Cystic FibrosisNCT00908830
Effects of Mycophenolate Mofetil in Cystic Fibrosis Lung Transplant Patients
An observational study of Cystic Fibrosis and Lung Transplant, run by University of Michigan.
Trial summary
Lung transplantation is a life saving procedure for patients with a terminal lung disease such as cystic fibrosis. Approximately, one in 3,500 children in the United States are born with cystic fibrosis each year with the predicted survival reaching 36.9 years in 2006. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Cystic Fibrosis, Lung Transplant
- How many people
- 10 participants
- Where
- No sites listed yet
- Study dates
- Jun 2009to May 2011
- Phase
- Observational
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Lung transplant patients with and without cystic fibrosis.
Who may be able to join
- Ability and willingness to provide informed consent and be compliant with the study procedures
- Between 18-70 years of age
- Greater than 1 year post-transplant
- Have no evidence of acute rejection at 1 year post-transplant biopsy or within three months of study entry
- Stable mycophenolate mofetil dose
- Stable renal function
Who cannot join
- Serum creatinine greater than 2 mg/dl
- Received pulse steroids within 3 months of the study entry
- Chronic diarrhea
- Concurrently on interacting medications (cholestyramine, etc)
About this study
Official title: Pharmacokinetics of Mycophenolic Acid in Cystic Fibrosis Lung Transplant Recipients
Lung transplantation is a life saving procedure for patients with a terminal lung disease such as cystic fibrosis. Approximately, one in 3,500 children in the United States are born with cystic fibrosis each year with the predicted survival reaching 36.9 years in 2006. Cystic fibrosis was the third lead indication for lung transplantation in 2006. Cystic fibrosis is a genetic disease that can affect the way the body can remove salt from various organs. It results in mucus blocking the ducts of the lungs and pancreas leading to inability to handle oxygen and malabsorption of nutrients. Malabsorption is a common complication of cystic fibrosis that can affect the way the anti-rejection medications are absorbed. One medication that is utilized after transplant to prevent rejection is mycophenolate mofetil. This medication may not be absorbed adequately in this population due to their disease thus placing these patients at increased risk of rejection. At the investigators' institution, all transplant patients are initiated at the same mycophenolate dose regardless of their underlying disease. The limited available literature regarding cystic fibrosis transplant patients and mycophenolate suggests that these patients require higher doses due to their erratic absorption. The purpose of this study is to evaluate the effects of mycophenolate mofetil on the body in lung transplant patients who have cystic fibrosis in efforts to improve survival outcomes.
Read the detailed description
Background:
Lung transplantation has been established as a viable treatment for cystic fibrosis (CF) patients who have end-stage lung disease. CF is a genetic disorder which is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. These mutations cause abnormal transport of sodium chloride which affects various organs. In the lungs, there is a reduction in mucociliary clearance leading to viscous mucus that can block the airways. In addition to obstruction of the airways, the stagnant mucus provides a good medium for microorganisms leading to infectious complications.1,2 Approximately one in 3,500 children in the United States are born with CF each year with the predicted survival reaching 36.9 years in 2006.3 CF was the third leading indication (16%) for lung transplantation in 2006.4
The success of transplantation has been due to the advances in immunosuppression over the years. Within the past ten years, the substantial changes in the immunosuppression regimen include more transplant centers utilizing induction therapy (29% vs. 50% in 1995 and 2004, respectively); and baseline immunosuppression shifted from cyclosporine-based in 1995 (77%) to tacrolimus-based in 2004 (70%).5 In addition, mycophenolate mofetil (MMF) has been replacing azathioprine as the purine synthesis antagonist in maintenance regimens in the recent years.4
Gastrointestinal malabsorption is a common complication of CF that can affect the impact of immunosuppression. It has been shown that CF patients can have sub-therapeutic calcineurin inhibitors.6,7 However, little information regarding MMF pharmacokinetics (PK) exist in this population. One small observational study of 30 stable lung-transplant recipients demonstrated that the CF patients (n=7) required at least 30% higher doses to achieve similar pre-dose levels of mycophenolic acid (MPA) to that of non-CF patients (n=6).8 The authors did not include any other PK parameters in their results. In a second study, 12-hour PK of MPA and its glucuronide metabolites were characterized in 21 stable lung transplant recipients. The authors included 5 CF patients and found no significant difference in PK parameters except for the ratio of MPA glucuronide and MPA (MPAG/MPA) between the CF and non-CF patients. However, the CF patients tended to have a lower area under the curve (AUC) than non-CF patients. Inter- or intra-patient variability of MPA AUC was not determined in this study.9 In addition, these previous studies did not distinguish tacrolimus-based regimen from cyclosporine-based regimen.
At our institution, CF patients are managed the same as any other lung transplant patients in regards to immunosuppression. Standard starting dose for MMF is 1000mg twice daily within our institution, and pre-dose MPA levels are not routinely measured since they do not reflect MPA exposure. In contrast, other transplant centers dose MMF higher in CF patients based on the limited reports above. The purpose of this study is to determine PK of MPA and MPAG in CF patients on tacrolimus and compare them to a cohort of non-CF lung transplant patients.
Outline of the study:
We will conduct an open-label, PK study in stable CF lung transplant patients. Our study will also evaluate non-CF patients as the control group. Each patient will have three biweekly PK study visits. On the PK study days, patients will be admitted to the Michigan Clinical Research Unit (MCRU) at the University of Michigan Health Center. After administration of morning dose of MMF, serial blood samples will be collected at the following time intervals: immediately before and 0.5, 1, 1.5, 2, 4, 6, 9, and 12 hours after dosing. Serum creatinine and serum albumin will also be drawn. Vial of blood will be also collected to measure the function of IMPDH. Standardized meals will be provided on PK study days. Serum concentrations of total MPA and MPAG will be determined by a validated liquid chromatography with tandem mass spectrometry method.10
Outcome Measures:
Pharmacokinetic parameters of MPA and MPAG will be determined by noncompartmental methods. The area under the plasma concentration-time curve from time 0 to 12 hours (AUC) will be calculated by the trapezoidal rule. Maximum serum concentration (Cmax) and time to reach Cmax (Tmax) will be determined from visual inspection of the concentration-time profile. Clearance (CL/F) will be calculated by dose divided by AUC. Samples will be obtained to measure IMPDH and correlated with PK parameters. These tests will be assayed by Les Shaw at the University of Pennsylvania.
Statistical Analysis and Sample Size All PK parameters will be reported as mean and standard deviation. To analyze the inter- and intra-patient variability, coefficients of variation of the MPA AUC's will be calculated. Differences in the variables between the CF and non-CF patients will be determined by Student's t-test or Wilcoxon signed rank test. A two-sided p-value less than 0.05 will be considered significant.
Our sample size will be five CF and non-CF lung transplant patients.
- Conditions
- Cystic Fibrosis, Lung Transplant
- Medical subject headings
- Cystic Fibrosis
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 |
|---|---|---|
| Cystic fibrosis | Lung transplant patients with cystic fibrosis. Measuring MPA levels in cystic fibrosis lung transplant patients for pharmacokinetic parameters. | |
| Non-cystic fibrosis lung transplant | Non-cystic fibrosis lung transplant patients. Non-cystic fibrosis lung transplant patients will have MPA levels drawn after their dose to determine pharmacokinetic parameters. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Steady-state Pharmacokinetics of Mycophenolic Acid and Mycophenolic Acid Glucuronide in Stable Cystic Fibrosis and Non-Cystic Fibrosis Lung Transplant Recipients.
The AUC is the area under the concentration-time curve from time 0 to 12 hours. The AUC is measured in units of micrograms of mycophenolic acid (MPA) per milliliter of plasma (mcg/mL) multiplied by time in hours (mg*h/L) and in units of micrograms of mycophenolic acid glucuronide (MPAG) per milliliter of plasma (mcg/mL) multiplied by time in hours (mg*h/L). Apparent oral clearance (CL/F) was calculated by dose/AUC0-12.
Measured: 0 hours pre-dose and again at 0.5, 1, 1.5, 2, 4, 6, 9, and 12 hours post-dose
Secondary outcomes (1)
Inter- and Intra-patient Variability of Mycophenolic Acid Exposure (AUC) in Cystic Fibrosis Lung Transplant Recipients on Tacrolimus Based Immunosuppression.
Inter- and intra-patient variability will be calculated by the coefficients of variation (CV) of the MPA AUC (mg*h/L).
To analyze the intra- and interindividual variability, the coefficient of variation (CV) was calculated by dividing the standard deviation by the mean of the PK parameters from the 3 PK visits and the 5 study patients in each group, respectively. Inter-individual CVs presented are only comparing within the individuals per arm, not across or between arms.
Measured: 0 hours pre-dose and again at 0.5, 1, 1.5, 2, 4, 6, 9, and 12 hours post-dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 May 2009 (estimated)
- Study startJun 2009
- Primary completionMay 2011
- Study completionMay 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Cystic FibrosisStudies of the same condition, open and under way.
- More trials run by University of MichiganThe sponsor's other registered studies.
- 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
- Other
- Time perspective
- Prospective
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Michigan
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Tammy Ojo Clark, MD, University of Michigan
- Investigators
- Tammy Ojo, MD, Principal investigator, University of Michigan
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00908830
- Sponsor's protocol ID
- UM 20989
- Status last verified
- Aug 2018
- First submitted
- 26 May 2009
- Last updated
- 6 Aug 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 6 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetics of Mycophenolic Acid in Cystic Fibrosis Lung Transplant Recipients
- ClinicalTrials.gov ID
- NCT00908830
- Acronym / sponsor ID
- UM 20989
- Conditions
- Cystic Fibrosis, Lung Transplant
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- University of MichiganUniversity, hospital or other
- Study start
- Jun 2009
- Primary completion
- May 2011 (actual)
- Study completion
- May 2011 (actual)
- First posted
- 27 May 2009 (estimated)
- Results
- Posted 6 Aug 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Lung transplantation is a life saving procedure for patients with a terminal lung disease such as cystic fibrosis. Approximately, one in 3,500 children in the United States are born with cystic fibrosis each year with the predicted survival reaching 36.9 years in 2006. Cystic fibrosis was the third lead indication for lung transplantation in 2006. Cystic fibrosis is a genetic disease that can affect the way the body can remove salt from various organs. It results in mucus blocking the ducts of the lungs and pancreas leading to inability to handle oxygen and malabsorption of nutrients. Malabsorption is a common complication of cystic fibrosis that can affect the way the anti-rejection medications are absorbed. One medication that is utilized after transplant to prevent rejection is mycophenolate mofetil. This medication may not be absorbed adequately in this population due to their disease thus placing these patients at increased risk of rejection. At the investigators' institution, all transplant patients are initiated at the same mycophenolate dose regardless of their underlying disease. The limited available literature regarding cystic fibrosis transplant patients and mycophenolate suggests that these patients require higher doses due to their erratic absorption. The purpose of this study is to evaluate the effects of mycophenolate mofetil on the body in lung transplant patients who have cystic fibrosis in efforts to improve survival outcomes.
Detailed description
Background:
Lung transplantation has been established as a viable treatment for cystic fibrosis (CF) patients who have end-stage lung disease. CF is a genetic disorder which is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. These mutations cause abnormal transport of sodium chloride which affects various organs. In the lungs, there is a reduction in mucociliary clearance leading to viscous mucus that can block the airways. In addition to obstruction of the airways, the stagnant mucus provides a good medium for microorganisms leading to infectious complications.1,2 Approximately one in 3,500 children in the United States are born with CF each year with the predicted survival reaching 36.9 years in 2006.3 CF was the third leading indication (16%) for lung transplantation in 2006.4
The success of transplantation has been due to the advances in immunosuppression over the years. Within the past ten years, the substantial changes in the immunosuppression regimen include more transplant centers utilizing induction therapy (29% vs. 50% in 1995 and 2004, respectively); and baseline immunosuppression shifted from cyclosporine-based in 1995 (77%) to tacrolimus-based in 2004 (70%).5 In addition, mycophenolate mofetil (MMF) has been replacing azathioprine as the purine synthesis antagonist in maintenance regimens in the recent years.4
Gastrointestinal malabsorption is a common complication of CF that can affect the impact of immunosuppression. It has been shown that CF patients can have sub-therapeutic calcineurin inhibitors.6,7 However, little information regarding MMF pharmacokinetics (PK) exist in this population. One small observational study of 30 stable lung-transplant recipients demonstrated that the CF patients (n=7) required at least 30% higher doses to achieve similar pre-dose levels of mycophenolic acid (MPA) to that of non-CF patients (n=6).8 The authors did not include any other PK parameters in their results. In a second study, 12-hour PK of MPA and its glucuronide metabolites were characterized in 21 stable lung transplant recipients. The authors included 5 CF patients and found no significant difference in PK parameters except for the ratio of MPA glucuronide and MPA (MPAG/MPA) between the CF and non-CF patients. However, the CF patients tended to have a lower area under the curve (AUC) than non-CF patients. Inter- or intra-patient variability of MPA AUC was not determined in this study.9 In addition, these previous studies did not distinguish tacrolimus-based regimen from cyclosporine-based regimen.
At our institution, CF patients are managed the same as any other lung transplant patients in regards to immunosuppression. Standard starting dose for MMF is 1000mg twice daily within our institution, and pre-dose MPA levels are not routinely measured since they do not reflect MPA exposure. In contrast, other transplant centers dose MMF higher in CF patients based on the limited reports above. The purpose of this study is to determine PK of MPA and MPAG in CF patients on tacrolimus and compare them to a cohort of non-CF lung transplant patients.
Outline of the study:
We will conduct an open-label, PK study in stable CF lung transplant patients. Our study will also evaluate non-CF patients as the control group. Each patient will have three biweekly PK study visits. On the PK study days, patients will be admitted to the Michigan Clinical Research Unit (MCRU) at the University of Michigan Health Center. After administration of morning dose of MMF, serial blood samples will be collected at the following time intervals: immediately before and 0.5, 1, 1.5, 2, 4, 6, 9, and 12 hours after dosing. Serum creatinine and serum albumin will also be drawn. Vial of blood will be also collected to measure the function of IMPDH. Standardized meals will be provided on PK study days. Serum concentrations of total MPA and MPAG will be determined by a validated liquid chromatography with tandem mass spectrometry method.10
Outcome Measures:
Pharmacokinetic parameters of MPA and MPAG will be determined by noncompartmental methods. The area under the plasma concentration-time curve from time 0 to 12 hours (AUC) will be calculated by the trapezoidal rule. Maximum serum concentration (Cmax) and time to reach Cmax (Tmax) will be determined from visual inspection of the concentration-time profile. Clearance (CL/F) will be calculated by dose divided by AUC. Samples will be obtained to measure IMPDH and correlated with PK parameters. These tests will be assayed by Les Shaw at the University of Pennsylvania.
Statistical Analysis and Sample Size All PK parameters will be reported as mean and standard deviation. To analyze the inter- and intra-patient variability, coefficients of variation of the MPA AUC's will be calculated. Differences in the variables between the CF and non-CF patients will be determined by Student's t-test or Wilcoxon signed rank test. A two-sided p-value less than 0.05 will be considered significant.
Our sample size will be five CF and non-CF lung transplant patients.
Study design
- Observational model
- Other
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cystic fibrosis | – | –Lung transplant patients with cystic fibrosis. Measuring MPA levels in cystic fibrosis lung transplant patients for pharmacokinetic parameters. |
| Non-cystic fibrosis lung transplant | – | –Non-cystic fibrosis lung transplant patients. Non-cystic fibrosis lung transplant patients will have MPA levels drawn after their dose to determine pharmacokinetic parameters. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Lung transplant patients with and without cystic fibrosis.
Key inclusion criteria (6 listed)
- Ability and willingness to provide informed consent and be compliant with the study procedures
- Between 18-70 years of age
- Greater than 1 year post-transplant
- Have no evidence of acute rejection at 1 year post-transplant biopsy or within three months of study entry
- Stable mycophenolate mofetil dose
Key exclusion criteria (4 listed)
- Serum creatinine greater than 2 mg/dl
- Received pulse steroids within 3 months of the study entry
- Chronic diarrhea
- Concurrently on interacting medications (cholestyramine, etc)
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
Steady-state Pharmacokinetics of Mycophenolic Acid and Mycophenolic Acid Glucuronide in Stable Cystic Fibrosis and Non-Cystic Fibrosis Lung Transplant Recipients.
Time frame: 0 hours pre-dose and again at 0.5, 1, 1.5, 2, 4, 6, 9, and 12 hours post-dose
The AUC is the area under the concentration-time curve from time 0 to 12 hours. The AUC is measured in units of micrograms of mycophenolic acid (MPA) per milliliter of plasma (mcg/mL) multiplied by time in hours (mg*h/L) and in units of micrograms of mycophenolic acid glucuronide (MPAG) per milliliter of plasma (mcg/mL) multiplied by time in hours (mg*h/L). Apparent oral clearance (CL/F) was calculated by dose/AUC0-12.
1 secondary outcome
Inter- and Intra-patient Variability of Mycophenolic Acid Exposure (AUC) in Cystic Fibrosis Lung Transplant Recipients on Tacrolimus Based Immunosuppression.
Time frame: 0 hours pre-dose and again at 0.5, 1, 1.5, 2, 4, 6, 9, and 12 hours post-dose
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Aug 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
Tammy Ojo, MD principal investigator
University of Michigan
Questions about this trial
What is this clinical trial studying?
An observational study of Cystic Fibrosis and Lung Transplant, run by University of Michigan.
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 6 inclusion and 4 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: finished, as of the sponsor's last update on 6 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.
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?
Yes. Results are posted in the registry (first posted 6 Aug 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Steady-state Pharmacokinetics of Mycophenolic Acid and Mycophenolic Acid Glucuronide in Stable Cystic Fibrosis and Non-Cystic Fibrosis Lung Transplant Recipients. (time frame: 0 hours pre-dose and again at 0.5, 1, 1.5, 2, 4, 6, 9, and 12 hours post-dose). It is what the study was designed to measure, not a finding.
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 6 Aug 2018.