Sequential Therapy With Tacrolimus and Rituximab in Primary Membranous Nephropathy

NCT01955187 | Completed Phase 3 DMC

• 2 other identifiers: STARMEN 01-20132013-000226-55
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 1

Brief Summary

In this study, investigators will evaluated the long-term efficacy and safety (two years) of Tacrolimus-Rituximab (RTX) therapy compared to Methylprednisolone-Cyclophosphamide (CYC) therapy in patients with primary Membranous Nephropathy (MN). PRINCIPAL OBJECTIVE To evaluate whether sequential therapy with tacrolimus leads to a greater increase in the proportion of primary MN patients with Complete or Partial Remission when compared with patients receiving standard treatment. It will be assessed 24 months after the beginning of treatment. Phase of the trial: and design: Phase III study, open label, randomized, and active controlled trial. This study will have 3 stages: screening and recruitment of patients for 18 months, treatment period for six months in corticosteroids plus CYC group and 9 months in Tacrolimus-RTX group, and finally post-treatment follow-up period until to complete 24 months of follow-up since initial treatment. This study will compare the standard therapy for primary MN patients with nephrotic range proteinuria (active control of steroids plus CYC) with a novel sequential therapy of tacrolimus and RTX, an approach of potential high efficacy, low toxicity and more acceptable safety profile.

Conditions

MEMBRANOUS NEPHROPATHY

Keywords

SEQUENTIAL THERAPY; PRIMARY MEMBRANOUS NEPHROPATHY; TACROLIMUS; RITUXIMAB

Outcome Measures

Primary Outcomes (1)

• Proportion of patients with complete and/or partial remission.

  The proportion of patients reaching complete remission, defined as a reduction of proteinuria since baseline level to a value equal or lower than 0.5 g/24 h proteinuria plus stable renal function (eGFR ≥ 45 ml/min/1.73m2) or partial remission, defined as a reduction of proteinuria since baseline level to a value less than 3.5 g/24 h and 50% lower than baseline proteinuria plus stable renal function (eGFR ≥ 45 ml/min/1.73m2) at 24 months of study treatment.

  24 months

Secondary Outcomes (4)

• Proportion of patients with limited response

  12, 18, and 24 months

• Proportion of patients with increase of baseline serum creatinine ≥ 50%

  12, 18, and 24 months

• Proportions of patients with relapses

  9, 12, 18, and 24 months

• Proportion of patients with drug-related adverse events

  During all therapy period and until 24 months post-beginning of therapy

Study Arms (2)

Sequential therapy: Tacrolimus-Rituximab

EXPERIMENTAL

Tacrolimus: Initial dose of 0.05 mg/Kg/day PO, adjusted to blood levels (5- 7 ng/ml) for six months. Starting at the end of month 6, tacrolimus will be reduced by 25% per month, resulting in a complete withdrawal at the end of month 9.

Drug: TACROLIMUS; Drug: RITUXIMAB

Cyclical therapy: Corticosteroids and Cyclophosphamide

ACTIVE COMPARATOR

Month 1, 3 and 5: 1g IV methylprednisolone daily for three doses, oral methylprednisolone (0.5mg/kg/day) Month 2, 4 and 6: Oral Cyclophosphamide (2.0 mg/kg/day)

Drug: METHYLPREDNISOLONE; Drug: CYCLOPHOSPHAMIDE

Interventions

TACROLIMUS DRUG

Initial dose: 0.05 mg/Kg/day, adjusted to achieve blood trough levels of 5-7 ng/ml) for six months. Starting at the end of month 6, tacrolimus dosage will be reduced by 25% per month, resulting in a complete withdrawal at the end of month 9.

Also known as: TACROLIMUS, ADVAGRAF

Sequential therapy: Tacrolimus-Rituximab

RITUXIMAB DRUG

A dose 1 g IV will be given during month 6 (at day 180), before the onset of tacrolimus dose reduction

Also known as: RITUXIMAB, MABTHERA

Sequential therapy: Tacrolimus-Rituximab

METHYLPREDNISOLONE DRUG

Month 1: 1g IV methylprednisolone daily for three doses (days 1, 2, and 3), Oral methylprednisolone (0.5mg/kg/day) for 27 days (days 4 to 30). Months 3, and 5: Repeat Month 1.

Also known as: METHYLPREDNISOLONE, URBASON, SOLUMODERIN

Cyclical therapy: Corticosteroids and Cyclophosphamide

CYCLOPHOSPHAMIDE DRUG

Month 2: Oral Cyclophosphamide (2.0 mg/kg/day) for 30 days. Months 4, and 6: Repeat month 2.

Also known as: CYCLOPHOSPHAMIDE, GENOXAL

Cyclical therapy: Corticosteroids and Cyclophosphamide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients are willing and able to read and correctly understand the patient's information sheet and give their consent for participation in the study (by correctly signing and dating the informed consent form document, which has been previously approved by an Ethics Committee/ International Review Board), before initiating any protocol specific selection procedure.
• Patients are able to understand study procedures and to comply with them for the entire length of the study.
• Age older than 18 years.

You may not qualify if:

• Estimated GFR ≥ 45 ml/min/1.73m2 in one measurement performed within the screening period (in the 30 days after informed consent signature).
• Nephrotic-range proteinuria (\>4 g/day and not decreasing \>50% in the last 6 months) accompanied by hypoalbuminemia ≤ 3, 5 g/dL during the screening period OR patients showing severe or disabling symptoms related to the nephrotic syndrome or severe hypoalbuminemia (\<2 g/dL), that can be included before the completion of this 6-month observation period, at the investigator's discretion, independently of proteinuria values.
• Treatment with an ACEI or ARB for at least 2 months before screening (unless intolerance to ACEI/ARB, contraindications to their use or a low blood pressure that could induce side effects at the investigator's discretion) with a controlled blood pressure for at least the last three months (Mean SBP/DBP ≤ 150/90 mmHg in the last three months).
• Negative urine pregnancy test for potentially fertile female.
• Diagnosis of secondary causes of membranous nephropathy: malignancy (cancer), systemic infections (which include B and C hepatitis), systemic autoimmune diseases (e.g. Systemic Lupus Erythematosus; SLE) or any other acute or chronic inflammatory disease.
• HIV infection.
• Moderate or severe liver disease (AST and ALT \> 2.5x upper range limit and total bilirubin \> 1.5 x upper range limit).
• Patients are taking part in any other study with an investigational study and/or are receiving or have received treatment with another investigational drug or intervention (within the first month prior to the signature of the informed consent).
• Suspected or known hypersensitivity, allergy and/or immunogenic reaction history to either rituximab, cyclosporine, tacrolimus, corticosteroids, CYC or any of their ingredients (which include excipients) and of any other drug from the same pharmacotherapeutic group (i.e. calcineurin inhibitors, specific monoclonal antibodies or alkylating agents).
• Previous treatment with corticosteroids in the three months period before screening, or previous treatment with other immunosuppressive agent in the six month period before screening.
• Previous treatment with rituximab or any other biological agent in the two years period before screening.
• Patients who were non-responders to previous immunosuppressants.
• Women with a positive pregnancy test at screening or in lactation period or planning to become pregnant within the next 24 months. Women not willing to use contraceptive methods during the complete study period.
• Inability or unwillingness of individual or legal guardian/representative to give written informed consent.
• Any other medical unstable, uncontrolled, or severe condition or any other relevant laboratory test finding which, at the investigator's own discretion, could possibly increase the associated risk of the patient's participation in the study.

Sponsors & Collaborators

• Hospital Universitario 12 de Octubre: lead
• Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz: collaborator
• Hospital Universitario Fundación Alcorcón: collaborator
• Fundación para la Investigación Biomédica Hospital Universitario 12 de Octubre: collaborator
• Biobanco REDinREN: collaborator
• ERA-EDTA: collaborator
• REDinREN: collaborator
• Spanish Society of Nephrology: collaborator
• Fundación de Investigación Biomédica - Hospital Universitario de La Princesa: collaborator
• University Hospital, Aachen: collaborator

Study Sites (1)

Hospital 12 de Octubre

Madrid, Spain

Location

Related Publications (1)

• von Groote TC, Williams G, Au EH, Chen Y, Mathew AT, Hodson EM, Tunnicliffe DJ. Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2021 Nov 15;11(11):CD004293. doi: 10.1002/14651858.CD004293.pub4.

  PMID: 34778952 DERIVED

MeSH Terms

Conditions

Glomerulonephritis, Membranous

Interventions

Tacrolimus; Rituximab; Methylprednisolone; Cyclophosphamide

Condition Hierarchy (Ancestors)

Glomerulonephritis; Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds

Study Officials

• GEMA FERNÁNDEZ-JUÁREZ, MD

  Hospital Universitario Fundación Alcorcón, Madrid. Spain

  PRINCIPAL INVESTIGATOR

• JESUS EGIDO, MD, PhD

  IIS Fundación Jiménez Díaz, Madrid. Spain

  PRINCIPAL INVESTIGATOR

• MARIAN GOICOCHEA, MD

  Hospital Universitario Gregorio Marañón, Madrid. Spain

  PRINCIPAL INVESTIGATOR

• ALFONS SEGARRA, MD, PhD

  Hospital Universitari Vall d´Hebron, Barcelona. Spain

  PRINCIPAL INVESTIGATOR

• GUILLERMO MARTÍN, MD

  Hospital Regional de Málaga, Spain

  PRINCIPAL INVESTIGATOR

• ILDEFONSO VALERA, MD

  Hospital Virgen de la Victoria de Málaga. Spain

  PRINCIPAL INVESTIGATOR

• VIRGINIA CABELLO, MD

  Hospital Virgen del Rocío, Sevilla. Spain

  PRINCIPAL INVESTIGATOR

• QUINTANA LUIS, MD

  Hospital Clinic de Barcelona. Spain

  PRINCIPAL INVESTIGATOR

• CAO MERCEDES, MD

  Hospital Universitario de A Coruña. Spain

  PRINCIPAL INVESTIGATOR

• AVILA ANA, MD

  Hospital Dr. Peset, Valencia. Spain

  PRINCIPAL INVESTIGATOR

• ESPINOSA MARIO, MD

  Hospital Reina Sofía, Córdoba. Spain

  PRINCIPAL INVESTIGATOR

• MONTSERRAT DIAZ, MD

  Fundación Puigvert, Barcelona. Spain

  PRINCIPAL INVESTIGATOR

• BONET JOSÉ, MD

  Hospital Germans Trias i Pujol, Barcelona. Spain

  PRINCIPAL INVESTIGATOR

• JUAN RAMÓN GÓMEZ-MARTINO, MD

  Hospital San Pedro de Alcántara, Cáceres. Spain

  PRINCIPAL INVESTIGATOR

• RIVAS BEGOÑA, MD

  Hospital Universitario La Paz

  PRINCIPAL INVESTIGATOR

• RODRIGUEZ ANTOLINA, MD

  Hospital Clínico San Carlos, Madrid. Spain

  PRINCIPAL INVESTIGATOR

• GALEANO CRISTINA, MD

  Hospital Universitario Ramón y Cajal, Madrid. Spain

  PRINCIPAL INVESTIGATOR

• RIVERA FRANCISCO, MD

  Hospital de Ciudad Real. Spain

  PRINCIPAL INVESTIGATOR

• WETZELS JACK, MD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

• JORGE ROJAS, MD

  IIS Fundación Jiménez Díaz, Madrid. Spain

  PRINCIPAL INVESTIGATOR

• MARUJA NAVARRO, MD

  Hospital Germans Trias i Pujol, Barcelona. Spain

  PRINCIPAL INVESTIGATOR

• ANA ROMERA, MD

  Hospital de Ciudad Real. Spain

  PRINCIPAL INVESTIGATOR

• IRENE AGRAZ, MD

  Hospital Universitari Vall d´Hebron, Barcelona. Spain

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: September 19, 2013
• First Posted: October 7, 2013
• Study Start: January 1, 2014
• Primary Completion: June 26, 2019
• Study Completion: June 26, 2019
• Last Updated: January 18, 2020

Record last verified: 2020-01

Locations

ES (1)