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| Name | Class |
|---|---|
| Astellas Scientific & Medical Affairs, Inc. | INDUSTRY |
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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).
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| Measure | Description | Time Frame |
|---|---|---|
| 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. | from 1 month up to 18 months post-transplant |
| 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. | from 1 month up to 18 months post-transplant |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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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.
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Lung transplant recipients
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| Name | Affiliation | Role |
|---|---|---|
| Greenland John, MD, PhD | University of California, San Francisco | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California | San Francisco | California | 94143 | United States |
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.
Lung transplant recipients treated at UCSF with tacrolimus-based immunosuppressive regimen recruited one to two months post-transplant.
| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Number of participants' study visits analyzed determined by the availability and quality of samples at both time points. | Posted | Mean | Standard Error | percentage of mean residual expression | from 1 month up to 18 months post-transplant | biopsies | biopsies |
from 1 month up to 18 months post-transplant
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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Higher than expected variance in MRE and missed study visits somewhat reduced statistical power.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. John Greenland | University of California, San Francisco | 415-476-0789 | john.greenland@ucsf.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| ICF | No | No | Yes | Informed Consent Form | Oct 19, 2016 | Apr 3, 2018 | ICF_000.pdf |
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 18, 2019 | Jun 20, 2019 | Prot_SAP_001.pdf |
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| from 1 month (4 weeks) up to 18 months (82 weeks) post-transplant |
| 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. | from 1 month up to 18 months post-transplant |
| 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. | from 1 month up to 18 months post-transplant |
| years |
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| Sex: Female, Male | Count of Participants | Participants | No |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants | No |
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| Lung Disease Diagnosis Group | Count of Participants | Participants | No |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Non-rejection | Blood draw samples collected at the time of bronchoscopy with biopsy. Samples included if both time points (before tacrolimus dose and 90 to 120 minutes after dose) were collected, samples provided good quality RNA, and the patient had no evidence of acute cellular rejection. Acute cellular rejection was determined based on clinical interpretation of transbronchial biopsy specimens and graded according to International Society of Heart and Lung Transplantation (ISHLT) guidelines, with non-rejection defined as "A0B0." |
| OG001 | Rejection | Transbronchial biopsy showing A>0 or B>0 pathology with no rejection defined as A = 0 in perivascular interstitial components of the lung and B = 0 in airway components of the lung. |
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| 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. | Number of participants' study visits | Posted | Mean | Standard Deviation | percentage of mean residual expression | from 1 month up to 18 months post-transplant | biopsies | biopsies |
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| 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. | Number of participants' study visits | Posted | Least Squares Mean | 95% Confidence Interval | percentage of mean residual expression | from 1 month (4 weeks) up to 18 months (82 weeks) post-transplant | biopsies | biopsies |
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| 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. | Number of participants' study visits | Posted | Least Squares Mean | 95% Confidence Interval | percentage of mean residual expression | from 1 month up to 18 months post-transplant | biopsies | biopsies |
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| 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. | Number of participants' study visits | Posted | Least Squares Mean | 95% Confidence Interval | percentage of mean residual expression | from 1 month up to 18 months post-transplant | biopsies | biopsies |
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| Title | Measurements |
|---|---|
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| 0.037 |
| Other |
Generalized estimating equation-adjusted linear models |
| P-value of mycophenolate mofetil dose | GEE-adjusted linear models | 0.456 | Other | Generalized-estimating equation-adjusted linear models |