Systemic Lupus ErythematosusNCT00441220
Cyclophosphamide in Lupus Nephritis
An observational study of Systemic Lupus Erythematosus, run by University of Auckland, New Zealand at 3 sites in New Zealand.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Systemic Lupus Erythematosus
- Type of treatment
- Injection or infusion
- How many people
- 60 participants
- Where
- 3 sitesNew Zealand
- Study dates
- Oct 2006to Oct 2010
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients with lupus nephritis who are receiving or have previously received intravenous cyclophosphamide.
Who may be able to join
- 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:
- histological evidence from renal biopsy;
- persistent proteinuria of >0.5 g/day or proteinuria >3+ on dipstick; or
- 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
Who cannot join
- Those who do not meet inclusion criteria
- Those patients in the retrospective study who have died
Trial locations and contacts
3 sites in 1 country.
New Zealand3 sites, 3 recruiting
- Recruiting
Auckland City Hospital
Auckland, North Island
Janak R de Zoysa, MBChB
- Recruiting
University Of Auckland
Auckland
Nuala Helsby, PhD
Nuala Helsby, PhD
- Recruiting
Middlemore Hospital
Manakau, Private Bag 93311
Peter Gow, MBChB, FRACP, 649276 0000, PGow@middlemore.co.nz
Peter Gow, MBChB
About this study
Official title: Failure of Cyclophosphamide Therapy in Lupus Nephritis Patients: the Role of Bioactivation Phenotype and Genotype
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.
Read the 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.
- Conditions
- Systemic Lupus Erythematosus
- Keywords
- Genetic polymorphisms, Cyclophosphamide, Cytochrome p450 CYP2C19 (Human), Systemic Lupus Erythematosus
- Medical subject headings
- Lupus Erythematosus, Systemic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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. |
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Feb 2007 (estimated)
- Study startOct 2006
- Study completionOct 2010 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Systemic Lupus ErythematosusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Auckland, New Zealand
- Sponsor type
- University, hospital or other
- Collaborators
- Auckland District Health Board, Counties Manukau Health, Auckland Medical Research Foundation, Arthritis New Zealand
- Investigators
- Nuala Helsby, PhD, Principal investigator, Senior Lecturer in Molecular Medicine and Pathology, University of Auckland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00441220
- Sponsor's protocol ID
- ADHB3557
- Status last verified
- Feb 2009
- First submitted
- 27 Feb 2007
- Last updated
- 5 Mar 2009
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 5 Mar 2009. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Failure of Cyclophosphamide Therapy in Lupus Nephritis Patients: the Role of Bioactivation Phenotype and Genotype
- ClinicalTrials.gov ID
- NCT00441220
- Acronym / sponsor ID
- ADHB3557
- Conditions
- Systemic Lupus Erythematosus
- Keywords
- Genetic polymorphisms, Cyclophosphamide, Cytochrome p450 CYP2C19 (Human), Systemic Lupus Erythematosus
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- University of Auckland, New ZealandUniversity, hospital or other
- Collaborators
- Auckland District Health Board, Counties Manukau Health, Auckland Medical Research Foundation, Arthritis New Zealand
- Study start
- Oct 2006
- Study completion
- Oct 2010 (estimated)
- First posted
- 28 Feb 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Observational model
- Case only
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 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. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients with lupus nephritis who are receiving or have previously received intravenous cyclophosphamide.
Key inclusion criteria (7 listed)
- 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:
- Patients ≥ 18 years of age
- Patients must be able to provide informed consent
Key exclusion criteria (2 listed)
- Those who do not meet inclusion criteria
- Those patients in the retrospective study who have died
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Not reported in the source record.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Mar 2009.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nuala Helsby, PhD principal investigator
Senior Lecturer in Molecular Medicine and Pathology, University of Auckland
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Systemic Lupus Erythematosus, run by University of Auckland, New Zealand at 3 sites in New Zealand.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 5 Mar 2009. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in New Zealand. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Peter Gow, MBChB (09 2760000, PGow@middlemore.co.nz), or a site near the patient. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Mar 2009.