A Study to Assess Immune Response in Pediatric Kidney Transplant Recipients Treated With Daclizumab (Zenapax)

Study Overview
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Brief Summary
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This study will assess whether daclizumab impairs the ability of children receiving a kidney transplant to elicit a primary immune response. The anticipated time on study treatment is 1 day, and the target sample size is 82 individuals.

Official Title
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Immune Response to Neoantigen and Recall Antigen in Pediatric Renal Transplant Recipients Treated With the IL-2R Alfa Monoclonal Antibody, Daclizumab (Zenapax®)

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Biological: DT
* Drug: Daclizumab
* Biological: KLH


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary renal transplant recipients between 2 and 19 years of age Receiving or have received daclizumab in the previous 4-18 months Receiving or have received daclizumab less than (<) 24 hours pretransplant and additional courses every other week Single organ recipients (kidney only) Previous vaccination with tetanus toxoid (TT) prior to transplant Receiving a maintenance immunosuppression regimen of a calcineurin inhibitor, mycophenolate mofetil, and prednisone (or equivalent corticosteroid) Exclusion Criteria: Received intravenous gamma globulin or a TT vaccination since transplant Experienced rejection within 3 months of receiving study vaccinations and/or treated with lymphocyte preparation or methylprednisolone to reverse suspected acute rejection within 3 months of receiving study vaccinations Received any vaccine within 30 days of receiving study vaccinations Received plasmapheresis treatment or growth hormone treatment since transplant

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (With Daclizumab Therapy)<br>Participants who were receiving a full course of 5 doses of daclizumab (1 milligram per kilogram [mg/kg]) with Day 1 vaccine administered immediately prior to the fifth dose. | Biological: DT<br>* Diphtheria and Tetanus Toxoid (DT) will be administered intramuscularly as a 1/3 dilution (0.33 flocculation units). The participants will be rechallenged with DT 6 months after Day 29 if failed to show >=1.5 fold increase in lymphocyte proliferative response but have a humoral response.<br>Drug: Daclizumab<br>* The fifth dose (1 milligram per kilogram [mg/kg]) of daclizumab will be administered in this study to participants who already received four doses (one dose at 1 mg/kg within 24 hours post-transplant and then every other week for 3 doses).<br>* Other names: Zenapax;Biological: KLH<br>* KLH will be administered intradermally with a dose of 250 mcg for participants aged 2 to less than 12 years, and 500 mcg for participants aged 12 to 19 years. The participants will be rechallenged with KLH 6 months after Day 29 if failed to show specified increase in lymphocyte proliferative response or humoral response.<br>|
| Active Comparator: Group B (Post Daclizumab Therapy)<br>Participants who completed a full course of daclizumab therapy in the previous 4 to 18 months. | Biological: DT<br>* Diphtheria and Tetanus Toxoid (DT) will be administered intramuscularly as a 1/3 dilution (0.33 flocculation units). The participants will be rechallenged with DT 6 months after Day 29 if failed to show >=1.5 fold increase in lymphocyte proliferative response but have a humoral response.<br>Biological: KLH<br>* KLH will be administered intradermally with a dose of 250 mcg for participants aged 2 to less than 12 years, and 500 mcg for participants aged 12 to 19 years. The participants will be rechallenged with KLH 6 months after Day 29 if failed to show specified increase in lymphocyte proliferative response or humoral response.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Developed a Positive Antibody Response (IgG) to Keyhole Limpet Hemocyanin (KLH) Immunization | Positive antibody response was defined as at least a 2-fold increase in antibody concentration on either Day 43 or Day 57 compared with baseline where baseline was assigned a value of 1 if it was below the limit of quantification. All humoral responses were assessed by enzyme-linked immunosorbent assay (ELISA). | Baseline and Day 43 or Day 57 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Developed a Positive Cellular Response to KLH Immunization | Positive cellular response was defined as an increase in the 5-bromo-2-deoxyuridine (BrdU) percent total net of at least 1.5-fold compared with baseline, where baseline was assigned a value of 0.5 if <=0, on at least one time point on Days 22, 29, 43 or 57. All cellular responses were assessed by BrdU proliferation assay. | Baseline, Day 22, Day 29, Day 43, and Day 57 | 
| Number of Participants Who Developed Both a Positive Antibody Response and a Positive Cellular Response to KLH Immunization | Positive antibody response was defined as at least a 2-fold increase in antibody concentration on either Day 43 or Day 57 compared with baseline where baseline was assigned a value of 1 if it was below the limit of quantification. Positive cellular response was defined as an increase in the 5-bromo-2-deoxyuridine (BrdU) percent total net of at least 1.5-fold compared with baseline, where baseline was assigned a value of 0.5 if <=0, on at least one time point on Days 22, 29, 43 or 57. All humoral responses were assessed by ELISA and all cellular responses were assessed by BrdU proliferation assay. | Baseline, Day 22, Day 29, Day 43 and Day 57 | 
| Number of Participants Who Developed a Positive Humoral Response to Tetanus Toxoid (TT) | Humoral response to TT was defined as >=1.5 fold increase in antibody concentration from baseline in participants with protective anti-TT IgG level >=0.1 IU/mL. All humoral responses were assessed by ELISA. | Baseline, Day 22, Day 29, Day 43 and Day 57 | 
| Number of Participants Who Developed a Positive Cellular Response to Tetanus Toxoid (TT) | Positive cellular response was defined as an increase in the BrdU percent total net of at least 1.5-fold compared with baseline, where baseline was assigned a value of 0.5 if <=0, on at least one time point on days 22, 29, 43 or 57. All cellular responses were assessed by BrdU proliferation assay. | Baseline, Day 22, Day 29, Day 43 and Day 57 | 
| Number of Participants Who Developed a Positive Antibody Response to KLH and Positive Cellular Responses to Both KLH and TT Immunizations | Positive antibody response was defined as at least a 2-fold increase in antibody concentration on either Day 43 or Day 57 compared with baseline where baseline was assigned a value of 1 if it was below the limit of quantification. Positive cellular response was defined as an increase in the 5-bromo-2-deoxyuridine (BrdU) percent total net of at least 1.5-fold compared with baseline, where baseline was assigned a value of 0.5 if <=0, on at least one time point on Days 22, 29, 43 or 57. All humoral responses were assessed by ELISA and all cellular responses were assessed by BrdU proliferation assay. | Baseline, Day 22, Day 29, Day 43 and Day 57 | 
| Number of KLH Cellular Nonresponders Who Were Rechallenged and Mounted a Cellular Response to KLH Immunization | Nonresponders (participants who failed to mount cellular responses to KLH) were rechallenged with KLH 6 months after Day 29 (Day 196). For nonresponders, positive cellular response to KLH was defined as an increase in the 5-bromo-2-deoxyuridine (BrdU) percent total net of at least 1.5-fold compared with baseline, where baseline was assigned a value of 0.5 if <=0, on at least one time point up to Day 252. All cellular responses were assessed by BrdU proliferation assay. | Up to Day 252 | 
| Number of Tetanus Cellular Nonresponders Who Were Rechallenged and Mounted a Cellular Tetanus Response | Nonresponders (participants who mount humoral responses but no cellular responses to tetanus vaccination) were rechallenged with TT 6 months after Day 29 (Day 196). For nonresponders, positive cellular response to TT was defined as an increase in the BrdU percent total net of at least 1.5-fold compared with baseline, where baseline was assigned a value of 0.5 if <=0, at any time point up to Day 252. All cellular responses were assessed by BrdU proliferation assay. | up to Day 252 | 
| Geometric Mean Antibody Concentrations for KLH (IgM and IgG) and TT (IgG) | Due to the small number of participants enrolled in the study, geometric means at Baseline and on Days 22, 29, 43 and 57 were not reported. | Screening, Day 22, Day 29, Day 43 and Day 57 | 
| Mean Percent Expression of 2A3/CD25+ Antibody | CD25 is an antigen that is present on a subset of peripheral blood lymphocytes. The expression of CD25+ on T cell was investigated using antibody 2A3. Blood samples were drawn for evaluation of CD25+ at screening and on Days 29, 57, and 168. | Screening, Day 29, Day 57 and Day 168 | 
| Mean Percent Expression of CD3, CD4, and CD8 | Blood samples were obtained for flow activated cell sorter (FACS) analyses of T cell subsets (CD3, CD4, and CD8) on Days 1, 22, 29, 43, and 57. These cells are present on white blood cells and are used as markers to associate cells with immune functions. | Days 1, 22, 29, 43 and 57 | 
| Mean Percent Expression of HLA-DR+, CD45RO+ and CD45RA+ | Blood samples were obtained for flow activated cell sorter (FACS) analyses of HLA-DR+, CD45RO+ and CD45RA+ on Days 1, 29, and 57. These cells are present on white blood cells and are used as markers to associate cells with immune functions. | Days 1, 29 and 57 | 
| Percentage of Participants With Positive Antibody Response to KLH Immunization at Month 6 | Positive antibody response was defined as at least a 2-fold increase in antibody concentration on Month 6 compared with baseline where baseline was assigned a value of 1 if it was below the limit of quantification. All humoral responses were assessed by enzyme-linked immunosorbent assay (ELISA). Due to the small number of participants enrolled in the study, percentage of participants with positive antibody response to KLH immunization at Month 6 was not reported. | Month 6 | 
| Number of KLH Antibody Nonresponders Who Underwent Rechallenge and Mounted a KLH Antibody Response | Nonresponders (participants who failed to mount antibody responses to KLH) were rechallenged with KLH 6 months after Day 29 (Day 196). For nonresponders, positive antibody response to KLH was defined as at least a 2-fold increase in antibody concentration at any time point up to Day 252 compared with baseline where baseline was assigned a value of 1 if it was below the limit of quantification. All humoral responses were assessed by enzyme-linked immunosorbent assay (ELISA). | Up to Day 252 | 
| Number of Participants With a Positive Delayed Type Hypersensitivity (DTH) Response After KLH Immunization | DTH skin reactions were assessed 48 hours after each KLH immunization given on Day 1 and on Day 29. A positive response was defined as an induration >=5 mm. | Day 1 and Day 29 | 
| Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is a significant medical event in the investigator's judgment or requires intervention to prevent one or other of these outcomes | Up to Month 12 |