Cyclophosphamide in Lupus Nephritis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00441220
Recruitment Status : Unknown
Verified February 2009 by University of Auckland, New Zealand.
Recruitment status was:  Recruiting
First Posted : February 28, 2007
Last Update Posted : March 5, 2009
Auckland District Health Board
Counties Manukau Health
Auckland Medical Research Foundation
Arthritis New Zealand
Information provided by:
University of Auckland, New Zealand

Brief Summary:

Cyclophosphamide is widely used in the treatment of cancer and autoimmune diseases such as lupus nephritis. However, there is considerable variability in the response to cyclophosphamide treatment. Cyclophosphamide is a pro-drug that requires initial activation by CYP liver enzymes. Recent clinical studies have indicated a possible role of one CYP enzyme, CYP2C19 in this activation step. This enzyme has a genetic polymorphism (variants which lack functional activity) and people who have inherited these variants are poor metabolisers of certain drugs.

The aim of this study is to determine whether response to therapy in a New Zealand population of lupus nephritis patients is determined by cyclophosphamide bioactivation (the metabolic phenotype) and CYP genotype.

Currently there is no way of predicting a patient's response to cyclophosphamide. An understanding of the factors which contribute to the therapeutic failure in lupus nephritis is particularly important due to the high morbidity and mortality associated with this disease. There are other treatment options for lupus nephritis patients who fail to respond to cyclophosphamide. If successful, this study may help identify patients who are unlikely to respond to cyclophosphamide and thus should not be unnecessarily be exposed to the drug and may justify the use of newer, more costly immunosuppressive drugs such as mycophenolate mofetil and rituximab.

Condition or disease
Systemic Lupus Erythematosus

Detailed Description:

The autoimmune disease systemic lupus erythematosus (SLE) commonly affects the kidneys (lupus nephritis) and for some patients leads to a progressive loss of kidney function. In patients with aggressive lupus nephritis, treatment with the cytotoxic agent Cyclophosphamide (CP), and modulation of the immune system has proven effective in delaying progression of renal disease however, there is variability in how patients respond to cyclophosphamide therapy with 10% - 40% of patients failing to achieve renal remission.

Cyclophosphamide is a pro-drug, which requires metabolic bioactivation by the liver to the active drug. The major enzymes involved are CYP2C19 and CYP2B61,2 however they display considerable functional activity in part due to genetic variants which lack functional activity3. A recent study has demonstrated that lack of response to cyclophosphamide is associated with CYP2C19 and CYP2B6 poor metaboliser variants4.

A retrospective review of patients with lupus nephritis at Middlemore hospital indicated that Polynesian patients respond poorly to cyclophosphamide progressing to end stage renal failure and having higher mortality rates compared with European patients.

We have hypothesised that failure of cyclophosphamide therapy may be due to a higher incidence of the CYP2C19 variant in Polynesian populations.

An extremely high incidence (70%) of the homozygous CYP2C19 variant has been reported in the Melanesian population5 and studies in Samoan, Tongan, Cook Island and Niuean pacific peoples indicates that the incidence may be more than 4-fold higher than the 3% incidence in European populations3,6. If CYP2C19 is clinically important in the bioactivation of cyclophosphamide then Polynesian populations may be at increased risk of therapeutic failure.

Other factors may also result in inter-patient differences in the activation of cyclophosphamide in the liver. Changes in metabolic phenotype can be the result of drug-drug interactions and/or disease modulation of CYP enzyme expression. Hence it is also important to also determine the functional activity (phenotype) of cyclophosphamide bioactivation as well as genotypic analysis by analysis of blood levels of cyclophosphamide and its active metabolite.

This study will determine both the genotype and phenotype of cyclophosphamide bioactivation in patients with lupus nephritis and determine whether this is an important determinant in response to therapy.

Study Type : Observational
Estimated Enrollment : 60 participants
Observational Model: Case-Only
Official Title: Failure of Cyclophosphamide Therapy in Lupus Nephritis Patients: the Role of Bioactivation Phenotype and Genotype
Study Start Date : October 2006
Estimated Study Completion Date : October 2010

Patients must have lupus nephritis and previously had therapy with intravenous cyclophosphamide.
Patients must have lupus nephritis and are currently receiving therapy with intravenous cyclophosphamide.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Patients with lupus nephritis who are receiving or have previously received intravenous cyclophosphamide.

Inclusion Criteria:

  • Patients with lupus nephritis requiring therapy with intravenous cyclophosphamide
  • Lupus nephritis is defined according to American College of Rheumatology criteria as the presence of either:

    1. histological evidence from renal biopsy;
    2. persistent proteinuria of >0.5 g/day or proteinuria >3+ on dipstick; or
    3. cellular casts of any type. Patients will have had a renal biopsy performed to determine the histological class of lupus nephritis. Therapy with cyclophosphamide is typically used in patients with Class III, IV and severe Class V lupus nephritis.
  • Patients ≥ 18 years of age
  • Patients must be able to provide informed consent

Exclusion Criteria:

  • Those who do not meet inclusion criteria
  • Those patients in the retrospective study who have died

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 identifier (NCT number): NCT00441220

Contact: Peter Gow, MBChB 09 2760000
Contact: Janak R de Zoysa, MBChB 09 367 0000 ext 23262

New Zealand
Auckland City Hospital Recruiting
Auckland, North Island, New Zealand
Principal Investigator: Janak R de Zoysa, MBChB         
University Of Auckland Recruiting
Auckland, New Zealand
Contact: Nuala Helsby, PhD         
Principal Investigator: Nuala Helsby, PhD         
Middlemore Hospital Recruiting
Manakau City, New Zealand, Private Bag 93311
Contact: Peter Gow, MBChB, FRACP    649276 0000   
Principal Investigator: Peter Gow, MBChB         
Sub-Investigator: May C Soh, MBChB         
Sponsors and Collaborators
University of Auckland, New Zealand
Auckland District Health Board
Counties Manukau Health
Auckland Medical Research Foundation
Arthritis New Zealand
Principal Investigator: Nuala Helsby, PhD Senior Lecturer in Molecular Medicine and Pathology, University of Auckland

Responsible Party: Dr Nuala Helsby, University of Auckland Identifier: NCT00441220     History of Changes
Other Study ID Numbers: ADHB3557
First Posted: February 28, 2007    Key Record Dates
Last Update Posted: March 5, 2009
Last Verified: February 2009

Keywords provided by University of Auckland, New Zealand:
Genetic polymorphisms
Cytochrome p450 CYP2C19 (Human)
Systemic Lupus Erythematosus

Additional relevant MeSH terms:
Lupus Erythematosus, Systemic
Lupus Nephritis
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Kidney Diseases
Urologic Diseases
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists