Steroid-Free Versus Steroid-Based Immunosuppression in Pediatric Renal (Kidney) Transplantation

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00141037
• Collaborator: Astellas Pharma Inc (Industry), Hoffmann-La Roche (Industry)
• Enrollment: 130
• Locations: 12
• Arms: 2
• Duration (Months): 80
• Patients Per Site: 10.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Over the last 40 years, corticosteroids (steroids) have been an important part of drug regimens used to prevent organ rejection and to maintain the immune health of individuals who have received organ transplants. Unfortunately, the negative physical effects of steroids can be severe, especially in children. The purpose of this study is to determine the safety and effectiveness of a steroid-free treatment regimen for children and adolescents who have received kidney (renal) transplants.

Condition or Disease	Intervention/Treatment	Phase
Kidney Diseases; Kidney Transplantation; Kidney Transplant; Renal Transplantation; Renal Transplant	Drug: Daclizumab; Drug: Mycophenolate mofetil (MMF); Drug: Prednisone; Drug: Tacrolimus; Drug: Ganciclovir; Drug: Valganciclovir; Drug: Trimethoprim and sulfamethoxazole	Phase 1/Phase 2

Detailed Description

Corticosteroids (steroids) have been a cornerstone of immunosuppressive therapy for kidney (renal) transplantation for over 40 years. However, poor growth and bone loss caused by the use of steroids are devastating to pediatric kidney recipients. The negative physical implications of steroid use also greatly impacts patients' compliance to their prescribed steroid-containing regimens.

The development of a steroid-free regimen for post-transplant pediatric patients is sorely needed. This study will evaluate the safety and efficacy of a steroid-free based treatment regimen in children and adolescents who have received kidney transplants, compared to a standard of care steroid-based regimen. Participants in this study will be pediatric patients with end-stage kidney disease who will undergo kidney transplantation at the start of the study.

Patients will participate in this study for 3 years. Participants will be randomized (1:1) to one of two groups. The study includes 23 study visits over 3 years. A physical exam, medication history, adverse events reporting, blood pressure readings, growth assessment, and blood collection will occur at most visits. At the time of transplantation, participants will have a kidney biopsy. Participants will also undergo cataract screening within 4 months of transplantation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 130 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized, Multi-Center Comparative Trial of Tacrolimus w/Steroids and Standard Daclizumab Induction vs a Novel Steroid-Free Tacrolimus Based Immunosuppression Protocol w/ Extended Daclizumab Induction in Pediatric Renal Transplantation
• Study Start Date: Mar 1, 2004
• Actual Primary Completion Date: Sep 1, 2006
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Steroid-Based Immunosuppression Subjects will receive prednisone immunosuppression (10 mg/kg peri-operatively followed by 2 mg/kg/day in subjects weighing <40kg and 1.5 mg/kg/day in subjects weighing >40 kg) and proceed with a prednisone taper according to the trial's protocol.	Drug: Daclizumab; Steroid-Based Immunosuppression(Prednisone) arm: 1 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, and 8 (e.g., standard dose of daclizumab induction until the second month post-transplant) Steroid-Free Immunosuppression (Extended daclizumab induction) arm: 2 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, 8, 11, and months 4, 5, and 6 (e.g., extended daclizumab induction until the sixth month post-transplant); Other Names: ZENAPAX® Humanised Anti-Tac Antibody Ro-24-7375 ; Drug: Mycophenolate mofetil (MMF); Intravenous MMF was dosed at 1200 mg/m^2/day in two divided doses preoperatively and for the first 48 hours postoperatively. Oral MMF was dosed at 600 to 900 mg/m^2/day in two divided doses; the dose range allowed for dose titration according to tolerability and side effects of MMF. This regimen was used in both arms.; Other Names: CellCept® ; Drug: Prednisone; Administered as 10 mg/kg peri-operatively followed by 2 mg/kg/day in subjects weighing <40 kg and 1.5 mg/kg/day in subjects weighing >40 kg. The prednisone dosing was tapered as follows: by the end of wks 1, 2, 4,6,12 and 16, dosages were 0.5, 0.4, 0.3, 0.2, 0.15 and 0.1 mg/kg/day, respectively. The prednisone dose of 0.1 mg/kg was achieved by no later than 6 months post-transplant.; Drug: Tacrolimus; Taken orally from immediately preoperatively to those>age 5 yrs. (starting dose= 0.1 mg/kg/dose twice daily (BID) for living donor recipients; 0.1 mg/kg/dose daily for deceased donor recipients).Subjects <age 5 yrs. received drug from immediately preoperatively at 0.15 mg/kg/dose BID (two preoperative doses) for living donor recipients and 0.15 mg/kg/dose daily (one preoperative dose) for deceased donor recipients. Postoperatively: 0.07 mg/kg/dose BID w/adjustment to achieve target levels of 12-14 ng/mL (days 0-7), 10-12 ng/mL (wks. 2-8), 7-10 ng/mL (wks. 9-12) &5-7 ng/mL >= 12 wks. Evidence of drug toxicity on any protocol biopsy resulted in a further lowering of the drug target level to 4-6 ng/mL before yr 1 & 3-5 ng/mL after yr 1 post-transplant. This regimen was used in both arms.; Other Names: Prograf® ; Drug: Ganciclovir; Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Prophylaxis: All participants will receive intravenous ganciclovir 5 mg/kg/day beginning after transplantation until tolerating oral medications, at which time oral valganciclovir will be initiated and continued for a minimum of 100 days.; Other Names: Cytovene ; Drug: Valganciclovir; Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Prophylaxis: All participants will receive intravenous ganciclovir 5 mg/kg/day beginning after transplantation until tolerating oral medications, at which time oral valganciclovir will be initiated and continued for a minimum of 100 days.; Other Names: Valcyte ; Drug: Trimethoprim and sulfamethoxazole; Pneumocystis pneumonia (PCP)/Urinary Tract Infection (UTI) Prophylaxis: Trimethoprim/sulfamethoxazole (Septra®) 2 mg/kg by mouth will be administered daily at bedtime for a minimum period of the first 6 months post-transplant. If unable to tolerate Septra®, inhaled pentamidine (8 mg/kg to a maximum dose of 300 mg monthly) or Dapsone (2 mg/kg PO to a maximum dose of 100 mg/day) may be substituted for a minimum of the first 6 months post-transplant. For UTI prophylaxis, if Septra® is not tolerated, nitrofurantoin (Macrodantin®), 2.5 mg/kg/day, may be given at bedtime up to a maximum dose of 100 mg/day.; Other Names: Septra®)
Experimental: Steroid-Free Immunosuppression Subjects will receive extended daclizumab induction until the sixth month post-transplant (2 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, 8, 11 and months 4, 5, and 6).	Drug: Daclizumab; Steroid-Based Immunosuppression(Prednisone) arm: 1 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, and 8 (e.g., standard dose of daclizumab induction until the second month post-transplant) Steroid-Free Immunosuppression (Extended daclizumab induction) arm: 2 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, 8, 11, and months 4, 5, and 6 (e.g., extended daclizumab induction until the sixth month post-transplant); Other Names: ZENAPAX® Humanised Anti-Tac Antibody Ro-24-7375 ; Drug: Mycophenolate mofetil (MMF); Intravenous MMF was dosed at 1200 mg/m^2/day in two divided doses preoperatively and for the first 48 hours postoperatively. Oral MMF was dosed at 600 to 900 mg/m^2/day in two divided doses; the dose range allowed for dose titration according to tolerability and side effects of MMF. This regimen was used in both arms.; Other Names: CellCept® ; Drug: Tacrolimus; Taken orally from immediately preoperatively to those>age 5 yrs. (starting dose= 0.1 mg/kg/dose twice daily (BID) for living donor recipients; 0.1 mg/kg/dose daily for deceased donor recipients).Subjects <age 5 yrs. received drug from immediately preoperatively at 0.15 mg/kg/dose BID (two preoperative doses) for living donor recipients and 0.15 mg/kg/dose daily (one preoperative dose) for deceased donor recipients. Postoperatively: 0.07 mg/kg/dose BID w/adjustment to achieve target levels of 12-14 ng/mL (days 0-7), 10-12 ng/mL (wks. 2-8), 7-10 ng/mL (wks. 9-12) &5-7 ng/mL >= 12 wks. Evidence of drug toxicity on any protocol biopsy resulted in a further lowering of the drug target level to 4-6 ng/mL before yr 1 & 3-5 ng/mL after yr 1 post-transplant. This regimen was used in both arms.; Other Names: Prograf® ; Drug: Ganciclovir; Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Prophylaxis: All participants will receive intravenous ganciclovir 5 mg/kg/day beginning after transplantation until tolerating oral medications, at which time oral valganciclovir will be initiated and continued for a minimum of 100 days.; Other Names: Cytovene ; Drug: Valganciclovir; Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Prophylaxis: All participants will receive intravenous ganciclovir 5 mg/kg/day beginning after transplantation until tolerating oral medications, at which time oral valganciclovir will be initiated and continued for a minimum of 100 days.; Other Names: Valcyte ; Drug: Trimethoprim and sulfamethoxazole; Pneumocystis pneumonia (PCP)/Urinary Tract Infection (UTI) Prophylaxis: Trimethoprim/sulfamethoxazole (Septra®) 2 mg/kg by mouth will be administered daily at bedtime for a minimum period of the first 6 months post-transplant. If unable to tolerate Septra®, inhaled pentamidine (8 mg/kg to a maximum dose of 300 mg monthly) or Dapsone (2 mg/kg PO to a maximum dose of 100 mg/day) may be substituted for a minimum of the first 6 months post-transplant. For UTI prophylaxis, if Septra® is not tolerated, nitrofurantoin (Macrodantin®), 2.5 mg/kg/day, may be given at bedtime up to a maximum dose of 100 mg/day.; Other Names: Septra®)

Outcome Measures

Primary Outcome Measures

1. The Difference in Linear Growth by Treatment Assignment at 1 Year Post Kidney Transplantation [One year post kidney transplantation procedure]

   Standardized Z-scores were computed following a formula using an age- and gender-specific calculation provided by the NHANES III 2000 Growth Data set. The Z-score system expresses anthropometric values of height as several standard deviations (SDs) below (e.g., a negative value) or above (a positive value) the reference mean or median value. In this study the measure was used to test whether there is a difference in the change in height between the treatment groups: Steroid-Based versus Steroid-Free

2. Comparison by Treatment Assignment in the Number of Biopsy-Proven Acute Rejections Within 12 Months Post Kidney Transplantation [Up to one year post kidney transplantation procedure]

   Biopsy-proven acute renal (kidney) rejection [1, 2]. Diagnosis of acute rejection was made by renal biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater, with higher scores indicating more severe rejection[2] Ref: Racusen LC et al. The Banff 97 working classification of renal allograft pathology. Kidney Int, 55: 713-723, 1999

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Primary recipient of a kidney transplant

• Meets site-specific transplant criteria

• Panel Reactive Antibody (PRA) of 20% or less

• Willing to use acceptable forms of contraception

• Parent or guardian willing to provide informed consent, if applicable

Exclusion Criteria:

• Previous treatment with steroids within 6 months prior to transplantation

• Received en-bloc kidney or other kidney that does not meet protocol-specified requirements

• Received an organ from an human leukocyte antigen (HLA) identical donor or a non-heart-beating donor

• Received a solid organ other than a kidney

• Received a bone marrow or hematopoietic stem cell transplant

• Received a repeat kidney transplant

• Currently receiving an investigational pharmacologic or biologic agent

• Human Immunodeficiency virus (HIV) infected or infected with another immunodeficiency virus

• Hypersensitivity to murine products or the study drugs or their formulations

• Inability to measure height accurately

• Pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama - Pediatric Nephrology	Birmingham	Alabama	United States	35233
2	Maxine Dunitz Children's Health Center Cedars-Sinai	Los Angeles	California	United States	90048
3	UCLA - Department of Pediatrics, Division of Nephrology	Los Angeles	California	United States	90095-1752
4	Stanford University Medical Center, Lucile Packard Children's Hospital	Palo Alto	California	United States	94304
5	UCSF Children's Hospital	San Francisco	California	United States	94143
6	University of Florida - Pediatric Nephrology	Gainesville	Florida	United States	32610-0296
7	Children's Hospital of New Orleans-Department of Pediatric Nephrology	New Orleans	Louisiana	United States	70118
8	Children's Hospital Boston - Division of Nephrology	Boston	Massachusetts	United States	02115
9	University of Michigan Medical Center, C.S. Mott Children's Hospital- Division of Nephrology & Transplantation	Ann Arbor	Michigan	United States	48109
10	Children's Mercy Hospital - Department of Nephrology	Kansas City	Missouri	United States	64108
11	The Children's Hospital of Philadelphia-Department of Nephrology	Philadelphia	Pennsylvania	United States	19104
12	Children's Hospital & Regional Medical Center - Division of Nephrology	Seattle	Washington	United States	98105

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Astellas Pharma Inc
• Hoffmann-La Roche

Investigators

• Study Chair: Minnie Sarwal, MD, PhD, California Pacific Medical Center
• Principal Investigator: Oscar Salvatierra, MD, Pediatric Kidney Transplant Program, Stanford University Medical Center, Stanford Hospital and Clinics

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)

Publications

• Cole E, Landsberg D, Russell D, Zaltzman J, Kiberd B, Caravaggio C, Vasquez AR, Halloran P. A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients. Transplantation. 2001 Sep 15;72(5):845-50.
• Sarwal MM, Vidhun JR, Alexander SR, Satterwhite T, Millan M, Salvatierra O Jr. Continued superior outcomes with modification and lengthened follow-up of a steroid-avoidance pilot with extended daclizumab induction in pediatric renal transplantation. Transplantation. 2003 Nov 15;76(9):1331-9.
• Vidhun JR, Sarwal MM. Corticosteroid avoidance in pediatric renal transplantation. Pediatr Nephrol. 2005 Mar;20(3):418-26. Epub 2005 Feb 3. Review.
• Vidhun JR, Sarwal MM. Corticosteroid avoidance in pediatric renal transplantation: can it be achieved? Paediatr Drugs. 2004;6(5):273-87. Review.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00141037
• Other Study ID Numbers: DAIT SNS01
• First Posted: Sep 1, 2005
• Last Update Posted: Nov 29, 2016
• Last Verified: Oct 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Organ Rejection; Corticosteroids; Child; Adolescent; Immunosuppression; Steroids
• Additional relevant MeSH terms: Kidney Diseases; Mycophenolic Acid; Trimethoprim; Sulfamethoxazole; Valganciclovir; Ganciclovir; Ganciclovir triphosphate; Prednisone; Tacrolimus; Daclizumab

Study Results

Participant Flow

Recruitment Details	Twelve pediatric kidney transplantation centers in the United States enrolled 130 subjects (less than 21 years of age) who received a primary kidney transplant from a deceased or living donor. Subject enrollment occurred between March 2004 and July 2006.

Arm/Group Title	Steroid-Free Immunosuppression	Steroid-Based Immunosuppression
Arm/Group Description	Subjects received extended daclizumab induction until the sixth month post-transplant (2 mg/kg pretransplant followed by 1 mg/kg at weeks 2, 4, 6, 8, 11 and months 4, 5, and 6), and maintenance combination tacrolimus and mycophenolate mofetil (MMF) immunosuppression. Anti-viral prophylactic treatment included: 1.) gancyclovir or oral valgancyclovir for at least the first 100 days post-transplantation and 2.) trimethoprim/sulfamethoxazole for a minimum first 6 months post-transplantation. Refer to Registration Assigned Interventions for more details.	Subjects received prednisone immunosuppression (10 mg/kg peri-operatively followed by 2 mg/kg/day in subjects weighing <40kg and 1.5 mg/kg/day in subjects weighing >40 kg, tapering according to the trial's protocol), standard daclizumab induction until the second month post transplant (1 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, and 8), and maintenance tacrolimus and mycophenolate mofetil (MMF) immunosuppression. Anti-viral prophylactic treatment included: 1.) gancyclovir or oral valgancyclovir for at least the first 100 days post-transplantation and 2.) trimethoprim/sulfamethoxazole for a minimum first 6 months post-transplantation. Refer to Registration Assigned Interventions for more details.
Period Title: Overall Study
STARTED	60	70
COMPLETED	50	52
NOT COMPLETED	10	18

Baseline Characteristics

Arm/Group Title	Steroid-Free Immunosuppression	Steroid-Based Immunosuppression	Total
Arm/Group Description	Subjects received extended daclizumab induction until the sixth month post-transplant (2 mg/kg pretransplant followed by 1 mg/kg at weeks 2, 4, 6, 8, 11 and months 4, 5, and 6), and maintenance combination tacrolimus and mycophenolate mofetil (MMF) immunosuppression. Anti-viral prophylactic treatment included: 1.) gancyclovir or oral valgancyclovir for at least the first 100 days post-transplantation and 2.) trimethoprim/sulfamethoxazole for a minimum first 6 months post-transplantation. Refer to Registration Assigned Interventions for more details.	Subjects received prednisone immunosuppression (10 mg/kg peri-operatively followed by 2 mg/kg/day in subjects weighing <40kg and 1.5 mg/kg/day in subjects weighing >40 kg, tapering according to the trial's protocol), standard daclizumab induction until the second month post transplant (1 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, and 8), and maintenance tacrolimus and mycophenolate mofetil (MMF) immunosuppression. Anti-viral prophylactic treatment included: 1.) gancyclovir or oral valgancyclovir for at least the first 100 days post-transplantation and 2.) trimethoprim/sulfamethoxazole for a minimum first 6 months post-transplantation. Refer to Registration Assigned Interventions for more details.	Total of all reporting groups
Overall Participants	60	70	130
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.8 (5.4)	11.9 (6.1)	11.9 (5.8)
Sex: Female, Male (Count of Participants)
Female	20 33.3%	28 40%	48 36.9%
Male	40 66.7%	42 60%	82 63.1%
Region of Enrollment (participants) [Number]
United States	60 100%	70 100%	130 100%

Outcome Measures

1. Primary Outcome

Title	The Difference in Linear Growth by Treatment Assignment at 1 Year Post Kidney Transplantation
Description	Standardized Z-scores were computed following a formula using an age- and gender-specific calculation provided by the NHANES III 2000 Growth Data set. The Z-score system expresses anthropometric values of height as several standard deviations (SDs) below (e.g., a negative value) or above (a positive value) the reference mean or median value. In this study the measure was used to test whether there is a difference in the change in height between the treatment groups: Steroid-Based versus Steroid-Free
Time Frame	One year post kidney transplantation procedure

Outcome Measure Data

Analysis Population Description

All Enrolled Subjects

Arm/Group Title	Steroid-Free Immunosuppression	Steroid-Based Immunosuppression
Arm/Group Description	Subjects received extended daclizumab induction until the sixth month post-transplant (2 mg/kg pretransplant followed by 1 mg/kg at weeks 2, 4, 6, 8, 11 and months 4, 5, and 6), and maintenance combination tacrolimus and mycophenolate mofetil (MMF) immunosuppression. Anti-viral prophylactic treatment included: 1.) gancyclovir or oral valgancyclovir for at least the first 100 days post-transplantation and 2.) trimethoprim/sulfamethoxazole for a minimum first 6 months post-transplantation. Refer to Registration Assigned Interventions for more details.	Subjects received prednisone immunosuppression (10 mg/kg peri-operatively followed by 2 mg/kg/day in subjects weighing <40kg and 1.5 mg/kg/day in subjects weighing >40 kg, tapering according to the trial's protocol), standard daclizumab induction until the second month post transplant (1 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, and 8), and maintenance tacrolimus and mycophenolate mofetil (MMF) immunosuppression. Anti-viral prophylactic treatment included: 1.) gancyclovir or oral valgancyclovir for at least the first 100 days post-transplantation and 2.) trimethoprim/sulfamethoxazole for a minimum first 6 months post-transplantation. Refer to Registration Assigned Interventions for more details.
Measure Participants	60	70
Mean (Standard Deviation) [Standard Deviation Score (SDS)]	0.37 (0.76)	0.35 (0.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Steroid-Free Immunosuppression, Steroid-Based Immunosuppression
	Comments	The endpoint is assessed using a Wilcoxon nonparametric test and missing values are imputed using the last observation carried forward.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.79
	Comments
	Method	Wilcoxon Nonparametric Test
	Comments

2. Primary Outcome

Title	Comparison by Treatment Assignment in the Number of Biopsy-Proven Acute Rejections Within 12 Months Post Kidney Transplantation
Description	Biopsy-proven acute renal (kidney) rejection [1, 2]. Diagnosis of acute rejection was made by renal biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater, with higher scores indicating more severe rejection[2] Ref: Racusen LC et al. The Banff 97 working classification of renal allograft pathology. Kidney Int, 55: 713-723, 1999
Time Frame	Up to one year post kidney transplantation procedure

Outcome Measure Data

Analysis Population Description

All Enrolled Subjects

Arm/Group Title	Steroid-Free Immunosuppression	Steroid-Based Immunosuppression
Arm/Group Description	Subjects received extended daclizumab induction until the sixth month post-transplant (2 mg/kg pretransplant followed by 1 mg/kg at weeks 2, 4, 6, 8, 11 and months 4, 5, and 6), and maintenance combination tacrolimus and mycophenolate mofetil (MMF) immunosuppression. Anti-viral prophylactic treatment included: 1.) gancyclovir or oral valgancyclovir for at least the first 100 days post-transplantation and 2.) trimethoprim/sulfamethoxazole for a minimum first 6 months post-transplantation. Refer to Registration Assigned Interventions for more details.	Subjects received prednisone immunosuppression (10 mg/kg peri-operatively followed by 2 mg/kg/day in subjects weighing <40kg and 1.5 mg/kg/day in subjects weighing >40 kg, tapering according to the trial's protocol), standard daclizumab induction until the second month post transplant (1 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, and 8), and maintenance tacrolimus and mycophenolate mofetil (MMF) immunosuppression. Anti-viral prophylactic treatment included: 1.) gancyclovir or oral valgancyclovir for at least the first 100 days post-transplantation and 2.) trimethoprim/sulfamethoxazole for a minimum first 6 months post-transplantation. Refer to Registration Assigned Interventions for more details.
Measure Participants	60	70
Number (95% Confidence Interval) [Rejection Events]	18	19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Steroid-Free Immunosuppression, Steroid-Based Immunosuppression
	Comments	The difference was analyzed using a Fisher's exact test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.85
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Renal (Kidney) transplantation through end of study
Arm/Group Title	Steroid-Based Immunosuppression		Steroid-Free Immunosuppression
Arm/Group Description	Subjects received prednisone immunosuppression (10 mg/kg peri-operatively followed by 2 mg/kg/day in subjects weighing <40kg and 1.5 mg/kg/day in subjects weighing >40 kg, tapering according to the trial's protocol), standard daclizumab induction until the second month post transplant (1 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, and 8), and maintenance tacrolimus and mycophenolate mofetil (MMF) immunosuppression. Anti-viral prophylactic treatment included: 1.) gancyclovir or oral valgancyclovir for at least the first 100 days post transplantation and 2.) trimethoprim/sulfamethoxazole for a minimum first 6 months post-transplantation. Refer to Registration Assigned Interventions for more details.		Subjects received extended daclizumab induction until the sixth month post-transplant (2 mg/kg pretransplant followed by 1 mg/kg at weeks 2, 4, 6, 8, 11 and months 4, 5, and 6), and maintenance combination tacrolimus and mycophenolate mofetil (MMF) immunosuppression. Anti-viral prophylactic treatment included: 1.) gancyclovir or oral valgancyclovir for at least the first 100 days post-transplantation and 2.) trimethoprim/sulfamethoxazole for a minimum first 6 months post-transplantation. Refer to Registration Assigned Interventions for more details.
All Cause Mortality
	Steroid-Based Immunosuppression		Steroid-Free Immunosuppression
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Steroid-Based Immunosuppression		Steroid-Free Immunosuppression
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/70 (85.7%)		52/60 (86.7%)
Blood and lymphatic system disorders
Anaemia	1/70 (1.4%)	1	0/60 (0%)	0
Febrile neutropenia	0/70 (0%)	0	1/60 (1.7%)	1
Leukocytosis	0/70 (0%)	0	1/60 (1.7%)	1
Neutropenia	2/70 (2.9%)	2	0/60 (0%)	0
Cardiac disorders
Atrioventricular block	1/70 (1.4%)	1	0/60 (0%)	0
Cardiac disorder	1/70 (1.4%)	1	0/60 (0%)	0
Pericardial effusion	0/70 (0%)	0	1/60 (1.7%)	1
Pericarditis	1/70 (1.4%)	1	0/60 (0%)	0
Congenital, familial and genetic disorders
Congenital nephrotic syndrome	1/70 (1.4%)	1	0/60 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/70 (1.4%)	1	0/60 (0%)	0
Aphthous stomatitis	0/70 (0%)	0	1/60 (1.7%)	1
Ascites	1/70 (1.4%)	1	0/60 (0%)	0
Colitis	0/70 (0%)	0	1/60 (1.7%)	1
Constipation	0/70 (0%)	0	1/60 (1.7%)	1
Diarrhoea	3/70 (4.3%)	3	3/60 (5%)	4
Faecaloma	1/70 (1.4%)	1	0/60 (0%)	0
Gastric outlet obstruction	1/70 (1.4%)	1	0/60 (0%)	0
Gastro-intestinal fistula	0/70 (0%)	0	1/60 (1.7%)	1
Gastrointestinal necrosis	1/70 (1.4%)	2	0/60 (0%)	0
Intestinal obstruction	1/70 (1.4%)	1	0/60 (0%)	0
Mouth ulceration	0/70 (0%)	0	1/60 (1.7%)	1
Peritoneal haemorrhage	0/70 (0%)	0	1/60 (1.7%)	1
Peritonitis	2/70 (2.9%)	3	0/60 (0%)	0
Small intestinal obstruction	1/70 (1.4%)	1	1/60 (1.7%)	1
General disorders
Adverse drug reaction	1/70 (1.4%)	1	0/60 (0%)	0
Difficulty in walking	0/70 (0%)	0	1/60 (1.7%)	1
Pyrexia	6/70 (8.6%)	6	12/60 (20%)	17
Immune system disorders
Graft loss	3/70 (4.3%)	3	0/60 (0%)	0
Kidney transplant rejection	26/70 (37.1%)	39	18/60 (30%)	32
Transplant rejection	9/70 (12.9%)	12	6/60 (10%)	6
Infections and infestations
Abdominal abscess	1/70 (1.4%)	1	0/60 (0%)	0
Adenovirus infection	0/70 (0%)	0	1/60 (1.7%)	1
Application site abscess	0/70 (0%)	0	1/60 (1.7%)	1
BK virus infection	2/70 (2.9%)	4	0/60 (0%)	0
Bacteraemia	1/70 (1.4%)	1	1/60 (1.7%)	1
Bacterial pyelonephritis	0/70 (0%)	0	1/60 (1.7%)	1
Bronchiolitis	1/70 (1.4%)	2	0/60 (0%)	0
Bronchitis	1/70 (1.4%)	1	0/60 (0%)	0
Cellulitis	1/70 (1.4%)	1	2/60 (3.3%)	2
Central line infection	0/70 (0%)	0	1/60 (1.7%)	3
Clostridial infection	1/70 (1.4%)	1	0/60 (0%)	0
Clostridium colitis	1/70 (1.4%)	1	0/60 (0%)	0
Cytomegalovirus hepatitis	1/70 (1.4%)	1	0/60 (0%)	0
Cytomegalovirus infection	3/70 (4.3%)	3	1/60 (1.7%)	1
Cytomegalovirus viraemia	1/70 (1.4%)	1	0/60 (0%)	0
Empyema	1/70 (1.4%)	1	0/60 (0%)	0
Encephalitis viral	0/70 (0%)	0	1/60 (1.7%)	1
Epstein-Barr virus infection	0/70 (0%)	0	1/60 (1.7%)	1
Febrile infection	1/70 (1.4%)	1	0/60 (0%)	0
Fungaemia	2/70 (2.9%)	3	0/60 (0%)	0
Gastroenteritis	8/70 (11.4%)	8	3/60 (5%)	3
Gastroenteritis rotavirus	1/70 (1.4%)	1	0/60 (0%)	0
Herpes simplex	0/70 (0%)	0	1/60 (1.7%)	1
Herpes zoster	2/70 (2.9%)	2	1/60 (1.7%)	1
Infectious mononucleosis	1/70 (1.4%)	1	0/60 (0%)	0
Influenza	1/70 (1.4%)	1	1/60 (1.7%)	1
Kidney infection	0/70 (0%)	0	1/60 (1.7%)	1
Pharyngitis	0/70 (0%)	0	1/60 (1.7%)	1
Pneumonia	4/70 (5.7%)	6	3/60 (5%)	4
Pneumonia mycoplasmal	1/70 (1.4%)	1	0/60 (0%)	0
Pneumonia primary atypical	0/70 (0%)	0	1/60 (1.7%)	1
Pseudomonal bacteraemia	1/70 (1.4%)	1	0/60 (0%)	0
Pyelonephritis	8/70 (11.4%)	11	7/60 (11.7%)	10
Pyelonephritis acute	0/70 (0%)	0	1/60 (1.7%)	1
Sepsis	0/70 (0%)	0	2/60 (3.3%)	2
Upper respiratory tract infection	3/70 (4.3%)	3	2/60 (3.3%)	2
Urinary tract infection	7/70 (10%)	11	7/60 (11.7%)	7
Urosepsis	0/70 (0%)	0	1/60 (1.7%)	1
Viral infection	1/70 (1.4%)	1	3/60 (5%)	3
Injury, poisoning and procedural complications
Ankle fracture	0/70 (0%)	0	1/60 (1.7%)	1
Collapse of lung	1/70 (1.4%)	1	0/60 (0%)	0
Complications of transplanted kidney	3/70 (4.3%)	3	3/60 (5%)	3
Graft dysfunction	0/70 (0%)	0	2/60 (3.3%)	3
Post procedural complication	1/70 (1.4%)	1	0/60 (0%)	0
Post procedural haemorrhage	2/70 (2.9%)	3	1/60 (1.7%)	1
Postoperative ileus	0/70 (0%)	0	2/60 (3.3%)	2
Procedural complication	0/70 (0%)	0	1/60 (1.7%)	1
Procedural hypotension	0/70 (0%)	0	1/60 (1.7%)	1
Road traffic accident	0/70 (0%)	0	1/60 (1.7%)	1
Treatment noncompliance	1/70 (1.4%)	1	0/60 (0%)	0
Investigations
Activated partial thromboplastin time prolonged	1/70 (1.4%)	1	0/60 (0%)	0
Blood creatinine increased	14/70 (20%)	23	20/60 (33.3%)	41
Blood potassium increased	2/70 (2.9%)	2	0/60 (0%)	0
Blood pressure increased	1/70 (1.4%)	1	0/60 (0%)	0
Cytomegalovirus antibody positive	1/70 (1.4%)	1	0/60 (0%)	0
Cytomegalovirus test positive	2/70 (2.9%)	2	1/60 (1.7%)	1
Drug level below therapeutic	2/70 (2.9%)	2	1/60 (1.7%)	1
Urine output decreased	2/70 (2.9%)	3	0/60 (0%)	0
Metabolism and nutrition disorders
Anorexia	0/70 (0%)	0	1/60 (1.7%)	1
Dehydration	7/70 (10%)	7	3/60 (5%)	4
Diabetes mellitus	3/70 (4.3%)	3	0/60 (0%)	0
Fluid overload	1/70 (1.4%)	1	0/60 (0%)	0
Hypercalcaemia	0/70 (0%)	0	1/60 (1.7%)	1
Hyperkalaemia	2/70 (2.9%)	2	3/60 (5%)	3
Musculoskeletal and connective tissue disorders
Neck mass	0/70 (0%)	0	1/60 (1.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm	0/70 (0%)	0	1/60 (1.7%)	1
Lymphoproliferative disorder	1/70 (1.4%)	1	0/60 (0%)	0
Nervous system disorders
Convulsion	0/70 (0%)	0	1/60 (1.7%)	1
Encephalitis	1/70 (1.4%)	1	0/60 (0%)	0
Headache	1/70 (1.4%)	1	2/60 (3.3%)	2
Psychiatric disorders
Schizophrenia	1/70 (1.4%)	1	0/60 (0%)	0
Renal and urinary disorders
Calculus urinary	0/70 (0%)	0	1/60 (1.7%)	1
Glomerulonephritis focal	0/70 (0%)	0	1/60 (1.7%)	1
Glomerulonephritis membranoproliferative	1/70 (1.4%)	1	0/60 (0%)	0
Haematuria	2/70 (2.9%)	2	2/60 (3.3%)	2
Hydronephrosis	1/70 (1.4%)	1	2/60 (3.3%)	4
Neurogenic bladder	0/70 (0%)	0	1/60 (1.7%)	1
Obstructive uropathy	1/70 (1.4%)	1	0/60 (0%)	0
Oliguria	0/70 (0%)	0	1/60 (1.7%)	1
Pelvi-ureteric obstruction	0/70 (0%)	0	1/60 (1.7%)	1
Renal artery stenosis	1/70 (1.4%)	1	0/60 (0%)	0
Renal failure acute	1/70 (1.4%)	1	1/60 (1.7%)	1
Renal impairment	0/70 (0%)	0	1/60 (1.7%)	1
Renal tubular necrosis	2/70 (2.9%)	2	1/60 (1.7%)	1
Ureteric obstruction	1/70 (1.4%)	2	1/60 (1.7%)	3
Ureteric stenosis	1/70 (1.4%)	1	0/60 (0%)	0
Urethral obstruction	1/70 (1.4%)	1	0/60 (0%)	0
Urinary bladder haemorrhage	0/70 (0%)	0	1/60 (1.7%)	1
Vesicoureteric reflux	2/70 (2.9%)	2	1/60 (1.7%)	1
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/70 (1.4%)	2	0/60 (0%)	0
Pleural effusion	0/70 (0%)	0	1/60 (1.7%)	1
Pneumonia aspiration	0/70 (0%)	0	1/60 (1.7%)	1
Pneumothorax	1/70 (1.4%)	1	0/60 (0%)	0
Pulmonary oedema	0/70 (0%)	0	1/60 (1.7%)	1
Respiratory disorder	0/70 (0%)	0	1/60 (1.7%)	1
Respiratory distress	1/70 (1.4%)	1	0/60 (0%)	0
Sleep apnoea syndrome	1/70 (1.4%)	1	2/60 (3.3%)	2
Stridor	0/70 (0%)	0	1/60 (1.7%)	1
Tonsillar hypertrophy	1/70 (1.4%)	1	2/60 (3.3%)	2
Skin and subcutaneous tissue disorders
Rash	1/70 (1.4%)	1	1/60 (1.7%)	1
Social circumstances
Exposure to communicable disease	1/70 (1.4%)	1	0/60 (0%)	0
Social problem	1/70 (1.4%)	1	0/60 (0%)	0
Surgical and medical procedures
Stent removal	1/70 (1.4%)	1	0/60 (0%)	0
Vascular disorders
Air embolism	1/70 (1.4%)	1	0/60 (0%)	0
Arterial thrombosis	0/70 (0%)	0	1/60 (1.7%)	1
Arteriovenous fistula	1/70 (1.4%)	1	0/60 (0%)	0
Deep vein thrombosis	1/70 (1.4%)	1	0/60 (0%)	0
Hypertension	3/70 (4.3%)	5	1/60 (1.7%)	1
Hypertensive emergency	0/70 (0%)	0	1/60 (1.7%)	2
Hypotension	0/70 (0%)	0	1/60 (1.7%)	1
Lymphocele	1/70 (1.4%)	1	0/60 (0%)	0
Other (Not Including Serious) Adverse Events
	Steroid-Based Immunosuppression		Steroid-Free Immunosuppression
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	64/70 (91.4%)		56/60 (93.3%)
Blood and lymphatic system disorders
Anaemia	21/70 (30%)	21	25/60 (41.7%)	31
Leukopenia	12/70 (17.1%)	22	14/60 (23.3%)	31
Neutropenia	21/70 (30%)	27	24/60 (40%)	38
Gastrointestinal disorders
Diarrhoea	19/70 (27.1%)	31	18/60 (30%)	26
Nausea	5/70 (7.1%)	6	6/60 (10%)	6
Vomiting	8/70 (11.4%)	12	11/60 (18.3%)	16
General disorders
Pyrexia	8/70 (11.4%)	14	13/60 (21.7%)	17
Infections and infestations
BK virus infection	3/70 (4.3%)	4	4/60 (6.7%)	6
Cytomegalovirus infection	6/70 (8.6%)	7	8/60 (13.3%)	8
Ear infection	4/70 (5.7%)	8	6/60 (10%)	7
Epstein-Barr virus infection	4/70 (5.7%)	5	6/60 (10%)	7
Gastroenteritis	5/70 (7.1%)	5	5/60 (8.3%)	6
Otitis media	8/70 (11.4%)	9	9/60 (15%)	16
Sinusitis	8/70 (11.4%)	14	5/60 (8.3%)	8
Upper respiratory tract infection	10/70 (14.3%)	19	20/60 (33.3%)	28
Urinary tract infection	20/70 (28.6%)	32	14/60 (23.3%)	20
Injury, poisoning and procedural complications
Incision site complication	5/70 (7.1%)	5	2/60 (3.3%)	2
Investigations
Blood bicarbonate decreased	4/70 (5.7%)	6	3/60 (5%)	3
Blood creatinine increased	6/70 (8.6%)	10	11/60 (18.3%)	16
Blood pressure increased	2/70 (2.9%)	2	6/60 (10%)	7
Metabolism and nutrition disorders
Hyperkalaemia	10/70 (14.3%)	20	12/60 (20%)	19
Hypomagnesaemia	6/70 (8.6%)	7	6/60 (10%)	6
Hyponatraemia	3/70 (4.3%)	3	4/60 (6.7%)	6
Hypophosphataemia	12/70 (17.1%)	12	10/60 (16.7%)	11
Metabolic acidosis	3/70 (4.3%)	3	5/60 (8.3%)	5
Nervous system disorders
Headache	7/70 (10%)	8	5/60 (8.3%)	7
Respiratory, thoracic and mediastinal disorders
Cough	9/70 (12.9%)	10	9/60 (15%)	10
Nasal congestion	2/70 (2.9%)	2	6/60 (10%)	7
Pharyngolaryngeal pain	5/70 (7.1%)	8	4/60 (6.7%)	4
Rhinorrhoea	6/70 (8.6%)	7	3/60 (5%)	3
Vascular disorders
Hypertension	19/70 (27.1%)	20	14/60 (23.3%)	15

Limitations/Caveats

The results cannot be generalized and daclizumab has since been withdrawn from the United States market (business-related, not due to any safety issues). The study was not powered to definitively evaluate small differences in rejection rate.

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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.