RAPA: Tacrolimus to Sirolimus Conversion for Delayed Graft Function

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00931255
• Collaborator: Wyeth is now a wholly owned subsidiary of Pfizer (Industry)
• Enrollment: 32
• Location: 1
• Arms: 2
• Duration (Months): 63
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The objective of this study is to evaluate the safety and efficacy of conversion from tacrolimus to sirolimus early after kidney transplantation in patients with delayed graft function (DGF)and slow graft function (SGF) in improving graft function and delaying chronic allograft nephropathy. The investigators hypothesize that conversion from tacrolimus to sirolimus in renal transplant recipients with DGF/SGF in early months after surgery will improve graft function and decrease the progression of graft fibrosis.

Condition or Disease	Intervention/Treatment	Phase
Kidney Transplant; Delayed Graft Function	Drug: Tacrolimus; Drug: Sirolimus	Phase 4

Detailed Description

Eligible study subjects will be randomized into two groups 8-18 weeks after surgery. One group will be maintained on tacrolimus according to the standard of care at our center. In the second group tacrolimus will be converted to sirolimus, with one week overlap between sirolimus therapy and tacrolimus taper. All the deceased donor kidney transplant recipients transplanted at our center who experience DGF/SGF are eligible for inclusion in this study, if they meet the inclusion/exclusion criteria as detailed later.

Data will be collected on patient demographics, duration on dialysis, history of diabetes and chronic hepatitis C, previous transplantation, PRA, donor source, warm and cold ischemia time, donor demographics and comorbidity such as diabetes and hypertension, serum creatinine at the time of organ removal, early graft function, number of dialysis treatments after transplantation, induction agent and immunosuppressive regimen including the dose or level of the drugs at 3, 6, 9, 12, 18, and 24 months. Similar data regarding use of ACE inhibitors/ARBs, erythropoietic agents, number of anti-hypertensives and lipid lowering agents will be collected. In addition, the following tests and procedures will be obtained for this study.

1. GFR measurement by cold iothalamate method at one year after transplantation.

2. Evaluation of routine surveillance graft biopsies for chronic changes at 3 and 12 months posttransplant by morphometric analysis.

3. Spot urine protein, albumin, and creatinine measurement at 3 and 12 months.

4. Estimate GFR at 3, and 12 months using MDRD, CG, and Nankivell formulas

5. Examine the surveillance and indicated biopsies for acute rejection and BK nephropathy.

6. Fasting lipid profile at 3 and 12 months for all patients, and 24 months for those with at least 2 years of follow up.

7. Office blood pressure measurements at 3 and 12 months for all patients, and 24 months for those with at least 2 years of follow up.

8. Measurement of CRP, IL-6, and MCP at 3 and 12 months.

The safety measures will include:

Incidence of leukopenia (WBC < 3000) or thrombocytopenia (PLT < 100,000); hemoglobin level at 12 months; proteinuria at 12 months; incidence of oral aphthous ulcers; incidence of new onset diabetes, incidence of CMV infection and rate of drug withdrawal due to side effects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Delayed Tacrolimus to Sirolimus Conversion in Renal Transplant Recipients With Delayed Graft Function
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Tacrolimus Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year.	Drug: Tacrolimus; 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol; Other Names: FK506, Prograf
Active Comparator: Sirolimus 5 mg, PO , daily	Drug: Sirolimus; 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol; Other Names: Rapamune, Rapamycin

Outcome Measures

Primary Outcome Measures

1. The Composite Endpoint of Reduction of e eGFR at One Year by More Than 15% & the Progression in Fibrosis Score at One Year by >=20% Compared With the Baseline Values [One year]

Secondary Outcome Measures

1. eGFR [One year]

2. Change in eGFR From Baseline to 1-year [1 year]

3. Graft Survival (Actual, Actuarial) [1 year]

4. Incidence of Acute Rejection (Actual, Actuarial) [1 year]

5. Incidence of BK Nephropathy (Cumulative) [1 year]

6. Change in Inflammatory Marker : CRP From Baseline [1 year]

7. Change in Inflammatory Marker, IL-6 From Baseline [1 Year]

8. Change in Inflammatory Marker, MCP, From Baseline [1 year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age => 18.

2. Recipient of a deceased donor kidney transplant.

3. Delayed graft function, defined as need for dialysis during first week after surgery or slow graft function, defined as creatinine >=3.0 by post-op day 5 without requiring dialysis

4. Stable serum creatinine for 2 weeks prior to enrollment.

5. Able to give informed consent.

6. Compliant with medical regimen and clinic visits.

Exclusion Criteria:

1. Episode of acute rejection within 4 weeks prior to enrollment.

2. Calculated GFR < 30 ml/min.

3. Interstitial fibrosis & tubular atrophy in transplant biopsy higher than grade II (Banff"05 update).

4. Proteinuria > 500 mg/24 h or spot urine protein/creatinine > 0.5.

5. Total fasting cholesterol level > 300 mg/dl or triglyceride > 500 mg/dl despite optimal lipid lowering therapy.

6. Recipient of pancreas or liver allografts.

7. Leukopenia (WBC < 3000 mm3) within 2 weeks prior to enrollment.

8. Leukopenia (WBC < 2000 mm3) within 4 weeks prior to enrollment.

9. Thrombocytopenia (platelets count < 100,000/mm3) within 2 weeks prior to enrollment.

10. Unwilling to comply with study protocol.

11. Enrollment in another drug trial that precludes use of sirolimus.

12. Diagnosis of malignancy within 2 years prior to enrollment, except adequately treated non-melanoma skin cancer.

13. For women, pregnancy.

14. Allergy to iodine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Maryland Medical Center	Baltimore	Maryland	United States	21201

Sponsors and Collaborators

• University of Maryland, Baltimore
• Wyeth is now a wholly owned subsidiary of Pfizer

Investigators

• Principal Investigator: Abdolreza Haririan, MD, MPH, University of Maryland

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Abdoleza Haririan, Principal Investigator, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT00931255
• Other Study ID Numbers: HP-00042201
• First Posted: Jul 2, 2009
• Last Update Posted: Mar 31, 2022
• Last Verified: Mar 1, 2022

• Keywords provided by Abdoleza Haririan, Principal Investigator, University of Maryland, Baltimore: kidney transplant; tacrolimus; sirolimus; delayed graft function; Graft survival; Acute rejection; Chronic allograft nephropathy
• Additional relevant MeSH terms: Delayed Graft Function; Sirolimus; Tacrolimus

Study Results

Participant Flow

Arm/Group Title	Tacrolimus	Sirolimus
Arm/Group Description	Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year. Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol	5 mg, PO , daily Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol
Period Title: Overall Study
STARTED	17	15
COMPLETED	15	12
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Tacrolimus	Sirolimus	Total
Arm/Group Description	Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year. Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol	5 mg, PO , daily Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol	Total of all reporting groups
Overall Participants	17	15	32
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.4 (9.7)	49.9 (10.1)	51.7 (9.9)
Sex: Female, Male (Count of Participants)
Female	4 23.5%	5 33.3%	9 28.1%
Male	13 76.5%	10 66.7%	23 71.9%

Outcome Measures

1. Primary Outcome

Title	The Composite Endpoint of Reduction of e eGFR at One Year by More Than 15% & the Progression in Fibrosis Score at One Year by >=20% Compared With the Baseline Values
Time Frame	One year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tacrolimus	Sirolimus
Arm/Group Description	Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year. Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol	5 mg, PO , daily Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol
Measure Participants	15	12
Number [participants]	6 35.3%	9 60%

2. Secondary Outcome

Title	eGFR
Time Frame	One year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tacrolimus	Sirolimus
Arm/Group Description	Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year. Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol	5 mg, PO , daily Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol
Measure Participants	17	15
Mean (Standard Deviation) [mL/min per 1.73 m^2]	56.4 (15.2)	53.7 (19.2)

3. Secondary Outcome

Title	Change in eGFR From Baseline to 1-year
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tacrolimus	Sirolimus
Arm/Group Description	Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year. Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol	5 mg, PO , daily Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol
Measure Participants	17	15
Mean (Standard Deviation) [mL/min per 1.73 m^2]	7.45 (11.5)	1.57 (10.7)

4. Secondary Outcome

Title	Graft Survival (Actual, Actuarial)
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tacrolimus	Sirolimus
Arm/Group Description	Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year. Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol	5 mg, PO , daily Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol
Measure Participants	17	15
Number [participants]	16 94.1%	14 93.3%

5. Secondary Outcome

Title	Incidence of Acute Rejection (Actual, Actuarial)
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tacrolimus	Sirolimus
Arm/Group Description	Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year. Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol	5 mg, PO , daily Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol
Measure Participants	17	15
Number [participants]	1 5.9%	1 6.7%

6. Secondary Outcome

Title	Incidence of BK Nephropathy (Cumulative)
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tacrolimus	Sirolimus
Arm/Group Description	Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year. Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol	5 mg, PO , daily Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol
Measure Participants	17	15
Number [participants]	1 5.9%	0 0%

7. Secondary Outcome

Title	Change in Inflammatory Marker : CRP From Baseline
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tacrolimus	Sirolimus
Arm/Group Description	Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year. Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol	5 mg, PO , daily Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol
Measure Participants	17	15
Mean (Standard Deviation) [mg/L]	-1668 (9403)	4510 (14495)

8. Secondary Outcome

Title	Change in Inflammatory Marker, IL-6 From Baseline
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tacrolimus	Sirolimus
Arm/Group Description	Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year. Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol	5 mg, PO , daily Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol
Measure Participants	17	15
Mean (Standard Deviation) [pg/mL]	-0.7 (8.53)	6.2 (14.1)

9. Secondary Outcome

Title	Change in Inflammatory Marker, MCP, From Baseline
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tacrolimus	Sirolimus
Arm/Group Description	Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year. Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol	5 mg, PO , daily Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol
Measure Participants	17	15
Mean (Standard Deviation) [pg/mL]	-787.5 (693.9)	-965.2 (753.6)

Adverse Events

Arm/Group Title	Tacrolimus		Sirolimus
Arm/Group Description	Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year. Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol		5 mg, PO , daily Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol
All Cause Mortality
	Tacrolimus		Sirolimus
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tacrolimus		Sirolimus
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Tacrolimus		Sirolimus
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/17 (5.9%)		0/15 (0%)
Blood and lymphatic system disorders
CMV viremia	1/17 (5.9%)	1	0/15 (0%)	0

Limitations/Caveats

The trial was stopped because of slow enrollment. Hence, the target enrollment number was not achieved.

More Information

Certain Agreements

Principal Investigators are NOT 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.