Transplantation, Lung
Conditions
Brief summary
This is a non-interventional cohort study to assess a novel assay to detect excessive or insufficient immunosuppression from the drug tacrolimus in lung transplant recipients. The assay measures mean residual expression (MRE) of genes downstream of nuclear factor of activated T cells (NFAT), a transcription factor regulated by tacrolimus. The investigators will assess whether MRE levels identify subjects at risk for rejection (insufficient immunosuppression) or infection (excessive immunosuppression).
Interventions
None listed
Sponsors
Astellas Scientific & Medical Affairs, Inc.
University of California, San Francisco
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
The study will include lung allograft recipients within 2 months of transplantation at UCSF.
Exclusion criteria
Subjects will be excluded who are (a) unable to provide consent or (b) if treating clinicians do not anticipate subject will start on tacrolimus. Recruitment and enrollment in this study are targeted equally between women and minorities and the study will not exclude any gender or racial/ethnic group. This study does not involve vulnerable populations.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Acute Cellular Rejection | from 1 month up to 18 months post-transplant | The prescribed tacrolimus dosage was determined by the treating physician who was not aware of the study-assay values. For the study assay, two blood draws were collected at a study visit during the assessment period (from 1 month up to 18 months post-transplant). The first draw occurred before tacrolimus dosage (trough) and the second occurred 90 to 120 minutes after tacrolimus dosage (peak). To determine MRE, whole blood was stimulated, RNA was extracted, and residual expression of NFAT-related cytokines (NFAT: nuclear factor of activated T-cells) was determined by quantitative polymerase chain reaction (qPCR). Researchers stratified blood draws based on subject's rejection pathology at time of blood draw and observed percentage distribution of MRE values within each rejection pathology group. Observed differences between MRE distributions within non-rejection group and rejection groups. |
| Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Infection | from 1 month up to 18 months post-transplant | Researchers stratified blood draws based on subject's airway infection status at time of blood draw (based on biopsy results) and observed percentage distribution of MRE values within each infection status group. Researchers observed differences between MRE distributions within subjects with airway infection at time of blood draw and subjects with no infection diagnosis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Weeks Post-Transplant | from 1 month (4 weeks) up to 18 months (82 weeks) post-transplant | Researchers observed percentage distribution of MRE values at time of blood draw from study visits at 4 weeks post-transplant up to 82 weeks post-transplant. Researchers observed association between percentage of MRE at time of blood draw and the number of weeks post-transplant. |
| Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Tacrolimus Trough Level | from 1 month up to 18 months post-transplant | Researchers observed percentage distribution of MRE values on the day of blood draws. Researchers measured tacrolimus concentration in blood drawn before tacrolimus dosage (trough) and observed the association between percentage of MRE on the day of blood draw and tacrolimus trough level. |
| Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Medication Dosages | from 1 month up to 18 months post-transplant | Researchers observed percentage distribution of MRE values on the day of blood draws and measured tacrolimus, prednisone, and mycophenolate dose at the time of blood draw. Researchers observed the association between percentage of MRE on the day of blood draw and tacrolimus, prednisone, and mycophenolate dose, respectively, at the time of blood draw. |
Countries
United States
Participant flow
Recruitment details
Lung transplant recipients treated at UCSF with tacrolimus-based immunosuppressive regimen recruited one to two months post-transplant.
Pre-assignment details
Participants followed for 6 to 18 months post transplantation. Study visits performed within one day of a clinical bronchoscopy scheduled either for cause, such as suspected infection or rejection, or for surveillance at 2, 3, 6, 12, or 18 months.
Participants by arm
| Arm | Count |
|---|---|
| Lung Transplant Participants Lung transplant participants treated at UCSF with tacrolimus-based immunosuppression were followed until 18 months post-transplant, or until the participant's death or withdrawal. | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Insufficient Sample | 6 |
Baseline characteristics
| Characteristic | Lung Transplant Participants |
|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Lung Disease Diagnosis Group A-Obstructive | 8 Participants |
| Lung Disease Diagnosis Group B-Pulmonary vascular | 1 Participants |
| Lung Disease Diagnosis Group C-Cystic Fibrosis | 2 Participants |
| Lung Disease Diagnosis Group D-Restrictive | 33 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 44 |
| other Total, other adverse events | 0 / 44 |
| serious Total, serious adverse events | 0 / 44 |
Outcome results
Primary
Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Acute Cellular Rejection
The prescribed tacrolimus dosage was determined by the treating physician who was not aware of the study-assay values. For the study assay, two blood draws were collected at a study visit during the assessment period (from 1 month up to 18 months post-transplant). The first draw occurred before tacrolimus dosage (trough) and the second occurred 90 to 120 minutes after tacrolimus dosage (peak). To determine MRE, whole blood was stimulated, RNA was extracted, and residual expression of NFAT-related cytokines (NFAT: nuclear factor of activated T-cells) was determined by quantitative polymerase chain reaction (qPCR). Researchers stratified blood draws based on subject's rejection pathology at time of blood draw and observed percentage distribution of MRE values within each rejection pathology group. Observed differences between MRE distributions within non-rejection group and rejection groups.
Time frame: from 1 month up to 18 months post-transplant
Population: Number of participants' study visits analyzed determined by the availability and quality of samples at both time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Non-rejection | Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Acute Cellular Rejection | 39.5 percentage of mean residual expression | Standard Error 2.9 |
| Rejection | Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Acute Cellular Rejection | 41.7 percentage of mean residual expression | Standard Error 6.9 |
p-value: 0.33GEE-adjusted models
Primary
Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Infection
Researchers stratified blood draws based on subject's airway infection status at time of blood draw (based on biopsy results) and observed percentage distribution of MRE values within each infection status group. Researchers observed differences between MRE distributions within subjects with airway infection at time of blood draw and subjects with no infection diagnosis.
Time frame: from 1 month up to 18 months post-transplant
Population: Number of participants' study visits
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Non-rejection | Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Infection | 14.4 percentage of mean residual expression | Standard Deviation 2.9 |
| Rejection | Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Infection | 22.2 percentage of mean residual expression | Standard Deviation 4.6 |
p-value: <0.0001GEE-adjusted linear model
Secondary
Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Medication Dosages
Researchers observed percentage distribution of MRE values on the day of blood draws and measured tacrolimus, prednisone, and mycophenolate dose at the time of blood draw. Researchers observed the association between percentage of MRE on the day of blood draw and tacrolimus, prednisone, and mycophenolate dose, respectively, at the time of blood draw.
Time frame: from 1 month up to 18 months post-transplant
Population: Number of participants' study visits
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Non-rejection | Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Medication Dosages | Tacrolimus dose | 0.676 percentage of mean residual expression |
| Non-rejection | Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Medication Dosages | Prednisone Dose | -1.687 percentage of mean residual expression |
| Non-rejection | Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Medication Dosages | Mycophenolate Mofetil Dose | -0.0035 percentage of mean residual expression |
Comparison: P-value of tacrolimus dosep-value: 0.47GEE-adjusted linear models
Comparison: P-value of Prednisone dosep-value: 0.037GEE-adjusted linear models
Comparison: P-value of mycophenolate mofetil dosep-value: 0.456GEE-adjusted linear models
Secondary
Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Tacrolimus Trough Level
Researchers observed percentage distribution of MRE values on the day of blood draws. Researchers measured tacrolimus concentration in blood drawn before tacrolimus dosage (trough) and observed the association between percentage of MRE on the day of blood draw and tacrolimus trough level.
Time frame: from 1 month up to 18 months post-transplant
Population: Number of participants' study visits
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Non-rejection | Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Tacrolimus Trough Level | -1.687 percentage of mean residual expression |
p-value: 0.114GEE-adjusted linear models
Secondary
Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Weeks Post-Transplant
Researchers observed percentage distribution of MRE values at time of blood draw from study visits at 4 weeks post-transplant up to 82 weeks post-transplant. Researchers observed association between percentage of MRE at time of blood draw and the number of weeks post-transplant.
Time frame: from 1 month (4 weeks) up to 18 months (82 weeks) post-transplant
Population: Number of participants' study visits
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Non-rejection | Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Weeks Post-Transplant | 0.35 percentage of mean residual expression |
p-value: 0.049GEE-adjusted linear models