Cyclophosphamide in Lupus Nephritis

The recruitment status of this study is unknown because the information has not been verified recently.
Verified February 2009 by University of Auckland, New Zealand.
Recruitment status was  Recruiting
Sponsor:
Collaborators:
Auckland District Health Board
Counties Manakau District Health Board
Auckland Medical Research Foundation
Arthritis New Zealand
Information provided by:
University of Auckland, New Zealand
ClinicalTrials.gov Identifier:
NCT00441220
First received: February 27, 2007
Last updated: March 4, 2009
Last verified: February 2009
  Purpose

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
Systemic Lupus Erythematosus

Study Type: Observational
Study Design: Observational Model: Case-Only
Official Title: Failure of Cyclophosphamide Therapy in Lupus Nephritis Patients: the Role of Bioactivation Phenotype and Genotype

Resource links provided by NLM:


Further study details as provided by University of Auckland, New Zealand:

Estimated Enrollment: 60
Study Start Date: October 2006
Estimated Study Completion Date: October 2010
Groups/Cohorts
A
Patients must have lupus nephritis and previously had therapy with intravenous cyclophosphamide.
B
Patients must have lupus nephritis and are currently receiving therapy with intravenous cyclophosphamide.

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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

Patients with lupus nephritis who are receiving or have previously received intravenous cyclophosphamide.

Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00441220

Contacts
Contact: Peter Gow, MBChB 09 2760000 PGow@middlemore.co.nz
Contact: Janak R de Zoysa, MBChB 09 367 0000 ext 23262 janakz@adhb.govt.nz

Locations
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    PGow@middlemore.co.nz   
Principal Investigator: Peter Gow, MBChB         
Sub-Investigator: May C Soh, MBChB         
Sponsors and Collaborators
University of Auckland, New Zealand
Auckland District Health Board
Counties Manakau District Health Board
Auckland Medical Research Foundation
Arthritis New Zealand
Investigators
Principal Investigator: Nuala Helsby, PhD Senior Lecturer in Molecular Medicine and Pathology, University of Auckland
  More Information

No publications provided

Responsible Party: Dr Nuala Helsby, University of Auckland
ClinicalTrials.gov Identifier: NCT00441220     History of Changes
Other Study ID Numbers: ADHB3557
Study First Received: February 27, 2007
Last Updated: March 4, 2009
Health Authority: New Zealand: Health and Disability Ethics Committees

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

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

ClinicalTrials.gov processed this record on July 20, 2014