A Phase 1/2 interventional study of Daclizumab and Mycophenolate mofetil (MMF) in Kidney Diseases, Kidney Transplantation and Kidney Transplant, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 12 sites in United States. Open to participants aged Up to 21 Years. Per ClinicalTrials.gov, last updated 2016-11-29.
Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 1/2, Interventional, and Treatment
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.
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.
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This study's enrollment of 130 is above the median of 70 across 2,640 interventional studies indexed under Kidney Diseases.
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Exclusion Criteria:
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 · Drug: Mycophenolate mofetil (MMF) · Drug: Prednisone · Drug: Tacrolimus · Drug: Ganciclovir · Drug: Valganciclovir · Drug: Trimethoprim and sulfamethoxazole
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 · Drug: Mycophenolate mofetil (MMF) · Drug: Tacrolimus · Drug: Ganciclovir · Drug: Valganciclovir · Drug: Trimethoprim and sulfamethoxazole
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)
Also known as: ZENAPAX®, Humanised Anti-Tac Antibody, Ro-24-7375
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.
Also known as: CellCept®
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.
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.
Also known as: Prograf®
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.
Also known as: Cytovene
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.
Also known as: Valcyte
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.
Also known as: Septra®)
The Difference in Linear Growth by Treatment Assignment at 1 Year Post Kidney Transplantation
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
Comparison by Treatment Assignment in the Number of Biopsy-Proven Acute Rejections Within 12 Months Post Kidney Transplantation
Biopsy-proven acute renal (kidney) rejection \[1, 2\]. 1. 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\[2\] 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
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.
| Milestone | Steroid-Free Immunosuppression | Steroid-Based Immunosuppression |
|---|---|---|
| Started | 60 | 70 |
| Completed | 50 | 52 |
| Not completed | 10 | 18 |
| Withdrew: Physician decision | 1 | 2 |
| Withdrew: Lost to follow-up | 3 | 1 |
| Withdrew: Protocol violation | 0 | 2 |
| Withdrew: Withdrawal by subject | 2 | 1 |
| Withdrew: Other | 0 | 1 |
| Withdrew: Moved from area | 1 | 7 |
| Withdrew: Graft failure | 3 | 4 |
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
| Standard Deviation Score (SDS) | Steroid-Free Immunosuppression | Steroid-Based Immunosuppression |
|---|---|---|
| The Difference in Linear Growth by Treatment Assignment at 1 Year Post Kidney Transplantation | 0.37 ± 0.76 | 0.35 ± 0.82 |
Biopsy-proven acute renal (kidney) rejection \[1, 2\]. 1. 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\[2\] 2. Ref: Racusen LC et al. The Banff 97 working classification of renal allograft pathology. Kidney Int, 55: 713-723, 1999
| Rejection Events | Steroid-Free Immunosuppression | Steroid-Based Immunosuppression |
|---|---|---|
| Comparison by Treatment Assignment in the Number of Biopsy-Proven Acute Rejections Within 12 Months Post Kidney Transplantation | 18 (17.85 to 43.21) | 19 (17.20 to 39.10) |
Collected over Renal (Kidney) transplantation through end of study. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Steroid-Based Immunosuppression | — | 60/70 (85.7%) | 64/70 (91.4%) |
| Steroid-Free Immunosuppression | — | 52/60 (86.7%) | 56/60 (93.3%) |
| Event | Steroid-Based Immunosuppression | Steroid-Free Immunosuppression |
|---|---|---|
| Kidney transplant rejectionImmune system disorders | 26/70 | 18/60 |
| Blood creatinine increasedInvestigations | 14/70 | 20/60 |
| PyrexiaGeneral disorders | 6/70 | 12/60 |
| Transplant rejectionImmune system disorders | 9/70 | 6/60 |
| PyelonephritisInfections and infestations | 8/70 | 7/60 |
| Urinary tract infectionInfections and infestations | 7/70 | 7/60 |
| GastroenteritisInfections and infestations | 8/70 | 3/60 |
| DehydrationMetabolism and nutrition disorders | 7/70 | 3/60 |
| PneumoniaInfections and infestations | 4/70 | 3/60 |
| DiarrhoeaGastrointestinal disorders | 3/70 | 3/60 |
| Event | Steroid-Based Immunosuppression | Steroid-Free Immunosuppression |
|---|---|---|
| AnaemiaBlood and lymphatic system disorders | 21/70 | 25/60 |
| NeutropeniaBlood and lymphatic system disorders | 21/70 | 24/60 |
| Upper respiratory tract infectionInfections and infestations | 10/70 | 20/60 |
| DiarrhoeaGastrointestinal disorders | 19/70 | 18/60 |
| Urinary tract infectionInfections and infestations | 20/70 | 14/60 |
| HypertensionVascular disorders | 19/70 | 14/60 |
| LeukopeniaBlood and lymphatic system disorders | 12/70 | 14/60 |
| PyrexiaGeneral disorders | 8/70 | 13/60 |
| HyperkalaemiaMetabolism and nutrition disorders | 10/70 | 12/60 |
| VomitingGastrointestinal disorders | 8/70 | 11/60 |
| Age, Continuous(years) | Steroid-Free Immunosuppression | Steroid-Based Immunosuppression | Total |
|---|---|---|---|
| Mean | 11.8 ± 5.4 | 11.9 ± 6.1 | 11.9 ± 5.8 |
| Sex: Female, Male(Participants) | Steroid-Free Immunosuppression | Steroid-Based Immunosuppression | Total |
|---|---|---|---|
| Female | 20 | 28 | 48 |
| Male | 40 | 42 | 82 |
| Region of Enrollment(participants) | Steroid-Free Immunosuppression | Steroid-Based Immunosuppression | Total |
|---|---|---|---|
| United States | 60 | 70 | 130 |
Plan to share: Yes — Participant level data and additional relevant materials are available to the public in the Immunology Database and Analysis Portal (ImmPort). ImmPort is a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
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