab on days 1 and 15
Drug: Rituximab
Rituximab,1 g IV, day 1 and day 15
Other Names:
  • Mabthera
  • Rituxan

Active Comparator: Corticosteroids and Cyclophosphamide
Month 1, 3 and 5: 1g IV methylprednisolone daily for 3 doses; oral methylprednisolone (0.4mg/kg/day) or prednisone (0.5/mg/kg/day); Month 2, 4 and 6: Oral Cyclophosphamide (2.0 mg/kg/day)
Drug: Methylprednisolone
Methylprednisolone 1 g IV daily for 3 doses, then oral methylprednisolone (0.4 mg/kg/day) or oral prednisone (0.5mg/kg/day) for 27 days during Month 1, 3, 5.
Other Names:
  • URBASON
  • SOLUMEDROL

Drug: Cyclophosphamide
Month 2, 4 and 6: Oral Cyclophosphamide (2.0 mg/kg/day) for 30 days
Other Names:
  • Cytoxan
  • Endoxan




Primary Outcome Measures :
  1. change in probability of complete remission (proteinuria < 0.3 g/day) Primary Outcome Measures The primary outcome measure is the change in probability of complete remission (proteinuria < 0.3 g/day) at one year (see Design and power considerations). [ Time Frame: 1 year ]
    The primary outcome measure is the change in probability of complete remission (proteinuria < 0.3 g/day) at one year


Secondary Outcome Measures :
  1. Change from baseline in proteinuria [ Time Frame: from randomization up to 36 months ]
    Change from baseline in proteinuria at 6,12, 18, 24 and 36 months following treatment

  2. CR (Complete Remission) or PR (Partial Remission: Reduction in UP of > 50% plus final UP ≤ 3.5 g but >0.3g ) [ Time Frame: from randomization up to 36 months ]
    CR (Complete Remission) or PR (Partial Remission) at 6, 12, 18, 24, and 36 months

  3. Estimated Glomerular filtration rate (MDRD formula) [ Time Frame: from randomization up to 36 months ]
    Estimated Glomerular filtration rate (MDRD formula) at 6, 12, 18, 24, and 36 months

  4. Serum creatinine level (mg/dl) [ Time Frame: from randomization up to 36 months ]
    Serum creatinine level (mg/dl) at 6, 12, 18, 24, and 36 months

  5. Frequency of and time to relapse of nephrotic syndrome [ Time Frame: up to 36 months ]
    Frequency of and time to relapse of nephrotic syndrome

  6. Frequency of auto-antibodies and its relation to therapy and proteinuria response in a subgroup of patients [ Time Frame: baseline and after treatment (day 3, month 1, 3, 6 , 6 and 12) ]
    Frequency of auto-antibodies and its relation to therapy and proteinuria response in a subgroup of patients at baseline and 3 days, 1 month, 3 months, 6 months and 12 months after treatment

  7. serious side effects: Death, Life-threatening event, Hospitalization, Disability in the patient's body function/structure or physical activity or quality of life, Congenital anomaly, Intervention to prevent permanent impairment or damage) [ Time Frame: up to 36 months ]
    serious side effects: Death, Life-threatening event, Hospitalization, Disability in the patient's body function/structure or physical activity or quality of life, Congenital anomaly, Intervention to prevent permanent impairment or damage.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Biopsy-proven diagnosis of idiopathic MN performed within the past 24 months
  2. Proteinuria > 3.5 g/24h on three 24-hour urine collection (once a week for 3 weeks)
  3. Estimated GFR (MDRD formula) ≥ 30ml/min/1.73m2 under ACEI/ARB therapy
  4. Post-menopausal females, or females surgically sterile or practicing a medically approved method of contraception (no birth-control pill)
  5. Three months of ACEI and/or ARB therapy before treatment
  6. Blood Pressure <130/80 mm Hg
  7. HMG-CoA reductase inhibitor therapy
  8. Patients remaining with proteinuria >3.5g/24h after 3 months of ACEI and/or ARB therapy and Blood Pressure <130/80 mm Hg may be randomized to RTX / cyclical corticosteroid/alkylating-agent therapy without the need of the run-in/conservative phase of the study.

Exclusion Criteria:

  1. serum creatinine >2.5 mg/dl; Estimated GFR < 30 ml/min/1.73m2
  2. previous treatment with Rituximab, Steroids, Alkylating Agents, Calcineurin Inhibitors, Synthetic ACTH, MMF, Azathioprine
  3. Presence of active infection
  4. Secondary cause of MN (e.g. hepatitis B, SLE, medications, malignancies). Testing for HIV, Hepatitis B and C should have occurred < 6 months prior to enrollment into the study
  5. Type 1 or 2 diabetes mellitus
  6. Pregnancy or nursing for safety reasons
  7. Renal vein thrombosis documented prior to entry by renal US or CT scan

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03018535


Contacts
Contact: FRANCESCO SCOLARI, MD +39 0309963200 ceccoscolari@gmail.com
Contact: PIETRO RAVANI, MD pravani@ucalgary.ca

Locations
Italy
Division of Nephrology, Montichiari Hospital, ASST Spedali Civili di Brescia Recruiting
Montichiari, Brescia, Italy, 25018
Contact: Francesco Scolari, MD    +39 030 9963200    ceccoscolari@gmail.com   
Sponsors and Collaborators
Azienda Ospedaliera Spedali Civili di Brescia
University of Bari
Azienda Ospedaliera Brotzu
University of Messina
University of Milan
Universita di Verona
University of Chieti
University of Bologna
Azienda Sanitaria Locale Roma E
Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi
Regione Piemonte
University of Modena and Reggio Emilia
University of Pisa
University of Milano Bicocca
Humanitas Hospital, Italy
Azienda Ospedaliera Universitaria Policlinico
Fondazione Salvatore Maugeri
University of Bern
University of Alberta
Istituto Giannina Gaslini
Investigators
Principal Investigator: FRANCESCO SCOLARI, MD Azienda Ospedaliera Spedali Civili di Brescia

Publications:
Responsible Party: Francesco Scolari, DIRECTOR OF THE DIVISION OF NEPHROLOGY, MONTICHIARI HOSPITAL, Azienda Ospedaliera Spedali Civili di Brescia
ClinicalTrials.gov Identifier: NCT03018535     History of Changes
Other Study ID Numbers: EudraCT 2011 006115-59
First Posted: January 12, 2017    Key Record Dates
Last Update Posted: January 12, 2017
Last Verified: January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Glomerulonephritis, Membranous
Glomerulonephritis
Nephritis
Kidney Diseases
Urologic Diseases
Autoimmune Diseases
Immune System Diseases
Cyclophosphamide
Rituximab
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents