TIMELY: Thymoglobulin Induction Therapy With Minimal Immunosuppression and Evaluation of Allograft Status

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00731874
• Collaborator: (none)
• Enrollment: 34
• Location: 1
• Arms: 2
• Duration (Months): 59
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Tacrolimus (Prograf) is a medication that is commonly used in patients who receive a kidney transplant. It is considered to be one of the most important medications that prevent rejection of the transplant kidney by suppressing the immune system. Although tacrolimus is good at preventing rejection, it does have some unwanted side effects. These side effects include high blood pressure, increase in blood sugar, headache, and tremor. In addition, tacrolimus causes some damage to the transplant kidney over time, by causing healthy tissue to turn into scar tissue that does not function as well as healthy tissue. Therefore, kidney function may be reduced over time. In the first three months after kidney transplant, Prograf levels are kept between 8 to 10 ng/mL. This study will compare two groups of patients that will both have their tacrolimus dose reduced slowly over three months to prevent rejection while decreasing the risk of causing toxic effects to the kidney. One group will have their Prograf levels kept between 6 and 8 ng/mL, while the second group will have their levels kept between 3 and 5 ng/mL. We will then compare the two groups to see if there are any differences in their kidney function over time.

Condition or Disease	Intervention/Treatment	Phase
Immunosuppression	Drug: Tacrolimus	Phase 4

Detailed Description

The objective of this study is to assess the safety and efficacy of an immunosuppression-minimizing regimen consisting initially of Thymoglobulin induction in combination with tacrolimus, mycophenolate mofetil, and rapid steroid withdrawal. The protocol will minimize long-term calcineurin inhibitor exposure and toxicity by weaning tacrolimus starting at 3 months after transplantation. Patients will be eligible to participate in this study only if they have already consented to participate in another study entitled "The use of urinary PCR test to help detect rejection in kidney transplant patients". In "The use of urinary PCR test to help detect rejection in kidney transplant patients", kidney allograft status (ie. whether or not there is any immunologic activity in the transplant kidney)is characterized with the use of protocol biopsies, diagnostic biopsies, and urinary PCR profiles. At 3 months after transplant, these patients are on an immunosuppression regimen consisting of tacrolimus (Prograf) and mycophenolate mofetil (CellCept). Prograf dosing is managed through the measurement of trough levels. For the first 3 months after transplant, patients are maintained at a trough level between 8 to 10 ng/ml. After 3 months, this target level is lowered in order to minimize long-term exposure to immunosuppressive agents. However, there is no consensus as to what the proper level should be after the first 3 months. Therefore, this study will randomize patients to 2 groups, one group will have their trough level targeted between 6 to 8 ng/mL while the other group will have their trough targeted between 3 and 5 ng/mL. By doing this study, we hope to determine which trough level is best, both for protecting the patient from rejection and protecting the patient from the adverse effects of the immunosuppressive medications.

At New York Weill Cornell Center, we are in a unique position to attempt immunosuppression minimization due to our ability to non-invasively monitor patients using their urine. Previous investigations performed at this center have demonstrated the diagnostic accuracy of mRNA levels of cytotoxic attack molecules in urinary cells. Preliminary data has shown that during acute rejection, Granzyme B and Perforin are strongly expressed in the urine. The sensitivity of the uPCR test was 88% with a specificity of 79%. All kidney transplant recipients at our center are invited to participate in the research study entitled "The use of urinary PCR test to help detect rejection in kidney transplant patients". In this protocol, serial analyses of urinary cells are performed to determine 1) if changes in mRNA levels will predict clinical acute rejection and 2) if these levels correlate with the presence of subclinical acute rejection. Kidney transplant recipients have serial urinary PCR measurements. In addition, patients undergo protocol biopsies of the transplant kidney at 3, 15, and 36 months after transplant. The biopsies help to show the correlation between the PCR results and the pathology of the kidney. It may also serve to detect rejection when the blood tests or urinary PCR do not show it. In a small subset of patients, urinary gene expression profile of cytotoxic attack molecules was able to predict acute rejection prior to clinical diagnosis by renal allograft biopsy.

Because we have the ability to monitor our transplant recipients using the urinary PCR protocol, we can safely minimize tacrolimus exposure over time by monitoring patients non-invasively on a real-time basis. Minimization of immunosuppression over time in a kidney transplant recipient is important in order to prevent or minimize some of the leading causes of kidney graft loss (defined as return to dialysis). Although immunosuppressive medications are excellent at preventing rejection, they do have detrimental effects on the cardiovascular system as well as to the transplant kidney itself. One major cause of kidney graft loss today is chronic allograft nephropathy (CAN). Formerly known as "chronic rejection", CAN has been described as the progressive decline in allograft function that occurs months or years after transplantation, and it is the second leading cause of kidney graft loss. Biopsies of kidney allografts with CAN may show inflammation, fibrosis, glomerulosclerosis, tubular atrophy, and vascular smooth muscle proliferation. The scarring and fibrosis associated with CAN is generally irreversible. A new goal within the modern transplant arena is to prevent CAN from occurring by:

1. decreasing early acute rejection episodes

2. decreasing calcineurin inhibitor-related nephrotoxicity

With the use of modern immunosuppressive agents and induction therapy, we have already decreased early acute rejection episodes significantly. At this time, we now want to begin to study the potentially beneficial effects that calcineurin inhibitor withdrawal may have on kidney function as well as long-term graft survival.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Thymoglobulin Induction Therapy With Minimal Immunosuppression and Evaluation of Allograft Status by Biopsy and mRNA Profiles (TIMELY Study)
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm 1 (6 to 8 ng/mL) Target tacrolimus trough concentration of 6 to 8 ng/mL	Drug: Tacrolimus; Dosed to achieve target trough concentrations.; Other Names: Prograf
Active Comparator: Arm 2 (3 to 5 ng.mL) Target tacrolimus trough concentration of 3 to 5 ng/mL	Drug: Tacrolimus; Dosed to achieve target trough concentrations.; Other Names: Prograf

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Biopsy-confirmed Acute Rejection and/or Progression of Histologically Proven Chronic Allograft Nephropathy at 15 Months After Transplantation. [15 months post-transplant]

Secondary Outcome Measures

1. Patient Survival [36 months post-transplant]

2. Graft Survival [36 months post-transplant]

3. Change in Incidence and Severity of Interstitial Fibrosis/Tubular Atrophy (IF/TA) From the Baseline 3-month Biopsy to the 36-month Biopsy [36 months post-transplant]

   Compared to the baseline biopsy performed at the time of study entry at 3 months, was there new development (incidence) or progression (severity) of interstitial fibrosis/tubular atrophy (formerly called chronic allograft nephropathy) in the biopsy performed at 36 months.

4. Renal Function (Estimated Glomerular Filtration Rate) [36 months post-transplant]

5. Development of Donor Specific Antibody (DSA) [36 months post-transplant]

   Percent of subjects who developed new donor specific antibody (mean fluorescence intensity > 3,000) after enrollment, within 36 months of transplant

6. Incidence of Acute Rejection [36 months post-transplant]

   Incidence of biopsy-proven acute rejection

7. Severity of Acute Rejection (by Banff Criteria and Need for Anti-lymphocyte Agents to Treat Acute Rejection) [36 months post-transplant]

   The severity of acute rejection may be assessed by the Banff criteria. The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of renal allograft biopsies, and provides critical information enabling the diagnosis and grading of pathologic changes, can help to predict response to treatment, and can help to determine the long-term prognosis of the organ. Anti-lymphocyte agents (specifically rabbit anti-thymocyte globulin) are used to treat more severe cases of acute rejection, and thus may serve as a surrogate marker of severity.

8. Incidence of Opportunistic Infection [36 months post-transplant]

9. Development of New Onset Diabetes Mellitus [36 months post-transplant]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age > 18 years

• Renal allograft recipients who received a steroid-sparing immunosuppression protocol with rabbit anti-thymocyte globulin (Thymoglobulin) induction

• Patient must have previously enrolled in protocol entitled "The use of urinary PCR test to help detect rejection in kidney transplant patients"

• Recipients must agree to undergo all standard post-transplant protocol biopsies

• Recipients must be at least 3 months post-transplant and the three most recent urinary profiles must demonstrate immunologic quiescence as determined by measurement of Granzyme B and Perforin copy numbers

• Patient must provide informed consent to participate in the research study

Exclusion Criteria:

• Patient is a high-risk recipient (defined as peak or current PRA >50% or a re-transplant recipient who lost prior graft within 1 year due to immunologic reasons)

• Patients who require maintenance steroids for another medical condition (such as asthma)

• Patients who are taking less than 1 gram/day of mycophenolate mofetil

• Multiple organ transplant recipients (such as kidney-pancreas)

• Patients with one or more acute rejection episodes within the first 3 months after transplant

• Three-month protocol biopsy showing clinical acute rejection (BANFF grade 1a or higher)

• Patient with documented or suspected non-compliance with transplant medications in the first 3 months after transplant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Weill Cornell Medical College/NewYork-Presbyterian Hospital	New York	New York	United States	10065

Sponsors and Collaborators

• Weill Medical College of Cornell University

Investigators

• Principal Investigator: Sandip Kapur, M.D., Weill Medical College of Cornell University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT00731874
• Other Study ID Numbers: 0608008711
• First Posted: Aug 11, 2008
• Last Update Posted: Jun 12, 2019
• Last Verified: May 1, 2019

• Keywords provided by Weill Medical College of Cornell University: Kidney transplantation; Immunosuppression; Minimization; Tacrolimus; Prograf; Thymoglobulin
• Additional relevant MeSH terms: Tacrolimus

Study Results

Participant Flow

Pre-assignment Detail	34 subjects consented for the study; 11 were enrolled but not randomized due to the following: withdrew consent/refused transplant biopsy (n=4); donor specific antibody detected during screening (n=3); excluded by findings of kidney transplant biopsy (n=2); fluctuation in renal function (n=1); study terminated prior to randomization (n=1).

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)	Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.
Period Title: Overall Study
STARTED	10	13
COMPLETED	10	13
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)	Arm 2 (Target Tacrolimus 3 to 5 ng/mL)	Total
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Total of all reporting groups
Overall Participants	10	13	23
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 100%	11 84.6%	21 91.3%
>=65 years	0 0%	2 15.4%	2 8.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.4 (11.3)	56.1 (10.2)	52.7 (11.1)
Sex: Female, Male (Count of Participants)
Female	4 40%	2 15.4%	6 26.1%
Male	6 60%	11 84.6%	17 73.9%
Region of Enrollment (participants) [Number]
United States	10 100%	13 100%	23 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Biopsy-confirmed Acute Rejection and/or Progression of Histologically Proven Chronic Allograft Nephropathy at 15 Months After Transplantation.
Time Frame	15 months post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)	Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.
Measure Participants	10	13
Number [participants]	0 0%	1 7.7%

2. Secondary Outcome

Title	Patient Survival
Time Frame	36 months post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)	Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.
Measure Participants	10	13
Count of Participants [Participants]	10 100%	13 100%

3. Secondary Outcome

Title	Graft Survival
Time Frame	36 months post-transplant

Outcome Measure Data

Analysis Population Description

Data are not included for one subject because one subject was lost to follow-up.

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)	Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.
Measure Participants	10	12
Count of Participants [Participants]	10 100%	12 92.3%

4. Secondary Outcome

Title	Change in Incidence and Severity of Interstitial Fibrosis/Tubular Atrophy (IF/TA) From the Baseline 3-month Biopsy to the 36-month Biopsy
Description	Compared to the baseline biopsy performed at the time of study entry at 3 months, was there new development (incidence) or progression (severity) of interstitial fibrosis/tubular atrophy (formerly called chronic allograft nephropathy) in the biopsy performed at 36 months.
Time Frame	36 months post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)	Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.
Measure Participants	10	13
Progression of IFTA	2 20%	5 38.5%
New IFTA	2 20%	1 7.7%
Stable Biopsy	4 40%	6 46.2%
No Data	2 20%	1 7.7%

5. Secondary Outcome

Title	Renal Function (Estimated Glomerular Filtration Rate)
Time Frame	36 months post-transplant

Outcome Measure Data

Analysis Population Description

Data are not included for one subject because one subject was lost to follow-up.

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)	Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.
Measure Participants	10	12
eGFR>60	2 20%	5 38.5%
eGFR 50-59	4 40%	3 23.1%
eGFR 40-49	2 20%	1 7.7%
eGFR 30-39	1 10%	2 15.4%
eGFR 20-29	1 10%	1 7.7%

6. Secondary Outcome

Title	Development of Donor Specific Antibody (DSA)
Description	Percent of subjects who developed new donor specific antibody (mean fluorescence intensity > 3,000) after enrollment, within 36 months of transplant
Time Frame	36 months post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)	Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.
Measure Participants	10	13
Count of Participants [Participants]	0 0%	5 38.5%

7. Secondary Outcome

Title	Incidence of Acute Rejection
Description	Incidence of biopsy-proven acute rejection
Time Frame	36 months post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)	Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.
Measure Participants	10	13
Count of Participants [Participants]	0 0%	5 38.5%

8. Secondary Outcome

Title	Severity of Acute Rejection (by Banff Criteria and Need for Anti-lymphocyte Agents to Treat Acute Rejection)
Description	The severity of acute rejection may be assessed by the Banff criteria. The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of renal allograft biopsies, and provides critical information enabling the diagnosis and grading of pathologic changes, can help to predict response to treatment, and can help to determine the long-term prognosis of the organ. Anti-lymphocyte agents (specifically rabbit anti-thymocyte globulin) are used to treat more severe cases of acute rejection, and thus may serve as a surrogate marker of severity.
Time Frame	36 months post-transplant

Outcome Measure Data

Analysis Population Description

Data reported only for those subjects who developed acute rejection during the study, per protocol. Three of the 5 subjects in Arm 2 with rejection were treated with rabbit anti-thymocyte globulin.

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)	Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.
Measure Participants	0	5
Mixed T cell and Antibody Mediated Rejection	0 0%	3 23.1%
Antibody Mediated Rejection	0 0%	2 15.4%

9. Secondary Outcome

Title	Incidence of Opportunistic Infection
Time Frame	36 months post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)	Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.
Measure Participants	10	13
Count of Participants [Participants]	1 10%	1 7.7%

10. Secondary Outcome

Title	Development of New Onset Diabetes Mellitus
Time Frame	36 months post-transplant

Outcome Measure Data

Analysis Population Description

Only subjects who did not have a diagnosis of diabetes mellitus at transplant are included, per protocol.

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)	Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.	Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.
Measure Participants	8	9
Count of Participants [Participants]	1 10%	2 15.4%

Adverse Events

Arm/Group Title	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)		Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
Arm/Group Description	Target tacrolimus trough concentration of 6 to 8 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.		Target tacrolimus trough concentration of 3 to 5 ng/mL Tacrolimus: Dosed to achieve target trough concentrations.
All Cause Mortality
	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)		Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)		Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Arm 1 (Target Tacrolimus 6 to 8 ng/mL)		Arm 2 (Target Tacrolimus 3 to 5 ng/mL)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/10 (30%)		7/13 (53.8%)
Cardiac disorders
Chest Pain	0/10 (0%)	0	1/13 (7.7%)	1
Infections and infestations
Cytomegalovirus viremia	0/10 (0%)	0	1/13 (7.7%)	1
Strongyloides infection	1/10 (10%)	1	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Pain, Hip	0/10 (0%)	0	1/13 (7.7%)	1
Renal and urinary disorders
Antibody-mediated rejection	0/10 (0%)	0	5/13 (38.5%)	5
Urinary Tract Infection	1/10 (10%)	1	0/13 (0%)	0
Reproductive system and breast disorders
Menorrhagia	1/10 (10%)	1	0/13 (0%)	0
Endometritis	1/10 (10%)	1	0/13 (0%)	0
Skin and subcutaneous tissue disorders
Non-melanoma skin cancer	1/10 (10%)	1	0/13 (0%)	0

Limitations/Caveats

The population reported is small because the study was stopped early due to the increase in late antibody mediated rejection (occurring after month 15) that was seen in Arm 2 (target tacrolimus trough 3 to 5 ng/mL).

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.