TANGELA: Tacrolimus Adjustment by NFAT-related Gene Expression in Lung Allograft Recipients.

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT02278952
• Collaborator: Astellas Scientific & Medical Affairs, Inc. (Industry)
• Enrollment: 50
• Location: 1
• Duration (Months): 37
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Transplantation, Lung

Study Design

• Study Type: Observational
• Actual Enrollment: 50 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Tacrolimus Adjustment by NFAT-related Gene Expression in Lung Allograft Recipients.
• Study Start Date: Dec 1, 2014
• Actual Primary Completion Date: May 1, 2017
• Actual Study Completion Date: Jan 1, 2018

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California	San Francisco	California	United States	94143

Sponsors and Collaborators

• University of California, San Francisco
• Astellas Scientific & Medical Affairs, Inc.

Investigators

• Principal Investigator: Greenland John, MD, PhD, University of California, San Francisco

Study Documents (Full-Text)

• Informed Consent Form - Oct 19, 2016
• Study Protocol and Statistical Analysis Plan - Jun 18, 2019

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02278952
• Other Study ID Numbers: Astellas ISR000990
• First Posted: Oct 30, 2014
• Last Update Posted: Dec 3, 2019
• Last Verified: Nov 1, 2019

Study Results

Participant Flow

Recruitment Details	Lung transplant recipients treated at UCSF with tacrolimus-based immunosuppressive regimen recruited one to two months post-transplant.
Pre-assignment Detail	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.

Arm/Group Title	Lung Transplant Participants
Arm/Group Description	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.
Period Title: Overall Study
STARTED	50
COMPLETED	44
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Lung Transplant Participants
Arm/Group Description	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.
Overall Participants	44
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58 (11)
Sex: Female, Male (Count of Participants)
Female	10 22.7%
Male	34 77.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 20.5%
Not Hispanic or Latino	35 79.5%
Unknown or Not Reported	0 0%
Lung Disease Diagnosis Group (Count of Participants)
A-Obstructive	8 18.2%
B-Pulmonary vascular	1 2.3%
C-Cystic Fibrosis	2 4.5%
D-Restrictive	33 75%

Outcome Measures

1. Primary Outcome

Title	Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Acute Cellular Rejection
Description	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

Outcome Measure Data

Analysis Population Description

Number of participants' study visits analyzed determined by the availability and quality of samples at both time points.

Arm/Group Title	Non-rejection	Rejection
Arm/Group Description	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."	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.
Measure Participants	33	11
Measure biopsies	106	11
Mean (Standard Error) [percentage of mean residual expression]	39.5 (2.9)	41.7 (6.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Non-rejection, Rejection
	Comments
	Type of Statistical Test	Other
	Comments	Generalized estimating equation-adjusted linear models
Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	GEE-adjusted models
	Comments

2. Primary Outcome

Title	Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Infection
Description	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

Outcome Measure Data

Analysis Population Description

Number of participants' study visits

Arm/Group Title	Non-Infection	Infection
Arm/Group Description	No airway infection as defined by presence of pathogenic species on bronchoalveolar lavage (BAL) culture and at least one of the following: semi-quantitative cultures with at least moderate quantity, CT findings, or symptoms consistent with acute infection.	Airway infection defined by presence of pathogenic species on BAL culture and at least one of the following: semi-quantitative cultures with at least moderate quantity, CT findings, or symptoms consistent with acute infection.
Measure Participants	32	12
Measure biopsies	100	17
Mean (Standard Deviation) [percentage of mean residual expression]	14.4 (2.9)	22.2 (4.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Non-rejection, Rejection
	Comments
	Type of Statistical Test	Other
	Comments	Generalized estimating equation-adjusted linear model
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	GEE-adjusted linear model
	Comments

3. Secondary Outcome

Title	Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Weeks Post-Transplant
Description	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

Outcome Measure Data

Analysis Population Description

Number of participants' study visits

Arm/Group Title	Lung Transplant Participants
Arm/Group Description	Time post-transplant determined by the number of weeks between the transplant date and the date of the blood draw. Outcome measures how mean residual expression values as a function of time post-transplant.
Measure Participants	44
Measure biopsies	117
Least Squares Mean (95% Confidence Interval) [percentage of mean residual expression]	0.35

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Non-rejection
	Comments
	Type of Statistical Test	Other
	Comments	Generalized estimating equation-adjusted linear models
Statistical Test of Hypothesis	p-Value	0.049
	Comments
	Method	GEE-adjusted linear models
	Comments

4. Secondary Outcome

Title	Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Tacrolimus Trough Level
Description	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

Outcome Measure Data

Analysis Population Description

Number of participants' study visits

Arm/Group Title	Lung Transplant Participants
Arm/Group Description	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. Tacrolimus trough levels were assayed on whole blood by the clinical lab using the Architect Immunoassay. The tacrolimus trough value closest in time to the study visit used.
Measure Participants	44
Measure biopsies	117
Least Squares Mean (95% Confidence Interval) [percentage of mean residual expression]	-1.687

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Non-rejection
	Comments
	Type of Statistical Test	Other
	Comments	Generalized estimating equation-adjusted linear models
Statistical Test of Hypothesis	p-Value	0.114
	Comments
	Method	GEE-adjusted linear models
	Comments

5. Secondary Outcome

Title	Association of Percentage of Mean Residual Expression (MRE%) of NFAT-related Cytokine Expression and Medication Dosages
Description	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

Outcome Measure Data

Analysis Population Description

Number of participants' study visits

Arm/Group Title	Lung Transplant Participants
Arm/Group Description	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. Tacrolimus, prednisone, and mycophenolate dose abstracted from medical charts at the time of blood draw.
Measure Participants	44
Measure biopsies	117
Tacrolimus dose	0.676
Prednisone Dose	-1.687
Mycophenolate Mofetil Dose	-0.0035

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Non-rejection
	Comments	P-value of tacrolimus dose
	Type of Statistical Test	Other
	Comments	Generalized estimating equation-adjusted linear models
Statistical Test of Hypothesis	p-Value	0.470
	Comments
	Method	GEE-adjusted linear models
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Non-rejection
	Comments	P-value of Prednisone dose
	Type of Statistical Test	Other
	Comments	Generalized estimating equation-adjusted linear models
Statistical Test of Hypothesis	p-Value	0.037
	Comments
	Method	GEE-adjusted linear models
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Non-rejection
	Comments	P-value of mycophenolate mofetil dose
	Type of Statistical Test	Other
	Comments	Generalized-estimating equation-adjusted linear models
Statistical Test of Hypothesis	p-Value	0.456
	Comments
	Method	GEE-adjusted linear models
	Comments

Adverse Events

Time Frame	from 1 month up to 18 months post-transplant
Arm/Group Title	Lung Transplant Participants
Arm/Group Description	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.
All Cause Mortality
	Lung Transplant Participants
	Affected / at Risk (%)	# Events
Total	0/44 (0%)
Serious Adverse Events
	Lung Transplant Participants
	Affected / at Risk (%)	# Events
Total	0/44 (0%)
Other (Not Including Serious) Adverse Events
	Lung Transplant Participants
	Affected / at Risk (%)	# Events
Total	0/44 (0%)

Limitations/Caveats

Higher than expected variance in MRE and missed study visits somewhat reduced statistical power.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.