Trial Outcomes & Findings for Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction (NCT NCT02474199)

Last Updated: 2021-02-09

Results Overview

The National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was used to grade the severity of all AEs. A participant was considered to have met this endpoint if they experienced at least one CTCAE Grade 3 or higher AE deemed attributable (i.e., considered at least possibly related) to darTreg infusion (infusion reaction, cytokine release syndrome).

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

15 participants

Primary outcome timeframe

From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion

Results posted on

2021-02-09

Participant Flow

Recruitment occurred between June 2016 and October 2018 at 3 clinical centers across the United States. A total of 15 participants were enrolled.

Five participants who signed informed consents did not proceed to immunosuppression withdrawal: 4 did not meet inclusion/exclusion criteria, 1 chose not to continue in the study.

Participant milestones

Participant milestones
Measure	Initiated Immunosuppression Withdrawal, Received darTregs Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.	Initiated Immunosuppression Withdrawal, Did Not Receive darTregs Initiated Immunosuppression Withdrawal, Did Not Receive darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and did not receive the darTreg infusion. Adverse events were collected for these participants.	Did Not Initiate Withdrawal, Screening Biopsy Performed Did Not Initiate Withdrawal, Screening Biopsy Performed: Adult liver transplant recipients who signed informed consent, had the protocol-mandated screening biopsy performed, and did not proceed to immunosuppression withdrawal. Adverse events were collected for these participants.	Did Not Initiate Withdrawal, Screening Biopsy Not Performed Did Not Initiate Withdrawal, Screening Biopsy Not Performed: Adult liver transplant recipients who signed informed consent, did not have the protocol-mandated screening biopsy performed, and did not proceed to immunosuppression withdrawal. Adverse events were not collected for these participants.
Overall Study STARTED	5	5	2	3
Overall Study COMPLETED	3	2	0	0
Overall Study NOT COMPLETED	2	3	2	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Initiated Immunosuppression Withdrawal, Received darTregs Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.	Initiated Immunosuppression Withdrawal, Did Not Receive darTregs Initiated Immunosuppression Withdrawal, Did Not Receive darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and did not receive the darTreg infusion. Adverse events were collected for these participants.	Did Not Initiate Withdrawal, Screening Biopsy Performed Did Not Initiate Withdrawal, Screening Biopsy Performed: Adult liver transplant recipients who signed informed consent, had the protocol-mandated screening biopsy performed, and did not proceed to immunosuppression withdrawal. Adverse events were collected for these participants.	Did Not Initiate Withdrawal, Screening Biopsy Not Performed Did Not Initiate Withdrawal, Screening Biopsy Not Performed: Adult liver transplant recipients who signed informed consent, did not have the protocol-mandated screening biopsy performed, and did not proceed to immunosuppression withdrawal. Adverse events were not collected for these participants.
Overall Study Lost to Follow-up	1	0	0	0
Overall Study Withdrawal by Subject	1	2	0	1
Overall Study Did not receive Tregs due to insufficient manufacture	0	1	0	0
Overall Study Did not meet eligibility criteria	0	0	2	2

Baseline Characteristics

Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Initiated Immunosuppression Withdrawal, Received darTregs n=5 Participants Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.	Initiated Immunosuppression Withdrawal, Did Not Receive darTregs n=5 Participants Initiated Immunosuppression Withdrawal, Did Not Receive darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and did not receive the darTreg infusion. Adverse events were collected for these participants.	Total n=10 Participants Total of all reporting groups
Age, Continuous	48.8 years STANDARD_DEVIATION 15.42 • n=5 Participants	57.6 years STANDARD_DEVIATION 19.03 • n=7 Participants	53.2 years STANDARD_DEVIATION 16.98 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment United States	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Time Post-Transplant	3.3 years STANDARD_DEVIATION 1.59 • n=5 Participants	3.4 years STANDARD_DEVIATION 1.43 • n=7 Participants	3.4 years STANDARD_DEVIATION 1.43 • n=5 Participants

PRIMARY outcome

Timeframe: From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion

Population: Participants who initiated immunosuppression withdrawal and received darTregs

Outcome measures

Outcome measures
Measure	Initiated Immunosuppression Withdrawal, Received darTregs n=5 Participants Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.
Number of Participants Who Experienced Grade 3 or Higher Adverse Events (AEs) Deemed Attributable to darTreg Infusion	0 Participants

PRIMARY outcome

Timeframe: From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion

Population: All participants who initiated immunosuppression withdrawal. Since both groups initiated immunosuppression withdrawal, the participants who received darTregs were combined with the participants who did not receive the darTreg infusion to form the pre-defined group for assessment of this outcome.

The following grading system was applied to AEs of infection: * Grade 1: asymptomatic; clinical or diagnostic observation only; intervention with oral antibiotic, antifungal, or antiviral agent only; no invasive intervention required * Grade 2: symptomatic; intervention with intravenous antibiotic, antifungal, or antiviral agent; invasive intervention may be required * Grade 3: any infection associated with hemodynamic compromise requiring pressors; any infection necessitating intensive care unit level of care; any infection necessitating operative intervention; any infection involving the central nervous system; any infection with a positive fungal blood culture; any proven or probable aspergillus infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection * Grade 4: life-threatening infection * Grade 5: death resulting from infection A participant was considered to have met this endpoint if they experienced at least one Grade 3 or higher infection.

Outcome measures

Outcome measures
Measure	Initiated Immunosuppression Withdrawal, Received darTregs n=10 Participants Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.
Number of Participants With Study Defined Grade 3 or Higher Infections	0 Participants

PRIMARY outcome

Timeframe: From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion

Number of participants with any malignancy, including Post -Transplant Lymphoproliferative Disorder (PTLD). PTLD is a specific type of malignancy that can occur following transplantation of a solid organ and is characterized by a proliferation of B cells, which may result in lymphoma.

Outcome measures

Outcome measures
Measure	Initiated Immunosuppression Withdrawal, Received darTregs n=10 Participants Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.
Number of Participants With Any Malignancy	0 Participants

PRIMARY outcome

Timeframe: From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion

The ability to reduce baseline, standard of care calcineurin inhibitor dosing following transplantation was measured by determining the number of subjects who were able to tolerate a 75 percent reduction in their calcineurin inhibitors along with discontinuation of either prednisone or mycophenolate mofetil following initiation of immunosuppression withdrawal.

Outcome measures

Outcome measures
Measure	Initiated Immunosuppression Withdrawal, Received darTregs n=10 Participants Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.
Proportion of Liver Transplant Recipients Who Are Able to Reduce Calcineurin Inhibitor Dosing by 75 Percent and Discontinue a Second Immunosuppression Drug (if Applicable) With Stable Liver Function Tests (LFTs) for ≥ 12 Weeks	0.20 Proportion of Participants Interval 0.0252 to 0.5561

SECONDARY outcome

Timeframe: From initiation of immunosuppression withdrawal to 52 weeks after darTreg infusion

This measure includes refractory acute rejection, chronic rejection, re-transplantation, and death. Rejection was diagnosed based on local pathology. Participants are considered to have met this endpoint if they experience any one of these events at least once.

Outcome measures

Outcome measures
Measure	Initiated Immunosuppression Withdrawal, Received darTregs n=10 Participants Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.
Number of Liver Transplant Recipients Who Experience the Composite Outcome	0 Participants

SECONDARY outcome

Timeframe: From initiation of immunosuppression withdrawal to 52 weeks after darTreg infusion

A participant was considered to have met this endpoint if they experienced at least one episode of biopsy proven acute rejection, clinical acute rejection, or chronic rejection based on local pathology. Biopsy proven acute rejection was assessed as Grade I or higher based on the Banff (1997) global criteria featuring the following grades: * Indeterminate * Grade I Mild Acute Rejection * Grade II Moderate Acute Rejection * Grade III Severe Acute Rejection. Clinical AR was determined based on the participant receiving treatment for rejection with or without biopsy confirmation of rejection. Chronic rejection was determined by the presence of abnormal total and direct bilirubin in the conjunction with liver pathology fulfilling the Banff (2000) criteria as outlined: * Early Stage Chronic Rejection * Late Stage Chronic Rejection.

Outcome measures

Outcome measures
Measure	Initiated Immunosuppression Withdrawal, Received darTregs n=10 Participants Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.
Number of Participants Who Experience at Least One Episode of Biopsy Proven Acute Rejection, Clinical Acute Rejection, or Chronic Rejection	5 Participants

SECONDARY outcome

Timeframe: From initiation of immunosuppression withdrawal to 52 weeks after darTregs infusion

Participants are counted in each grade of rejection they experienced; however, a participant is only counted once within a specific grade. Biopsy proven acute rejection and Chronic rejection were graded based on local pathology according to the Banff (1997 for Acute Rejection; 2000 for Chronic Rejection) global assessment criteria as outlined below. Biopsy proven acute rejection was assessed as Grade I or higher using the following grades: * Indeterminate * Grade I Mild Acute Rejection * Grade II Moderate Acute Rejection * Grade III Severe Acute Rejection. Chronic rejection was determined by the presence of abnormal total and direct bilirubin in the conjunction with liver pathology fulfilling the Banff criteria as outlined: * Early Stage Chronic Rejection * Late Stage Chronic Rejection.

Outcome measures

Outcome measures
Measure	Initiated Immunosuppression Withdrawal, Received darTregs n=10 Participants Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.
Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection Severe Acute Rejection	0 Participants
Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection Early Stage Chronic Rejection	0 Participants
Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection Mild Acute Rejection	2 Participants
Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection Moderate Acute Rejection	0 Participants
Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection Late Stage Chronic Rejection	0 Participants

SECONDARY outcome

Timeframe: From initiation of immunosuppression withdrawal to 52 weeks after darTreg infusion

Population: Participants who initiated immunosuppression withdrawal and received darTregs.

Efficacy was assessed by determining the number (and percentage) of participants who have received darTreg infusion and are identified as operationally tolerant, defined by maintaining stable allograft function (assessed by liver tests) and histology (determined by central pathologist reading in comparison to screening liver biopsy at study entry) in the absence of immunosuppression for one year.

Outcome measures

Outcome measures
Measure	Initiated Immunosuppression Withdrawal, Received darTregs n=5 Participants Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.
Number of Participants Achieving Efficacy Status Post Receipt of a Single Intravenous (IV) Dose of Donor Alloantigen Reactive Regulatory T Cells (darTregs)	0 Participants

Adverse Events

Initiated Immunosuppression Withdrawal, Received darTregs

Serious events: 4 serious events

Other events: 0 other events

Deaths: 0 deaths

Initiated Immunosuppression Withdrawal, Did Not Receive darTregs

Serious events: 1 serious events

Other events: 2 other events

Deaths: 0 deaths

Did Not Initiate Withdrawal, Screening Biopsy Performed

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Initiated Immunosuppression Withdrawal, Received darTregs n=5 participants at risk Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.	Initiated Immunosuppression Withdrawal, Did Not Receive darTregs n=5 participants at risk Initiated Immunosuppression Withdrawal, Did Not Receive darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and did not receive the darTreg infusion. Adverse events were collected for these participants.	Did Not Initiate Withdrawal, Screening Biopsy Performed n=2 participants at risk Did Not Initiate Withdrawal, Screening Biopsy Performed: Adult liver transplant recipients who signed informed consent, had the protocol-mandated screening biopsy performed, and did not proceed to immunosuppression withdrawal. Adverse events were collected for these participants.
Immune system disorders Transplant rejection	80.0% 4/5 • Number of events 4 • Up to 2 years (24 months) Only adverse events (AEs) grade 2 or higher were collected. Only AEs associated with protocol mandated liver biopsy were collected from the time of the biopsy to the initiation of initial immunosuppression (IS) withdrawal. All SAEs, regardless of relationship or expectedness to blood draw or liver biopsy with research specimen collection, IS withdrawal, or Treg infusion were to be reported within 24 hours of awareness.	20.0% 1/5 • Number of events 1 • Up to 2 years (24 months) Only adverse events (AEs) grade 2 or higher were collected. Only AEs associated with protocol mandated liver biopsy were collected from the time of the biopsy to the initiation of initial immunosuppression (IS) withdrawal. All SAEs, regardless of relationship or expectedness to blood draw or liver biopsy with research specimen collection, IS withdrawal, or Treg infusion were to be reported within 24 hours of awareness.	0.00% 0/2 • Up to 2 years (24 months) Only adverse events (AEs) grade 2 or higher were collected. Only AEs associated with protocol mandated liver biopsy were collected from the time of the biopsy to the initiation of initial immunosuppression (IS) withdrawal. All SAEs, regardless of relationship or expectedness to blood draw or liver biopsy with research specimen collection, IS withdrawal, or Treg infusion were to be reported within 24 hours of awareness.

Other adverse events

Other adverse events
Measure	Initiated Immunosuppression Withdrawal, Received darTregs n=5 participants at risk Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants.	Initiated Immunosuppression Withdrawal, Did Not Receive darTregs n=5 participants at risk Initiated Immunosuppression Withdrawal, Did Not Receive darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and did not receive the darTreg infusion. Adverse events were collected for these participants.	Did Not Initiate Withdrawal, Screening Biopsy Performed n=2 participants at risk Did Not Initiate Withdrawal, Screening Biopsy Performed: Adult liver transplant recipients who signed informed consent, had the protocol-mandated screening biopsy performed, and did not proceed to immunosuppression withdrawal. Adverse events were collected for these participants.
Hepatobiliary disorders Cholangitis	0.00% 0/5 • Up to 2 years (24 months) Only adverse events (AEs) grade 2 or higher were collected. Only AEs associated with protocol mandated liver biopsy were collected from the time of the biopsy to the initiation of initial immunosuppression (IS) withdrawal. All SAEs, regardless of relationship or expectedness to blood draw or liver biopsy with research specimen collection, IS withdrawal, or Treg infusion were to be reported within 24 hours of awareness.	20.0% 1/5 • Number of events 1 • Up to 2 years (24 months) Only adverse events (AEs) grade 2 or higher were collected. Only AEs associated with protocol mandated liver biopsy were collected from the time of the biopsy to the initiation of initial immunosuppression (IS) withdrawal. All SAEs, regardless of relationship or expectedness to blood draw or liver biopsy with research specimen collection, IS withdrawal, or Treg infusion were to be reported within 24 hours of awareness.	0.00% 0/2 • Up to 2 years (24 months) Only adverse events (AEs) grade 2 or higher were collected. Only AEs associated with protocol mandated liver biopsy were collected from the time of the biopsy to the initiation of initial immunosuppression (IS) withdrawal. All SAEs, regardless of relationship or expectedness to blood draw or liver biopsy with research specimen collection, IS withdrawal, or Treg infusion were to be reported within 24 hours of awareness.
Infections and infestations Bronchitis	0.00% 0/5 • Up to 2 years (24 months) Only adverse events (AEs) grade 2 or higher were collected. Only AEs associated with protocol mandated liver biopsy were collected from the time of the biopsy to the initiation of initial immunosuppression (IS) withdrawal. All SAEs, regardless of relationship or expectedness to blood draw or liver biopsy with research specimen collection, IS withdrawal, or Treg infusion were to be reported within 24 hours of awareness.	20.0% 1/5 • Number of events 1 • Up to 2 years (24 months) Only adverse events (AEs) grade 2 or higher were collected. Only AEs associated with protocol mandated liver biopsy were collected from the time of the biopsy to the initiation of initial immunosuppression (IS) withdrawal. All SAEs, regardless of relationship or expectedness to blood draw or liver biopsy with research specimen collection, IS withdrawal, or Treg infusion were to be reported within 24 hours of awareness.	0.00% 0/2 • Up to 2 years (24 months) Only adverse events (AEs) grade 2 or higher were collected. Only AEs associated with protocol mandated liver biopsy were collected from the time of the biopsy to the initiation of initial immunosuppression (IS) withdrawal. All SAEs, regardless of relationship or expectedness to blood draw or liver biopsy with research specimen collection, IS withdrawal, or Treg infusion were to be reported within 24 hours of awareness.
Infections and infestations Sinusitis	0.00% 0/5 • Up to 2 years (24 months) Only adverse events (AEs) grade 2 or higher were collected. Only AEs associated with protocol mandated liver biopsy were collected from the time of the biopsy to the initiation of initial immunosuppression (IS) withdrawal. All SAEs, regardless of relationship or expectedness to blood draw or liver biopsy with research specimen collection, IS withdrawal, or Treg infusion were to be reported within 24 hours of awareness.	20.0% 1/5 • Number of events 1 • Up to 2 years (24 months) Only adverse events (AEs) grade 2 or higher were collected. Only AEs associated with protocol mandated liver biopsy were collected from the time of the biopsy to the initiation of initial immunosuppression (IS) withdrawal. All SAEs, regardless of relationship or expectedness to blood draw or liver biopsy with research specimen collection, IS withdrawal, or Treg infusion were to be reported within 24 hours of awareness.	0.00% 0/2 • Up to 2 years (24 months) Only adverse events (AEs) grade 2 or higher were collected. Only AEs associated with protocol mandated liver biopsy were collected from the time of the biopsy to the initiation of initial immunosuppression (IS) withdrawal. All SAEs, regardless of relationship or expectedness to blood draw or liver biopsy with research specimen collection, IS withdrawal, or Treg infusion were to be reported within 24 hours of awareness.

Additional Information

Director, Clinical Research Operations Program

DAIT/NIAID

Phone: 301-594-7669

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place