Trial Outcomes & Findings for Kidney Biopsy Controlled Trial of Calcineurin Inhibitor Withdrawal (NCT NCT00896012)

NCT ID: NCT00896012

Last Updated: 2023-08-14

Results Overview

Graft survival is defined as no rejection or inflammation at 12 months.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

58 participants

Primary outcome timeframe

Number of participants biopsied at 12 months post-transplant

Results posted on

2023-08-14

Participant Flow

Adult participants who received their first kidney transplant were eligible to participate. Recruitment occurred from January 2008 until October 2010.

Of the total 58 participants enrolled in the study, 6 participants were not randomized to either the Low Dose Tacrolimus or Rapamycin Conversion arm. Only those showing no evidence of subclinical rejection or borderline changes on 3-month protocol biopsy were eligible for randomization.

Participant milestones

Participant milestones
Measure	1. Low-dose Tacrolimus Arm Patients in this group will continue to receive tacrolimus at reduced doses. Doses will be titrated to achieve tacrolimus trough blood levels between 4 and 6. Myfortic at doses of 720 mg BID and steroids will be continued for the duration of the study (12 months). All patients will undergo a second protocol biopsy at 12 months.	2. Rapamune Conversion Arm: Patients in this group will undergo a gradual conversion from tacrolimus to Rapamune therapy. Tacrolimus will be withdrawn progressively over a period of 7-10 days. Dosage adjustments will be made with the aim of reducing the blood levels of tacrolimus by 25% every other day until tacrolimus is discontinued. Rapamune will be given at a dose of 5mg/day for two days beginning at the initiation of tacrolimus reduction. Thereafter, Rapamune will be given at a dose of 3 mg/day. The dose of Rapamune will be titrated to achieve a blood level (by HPLC) between 5 and 10 for the duration of the study.
Overall Study STARTED	29	23
Overall Study COMPLETED	18	12
Overall Study NOT COMPLETED	11	11

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Kidney Biopsy Controlled Trial of Calcineurin Inhibitor Withdrawal

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	1. Low-dose Tacrolimus Arm n=29 Participants Patients in this group will continue to receive tacrolimus at reduced doses. Doses will be titrated to achieve tacrolimus trough blood levels between 4 and 6. Myfortic at doses of 720 mg BID and steroids will be continued for the duration of the study (12 months). All patients will undergo a second protocol biopsy at 12 months.	2. Rapamune Conversion Arm: n=23 Participants Patients in this group will undergo a gradual conversion from tacrolimus to Rapamune therapy. Tacrolimus will be withdrawn progressively over a period of 7-10 days. Dosage adjustments will be made with the aim of reducing the blood levels of tacrolimus by 25% every other day until tacrolimus is discontinued. Rapamune will be given at a dose of 5mg/day for two days beginning at the initiation of tacrolimus reduction. Thereafter, Rapamune will be given at a dose of 3 mg/day. The dose of Rapamune will be titrated to achieve a blood level (by HPLC) between 5 and 10 for the duration of the study.	Total n=52 Participants Total of all reporting groups
Age, Continuous	56.8 years STANDARD_DEVIATION 12.4 • n=5 Participants	51.1 years STANDARD_DEVIATION 13.6 • n=7 Participants	54.3 years STANDARD_DEVIATION 13.1 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	8 Participants n=7 Participants	16 Participants n=5 Participants
Sex: Female, Male Male	21 Participants n=5 Participants	15 Participants n=7 Participants	36 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity · American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity · Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity · Black or African American	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity · White	22 Participants n=5 Participants	16 Participants n=7 Participants	38 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity · Hispanic or Latino	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Region of Enrollment United States	29 participants n=5 Participants	23 participants n=7 Participants	52 participants n=5 Participants
Donor Type Living Donor	13 Participants n=5 Participants	15 Participants n=7 Participants	28 Participants n=5 Participants
Donor Type Deceased Donor	16 Participants n=5 Participants	8 Participants n=7 Participants	24 Participants n=5 Participants
Diagnosis Diabetes	16 Participants n=5 Participants	7 Participants n=7 Participants	23 Participants n=5 Participants
Diagnosis Hypertension	6 Participants n=5 Participants	3 Participants n=7 Participants	9 Participants n=5 Participants
Diagnosis Other/Unknown	7 Participants n=5 Participants	13 Participants n=7 Participants	20 Participants n=5 Participants
Post-kidney transplant function Delayed graft function	5 Participants n=5 Participants	1 Participants n=7 Participants	6 Participants n=5 Participants
Post-kidney transplant function Immediate graft function	24 Participants n=5 Participants	22 Participants n=7 Participants	46 Participants n=5 Participants
Donor type-Expanded criteria donors Expanded criteria donors	7 Participants n=5 Participants	1 Participants n=7 Participants	8 Participants n=5 Participants
Donor type-Expanded criteria donors Non-expanded criteria donors	22 Participants n=5 Participants	22 Participants n=7 Participants	44 Participants n=5 Participants
Total rATG dose	2.9 mg/kg STANDARD_DEVIATION .79 • n=5 Participants	3.0 mg/kg STANDARD_DEVIATION .32 • n=7 Participants	3.0 mg/kg STANDARD_DEVIATION .63 • n=5 Participants
HLA mismatch	3.7 mismatched antigens STANDARD_DEVIATION 1.7 • n=5 Participants	3.8 mismatched antigens STANDARD_DEVIATION 1.4 • n=7 Participants	3.8 mismatched antigens STANDARD_DEVIATION 1.5 • n=5 Participants

PRIMARY outcome

Timeframe: Number of participants biopsied at 12 months post-transplant

Population: At 12 month, patients underwent a second surveillance biopsy. All biopsies were reviewed and scored using the 2005 updated Banff 1997 criteria.

Graft survival is defined as no rejection or inflammation at 12 months.

Outcome measures

Outcome measures
Measure	1. Low-dose Tacrolimus Arm n=29 Participants Patients in this group will continue to receive tacrolimus at reduced doses. Doses will be titrated to achieve tacrolimus trough blood levels between 4 and 6. Myfortic at doses of 720 mg BID and steroids will be continued for the duration of the study (12 months). All patients will undergo a second protocol biopsy at 12 months.	2. Rapamune Conversion Arm: n=23 Participants Patients in this group will undergo a gradual conversion from tacrolimus to Rapamune therapy. Tacrolimus will be withdrawn progressively over a period of 7-10 days. Dosage adjustments will be made with the aim of reducing the blood levels of tacrolimus by 25% every other day until tacrolimus is discontinued. Rapamune will be given at a dose of 5mg/day for two days beginning at the initiation of tacrolimus reduction. Thereafter, Rapamune will be given at a dose of 3 mg/day. The dose of Rapamune will be titrated to achieve a blood level (by HPLC) between 5 and 10 for the duration of the study.
Number of Participants With Graft Survival at 12 Months	18 Participants	12 Participants

PRIMARY outcome

Timeframe: 1 year post-transplant

Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula.

Outcome measures

Outcome measures
Measure	1. Low-dose Tacrolimus Arm n=29 Participants Patients in this group will continue to receive tacrolimus at reduced doses. Doses will be titrated to achieve tacrolimus trough blood levels between 4 and 6. Myfortic at doses of 720 mg BID and steroids will be continued for the duration of the study (12 months). All patients will undergo a second protocol biopsy at 12 months.	2. Rapamune Conversion Arm: n=23 Participants Patients in this group will undergo a gradual conversion from tacrolimus to Rapamune therapy. Tacrolimus will be withdrawn progressively over a period of 7-10 days. Dosage adjustments will be made with the aim of reducing the blood levels of tacrolimus by 25% every other day until tacrolimus is discontinued. Rapamune will be given at a dose of 5mg/day for two days beginning at the initiation of tacrolimus reduction. Thereafter, Rapamune will be given at a dose of 3 mg/day. The dose of Rapamune will be titrated to achieve a blood level (by HPLC) between 5 and 10 for the duration of the study.
Either Equivalent or Improved Estimated Glomerular Filtration Rate (eGFR) at One Year in the Rapamycin Group eGFR at 1 Month	65.5 mL/min Standard Deviation 16.8	58.3 mL/min Standard Deviation 13.6
Either Equivalent or Improved Estimated Glomerular Filtration Rate (eGFR) at One Year in the Rapamycin Group eGFR at 3 Months	68.6 mL/min Standard Deviation 18.1	58.7 mL/min Standard Deviation 13.7
Either Equivalent or Improved Estimated Glomerular Filtration Rate (eGFR) at One Year in the Rapamycin Group eGRF at 6 Months	75 mL/min Standard Deviation 19	67 mL/min Standard Deviation 14
Either Equivalent or Improved Estimated Glomerular Filtration Rate (eGFR) at One Year in the Rapamycin Group eGRF at 12 Months	74 mL/min Standard Deviation 15	66 mL/min Standard Deviation 18

PRIMARY outcome

Timeframe: 3 and 12 months

Population: At one year the number of participants in LowTAC group was n=18 and Sirolimus group n= 12

Chronic allograft damage index (CADI) scores. It's a sum score of six histo- pathological lesions commonly seen in biopsies taken from transplanted kidneys that correlate with the function and outcome of the graft. The maximum CADI score can go up to 18. In this case the lesions found were Interstitial fibrosis (IF) and Tubular Atrophy (TA) subscales from 0 (min) to 5 (max) . A score of 0 to 1 means absence of chronic allograft damage, a score of 4 is severe damage. .

Outcome measures

Outcome measures
Measure	1. Low-dose Tacrolimus Arm n=29 Participants Patients in this group will continue to receive tacrolimus at reduced doses. Doses will be titrated to achieve tacrolimus trough blood levels between 4 and 6. Myfortic at doses of 720 mg BID and steroids will be continued for the duration of the study (12 months). All patients will undergo a second protocol biopsy at 12 months.	2. Rapamune Conversion Arm: n=23 Participants Patients in this group will undergo a gradual conversion from tacrolimus to Rapamune therapy. Tacrolimus will be withdrawn progressively over a period of 7-10 days. Dosage adjustments will be made with the aim of reducing the blood levels of tacrolimus by 25% every other day until tacrolimus is discontinued. Rapamune will be given at a dose of 5mg/day for two days beginning at the initiation of tacrolimus reduction. Thereafter, Rapamune will be given at a dose of 3 mg/day. The dose of Rapamune will be titrated to achieve a blood level (by HPLC) between 5 and 10 for the duration of the study.
Improved Histology at 12 Months in the Rapamycin Group CADI Score at 3-Month Randomization Follow-Up	1.1 score on a scale Standard Deviation 1.3	1.0 score on a scale Standard Deviation 1.5
Improved Histology at 12 Months in the Rapamycin Group CADI Score at 12-Month Randomization Follow-up	2.8 score on a scale Standard Deviation 2.4	2.0 score on a scale Standard Deviation 2.7

Adverse Events

1. Low-dose Tacrolimus Arm

Serious events: 4 serious events

Other events: 10 other events

Deaths: 0 deaths

2. Rapamune Conversion Arm:

Serious events: 6 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	1. Low-dose Tacrolimus Arm n=29 participants at risk Patients in this group will continue to receive tacrolimus at reduced doses. Doses will be titrated to achieve tacrolimus trough blood levels between 4 and 6. Myfortic at doses of 720 mg BID and steroids will be continued for the duration of the study (12 months). All patients will undergo a second protocol biopsy at 12 months.	2. Rapamune Conversion Arm: n=23 participants at risk Patients in this group will undergo a gradual conversion from tacrolimus to Rapamune therapy. Tacrolimus will be withdrawn progressively over a period of 7-10 days. Dosage adjustments will be made with the aim of reducing the blood levels of tacrolimus by 25% every other day until tacrolimus is discontinued. Rapamune will be given at a dose of 5mg/day for two days beginning at the initiation of tacrolimus reduction. Thereafter, Rapamune will be given at a dose of 3 mg/day. The dose of Rapamune will be titrated to achieve a blood level (by HPLC) between 5 and 10 for the duration of the study.
Infections and infestations Bacterial Infection	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	26.1% 6/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Blood and lymphatic system disorders Leukopenia	17.2% 5/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	21.7% 5/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Gastrointestinal disorders Diarrhea	13.8% 4/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	0.00% 0/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Infections and infestations Urinary Tract Infection	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	13.0% 3/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Infections and infestations BK Infection	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	13.0% 3/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Infections and infestations Fever	6.9% 2/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	0.00% 0/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Infections and infestations Sinus Infection	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	8.7% 2/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Infections and infestations Toe Infection	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	8.7% 2/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Renal and urinary disorders Proteinuria	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	8.7% 2/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.

Additional Information

Oleh G. Pankewycz, MD

University at Buffalo

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	1. Low-dose Tacrolimus Arm n=29 participants at risk Patients in this group will continue to receive tacrolimus at reduced doses. Doses will be titrated to achieve tacrolimus trough blood levels between 4 and 6. Myfortic at doses of 720 mg BID and steroids will be continued for the duration of the study (12 months). All patients will undergo a second protocol biopsy at 12 months.	2. Rapamune Conversion Arm: n=23 participants at risk Patients in this group will undergo a gradual conversion from tacrolimus to Rapamune therapy. Tacrolimus will be withdrawn progressively over a period of 7-10 days. Dosage adjustments will be made with the aim of reducing the blood levels of tacrolimus by 25% every other day until tacrolimus is discontinued. Rapamune will be given at a dose of 5mg/day for two days beginning at the initiation of tacrolimus reduction. Thereafter, Rapamune will be given at a dose of 3 mg/day. The dose of Rapamune will be titrated to achieve a blood level (by HPLC) between 5 and 10 for the duration of the study.
Cardiac disorders Chest Pain	3.4% 1/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	0.00% 0/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Renal and urinary disorders Elevated Creatinine	6.9% 2/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	0.00% 0/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Infections and infestations Fever	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	8.7% 2/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Respiratory, thoracic and mediastinal disorders Shortness of Breath	6.9% 2/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	0.00% 0/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Respiratory, thoracic and mediastinal disorders Acute Bronchitis	3.4% 1/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	0.00% 0/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Renal and urinary disorders Acute Humoral Kidney Transplant Rejection	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	4.3% 1/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Cardiac disorders Atrial Arrhythmia	3.4% 1/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	0.00% 0/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Metabolism and nutrition disorders Dehydration	3.4% 1/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	0.00% 0/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Infections and infestations Diabetic Foot Infection	3.4% 1/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	0.00% 0/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Blood and lymphatic system disorders Leukopenia	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	4.3% 1/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Social circumstances Motor Vehicle Accident	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	4.3% 1/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Cardiac disorders Pericardial Effusion	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	4.3% 1/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Respiratory, thoracic and mediastinal disorders Pleural Effusion	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	4.3% 1/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Infections and infestations Pneumonia	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	4.3% 1/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Reproductive system and breast disorders Prostate Cancer	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	4.3% 1/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Infections and infestations Upper Respiratory Infection	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	4.3% 1/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Surgical and medical procedures Ventral Hernia Repair	3.4% 1/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	0.00% 0/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Reproductive system and breast disorders Non-Cardiac Chest Pain	3.4% 1/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	0.00% 0/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Renal and urinary disorders Acute Cellular Kidney Rejection	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	4.3% 1/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.
Surgical and medical procedures Pancreas Transplant	0.00% 0/29 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.	4.3% 1/23 • Adverse Event data collection occurred from Transplant Day 0 to 12 months post-transplant.