A Study to Assess the Safety and Efficacy of Alefacept in Kidney Transplant Recipients

Study Overview
=================
Brief Summary
-----------------
A study to assess the safety and efficacy of Alefacept in de novo kidney transplant patients.

Detailed Description
-----------------
This is a 4 arm (all active) study to determine the safety and efficacy of Alefacept in de novo kidney transplant recipients.

Official Title
-----------------
A Phase 2, Randomized, Open-Label, Parallel Group, Multi-Center Study to Assess the Safety and Efficacy of Alefacept in de Novo Kidney Transplant Recipients

Conditions
-----------------
Kidney Transplantation

Intervention / Treatment
-----------------
* Drug: Alefacept
* Drug: tacrolimus
* Drug: basiliximab
* Drug: mycophenolate mofetil
* Drug: Corticosteroids


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject is anticipated to receive first oral dose of tacrolimus within 48 hours of transplant procedure Subject is a recipient of a de novo kidney transplant Subject is a recipient of a kidney from a non-human leukocyte antigen (HLA) identical related living donor, a non-related living donor, or a deceased donor Exclusion Criteria: Subject has a screening (pre-operative)estimated cluster of differentiation (CD) 4+ T-cell count of < 250 cells/µL Subject will receive a kidney with an anticipated cold ischemia time (CIT) of > 30 hours Recipient has a positive T or B-cell cross match by investigational site's standard method of determination Subject will receive a kidney from a 50-65 year old deceased donor with one of the following: History of hypertension and a terminal serum creatinine > 1.5 mg/dL Cerebrovascular accident as cause of death and a terminal serum creatinine > 1.5 mg/dL History of hypertension and cerebrovascular accident as cause of death and a terminal serum creatinine > 1.5 mg/dL

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tacrolimus/MMF/Basiliximab<br>Participants received tacrolimus at a starting dose of 0.20 mg/kg/day, mycophenolate mofetil (MMF) 750 or 1000 mg twice daily (BID), basiliximab administered as a 20 mg bolus injection 2 hours prior to transplantation on Day 0 and a 20 mg bolus injection on Day 3 and tapered corticosteroids for 6 months. | Drug: tacrolimus<br>* The initial dose of tacrolimus was administered orally within 48 hours post-transplant. Subsequent doses were to be adjusted to achieve target whole blood trough concentrations.<br>* Other names: Prograf, FK506;Drug: basiliximab<br>* Administered as a 20 mg bolus injection within 2 hours prior to transplantation and a 20 mg bolus injection on Day 3.<br>* Other names: Simulect;Drug: mycophenolate mofetil<br>* Administered at 750 mg twice per day orally or intravenously for patients enrolled under Amendment 6 or earlier and at 1000 mg twice per day orally or intravenously for patients enrolled under Amendment 7. The dose of MMF could be adjusted based on clinical symptoms.<br>* Other names: CellCept, MMF;Drug: Corticosteroids<br>* Corticosteroids were administered as a 500 to 1000 mg intravenous bolus on Day 0 and a 125 to 250 mg methylprednisone (or equivalent oral/intravenous corticosteroid dose) on Day 1. Oral prednisone was to be tapered per protocol.<br>|
| Experimental: Alefacept QW/Tacrolimus/MMF<br>Participants received alefacept administered as a 7.5 mg intravenous (IV) bolus on Days 0 and 3; 15 mg subcutaneously on Day 7 then weekly (QW) for 12 weeks, then 15 mg subcutaneously monthly until the end of month 6, in addition to tacrolimus at a starting dose of 0.10 mg/kg/day, MMF 750 or 1000 mg BID and tapered corticosteroids for 6 months. | Drug: Alefacept<br>* Administered as a 7.5 mg intravenous bolus on day 0 (intraoperatively, prior to kidney revascularization) and Day 3; subsequently administered subcutaneously either weekly or every 2 weeks.<br>* Other names: Amevive, ASP0485;Drug: tacrolimus<br>* The initial dose of tacrolimus was administered orally within 48 hours post-transplant. Subsequent doses were to be adjusted to achieve target whole blood trough concentrations.<br>* Other names: Prograf, FK506;Drug: mycophenolate mofetil<br>* Administered at 750 mg twice per day orally or intravenously for patients enrolled under Amendment 6 or earlier and at 1000 mg twice per day orally or intravenously for patients enrolled under Amendment 7. The dose of MMF could be adjusted based on clinical symptoms.<br>* Other names: CellCept, MMF;Drug: Corticosteroids<br>* Corticosteroids were administered as a 500 to 1000 mg intravenous bolus on Day 0 and a 125 to 250 mg methylprednisone (or equivalent oral/intravenous corticosteroid dose) on Day 1. Oral prednisone was to be tapered per protocol.<br>|
| Experimental: Alefacept QW/Tacrolimus<br>Participants received alefacept administered as a 7.5 mg IV bolus on Days 0 and 3; 15 mg subcutaneously on Day 7 then weekly for 12 weeks, then 15 mg subcutaneously monthly until the end of month 6, in addition to tacrolimus at a starting dose of 0.20 mg/kg/day, and tapered corticosteroids for 6 months. | Drug: Alefacept<br>* Administered as a 7.5 mg intravenous bolus on day 0 (intraoperatively, prior to kidney revascularization) and Day 3; subsequently administered subcutaneously either weekly or every 2 weeks.<br>* Other names: Amevive, ASP0485;Drug: tacrolimus<br>* The initial dose of tacrolimus was administered orally within 48 hours post-transplant. Subsequent doses were to be adjusted to achieve target whole blood trough concentrations.<br>* Other names: Prograf, FK506;Drug: Corticosteroids<br>* Corticosteroids were administered as a 500 to 1000 mg intravenous bolus on Day 0 and a 125 to 250 mg methylprednisone (or equivalent oral/intravenous corticosteroid dose) on Day 1. Oral prednisone was to be tapered per protocol.<br>|
| Experimental: Alefacept QOW/Tacrolimus/MMF<br>Participants received alefacept administered as a 7.5 mg IV bolus on Days 0 and 3; 30 mg subcutaneously on Day 7 then weekly for 12 weeks, then 15 mg subcutaneously monthly until the end of month 6, in addition to tacrolimus at a starting dose of 0.10 mg/kg/day, MMF 750 or 1000 mg BID, and tapered corticosteroids for 6 months. | Drug: Alefacept<br>* Administered as a 7.5 mg intravenous bolus on day 0 (intraoperatively, prior to kidney revascularization) and Day 3; subsequently administered subcutaneously either weekly or every 2 weeks.<br>* Other names: Amevive, ASP0485;Drug: tacrolimus<br>* The initial dose of tacrolimus was administered orally within 48 hours post-transplant. Subsequent doses were to be adjusted to achieve target whole blood trough concentrations.<br>* Other names: Prograf, FK506;Drug: mycophenolate mofetil<br>* Administered at 750 mg twice per day orally or intravenously for patients enrolled under Amendment 6 or earlier and at 1000 mg twice per day orally or intravenously for patients enrolled under Amendment 7. The dose of MMF could be adjusted based on clinical symptoms.<br>* Other names: CellCept, MMF;Drug: Corticosteroids<br>* Corticosteroids were administered as a 500 to 1000 mg intravenous bolus on Day 0 and a 125 to 250 mg methylprednisone (or equivalent oral/intravenous corticosteroid dose) on Day 1. Oral prednisone was to be tapered per protocol.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Biopsy-confirmed Acute Rejection (BCAR) at Month 6 Assessed by Local Review | Rejection episodes were confirmed by biopsy by the clinical site pathologist. Biopsies were graded according to the 2005 Banff criteria. All biopsies (T-cell and/or antibody mediated) of grade 1 or higher were considered a BCAR. The Kaplan-Meier estimates at Day 182 was used for the analyses at 6 months. Lost to follow-up or patients with missing outcomes were censored at their last follow up visit. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Survival at Month 6 and Month 12 | Patient survival is any participant who is known to be alive 6 months and 12 months after the skin closure date. The Kaplan-Meier estimates at Days 182 and 365 were used for the analyses at 6 months and 12 months respectively. Lost to follow-up or participants with missing outcomes were censored at their last follow up visit. | 6 months and 12 months | 
| Graft Survival at Month 6 and Month 12 | Graft survival was defined as any participant who was known to have a functioning graft (i.e., not graft loss) at 6 months and 12 months after the skin closure date. Graft loss was defined as patient death, retransplant, permanent return to dialysis (dialysis greater than 30 days) or transplant nephrectomy. The Kaplan-Meier estimates at Days 182 and 365 were used for the analyses at 6 months and 12 months respectively. Lost to follow-up or participants with missing outcomes were censored at their last follow up visit. | 6 months and 12 months | 
| Percentage of Participants With BCAR at Month 12 Assessed by Local Review | Rejection episodes were confirmed by biopsy by the clinical site pathologist. Biopsies were graded according to the 2005 Banff criteria. All biopsies (T-cell and/or antibody mediated) of grade 1 or higher were considered a BCAR. The Kaplan-Meier estimates at Day 365 was used for the analyses at 12 months. Lost to follow-up or participants with missing outcomes were censored at their last follow up visit. | 12 months | 
| Percentage of Participants With BCAR at Month 6 and 12 Assessed by Central Review | Rejection episodes were confirmed by biopsy by a central reviewer. Biopsies were graded according to the 2005 Banff criteria. All biopsies (T-cell and/or antibody mediated) of grade 1 or higher were considered a BCAR. The Kaplan-Meier estimates at Days 182 and 365 were used for the analyses at 6 months and 12 months respectively. Lost to follow-up or participants with missing outcomes were censored at their last follow up visit. | 6 months and 12 months | 
| Percentage of Participants With T-cell Mediated BCAR at Month 6 and 12 Assessed by Local Review | Rejection episodes were confirmed by biopsy by the clinical site pathologist. Biopsies were graded according to the 2005 Banff criteria. All biopsies of grade 1 or higher were considered a BCAR. The Kaplan-Meier estimates at Days 182 and 365 were used for the analyses at 6 months and 12 months respectively. Lost to follow-up or participants with missing outcomes were censored at their last follow up visit. | 6 months and 12 months | 
| Percentage of Participants With T-cell Mediated BCAR at Month 6 and 12 Assessed by Central Review | Rejection episodes were confirmed by biopsy by the central reviewer. Biopsies were graded according to the 2005 Banff criteria. All biopsies of grade 1 or higher were considered a BCAR. The Kaplan-Meier estimates at Days 182 and 365 were used for the analyses at 6 months and 12 months respectively. Lost to follow-up or participants with missing outcomes were censored at their last follow up visit. | 6 months and 12 months | 
| Change From Week 4 in Glomerular Filtration Rate Estimated by the MDRD Method at Month 6 and Month 12 | The glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease (MDRD) method. | Week 4, Month 6 and Month 12 | 
| Change From Week 4 in GFR by Iothalamate Clearance at Month 6 | The glomerular filtration rate was measured directly using iothalamate clearance. | Week 4 and Month 6 | 
| Change From Week 4 in Serum Creatinine at Month 6 and 12 |  | Week 4 and Month 6 and 12 | 
| Percentage of Participants With Efficacy Failure at 6 and 12 Months Assessed by Local Review | Efficacy failure is defined as death, graft failure (permanent return to dialysis [>30 days] or retransplant), BCAR according to local review, or lost to follow-up. | 6 months and 12 months | 
| Percentage of Participants With Efficacy Failure at 6 and 12 Months Assessed by Central Review | Efficacy failure is defined as death, graft failure (permanent return to dialysis [>30 days] or retransplant), BCAR according to central review, or lost to follow-up. | 6 months and 12 months | 
| Time to First BCAR Assessed by Local Review | The time to first BCAR (local review) was calculated as the first biopsy date in which the local reviewer confirmed an acute rejection minus the date of skin closure +1. Only participants with a BCAR are included in the analysis. | 12 months | 
| Time to First BCAR Assessed by Central Review | The time to first BCAR (central review) was calculated as the first biopsy date in which the central reviewer confirmed an acute rejection minus the date of skin closure +1. Only participants with a BCAR are included in the analysis. | 12 months | 
| Time to First T-cell Mediated BCAR Assessed by Local Review | The time to first T-cell mediated BCAR (local review) was calculated as the first biopsy date in which the local reviewer confirmed an acute rejection minus the date of skin closure +1. | 12 months | 
| Time to First T-cell Mediated BCAR Assessed by Central Review | The time to first T-cell mediated BCAR (central review) was calculated as the first biopsy date in which the central reviewer confirmed an acute rejection minus the date of skin closure +1. Only participants with a T-cell mediated BCAR are included in the analysis. | 12 months | 
| Maximum Grade of T-cell Mediated Rejection Assessed by Local Review | The grade of acute T-cell mediated rejection was classified as IA, IB, IIA, IIB and III according to Banff 2005 criteria. If a patient had more than 1 T-cell mediated rejection, the episode with the most severe grade was used in the analysis. Grade IA: Cases with significant interstitial infiltration (> 25% of parenchyma affected) and foci of moderate tubulitis; Grade IB: Cases with significant interstitial infiltration (> 25% of parenchyma affected) and foci of severe tubulitis; Grade IIA: Cases with mild to moderate intimal arteritis; Grade IIB: Cases with severe intimal arteritis comprising >25% of the luminal area; Grade III: Cases with transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation. | 6 months and 12 months | 
| Maximum Grade of T-cell Mediated Rejection as Assessed by Central Review | The grade of acute T-cell mediated rejection was classified as IA, IB, IIA, IIB and III according to Banff 2005 criteria. If a patient had more than 1 T-cell mediated rejection, the episode with the most severe grade was used in the analysis. Grade IA: Cases with significant interstitial infiltration (> 25% of parenchyma affected) and foci of moderate tubulitis; Grade IB: Cases with significant interstitial infiltration (> 25% of parenchyma affected) and foci of severe tubulitis; Grade IIA: Cases with mild to moderate intimal arteritis; Grade IIB: Cases with severe intimal arteritis comprising >25% of the luminal area; Grade III: Cases with transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation. | 6 months and 12 months | 
| Percentage of Participants With Clinically Treated Acute Rejection at Month 6 and Month 12 | Patients who received immunosuppressive medications for the treatment of suspected or BCAR were considered to have a clinically-treated acute rejection. | 6 months and 12 months | 
| Percentage of Participants With Anti-lymphocyte-treated Rejection at Months 6 and 12 | Participants with histologically proved Banff Grade II or III rejection could receive anti-rejection therapy with anti-lymphocyte antibodies per institutional protocol. The use of anti-lymphocyte antibody therapy at any time during a suspected or proven rejection episode for the treatment of acute rejection was considered an event. | 6 months and 12 months | 
| Percentage of Participants With Multiple Rejection Episodes at Months 6 and 12 | All participants were evaluated for the incidence of multiple rejection episodes (clinically treated and/or BCAR as assessed by the local reviewer) through 6 months and 12 months. | 6 months and 12 months | 
| Percentage of Participants With Treatment Failure at Month 6 and 12 | Treatment failure was defined as death, graft loss, BCAR (local review), lost to follow-up or early discontinuation of treatment regimen. The Kaplan-Meier estimates at Days 182 and 365 were used for the analyses at 6 months and 12 months respectively. Lost to follow-up or participants with missing outcomes were censored at their last follow up visit. | 6 months and 12 months | 
| Gastrointestinal Quality of Life Index Score Over Time | The impact of gastrointestinal (GI) symptoms on health-related quality of life was assessed using the Gastrointestinal Quality of Life Index (GIQLI) symptom severity score. The GIQLI is a 36-item self-administered questionnaire that assesses the impact of gastrointestinal symptoms during the past 2 weeks on a scale from 0 (all of the time) to 4 (never). Possible overall scores ranged from 0 to 4, with higher scores indicating a better quality of life according to the different symptomatic criteria. | Months 1, 3, 6, and 12 | 
| Gastrointestinal Symptom Rating Scale Scores Over Time | The impact of gastrointestinal (GI) symptoms on health-related quality of life was assessed using the Gastrointestinal Symptom Rating Scale Scores (GSRS). The GSRS a 15-item self-administered questionnaire that assesses the impact of gastrointestinal symptoms during the past week on a scale from 1 (no discomfort at all) to 7 (very severe discomfort). Possible overall scores range from 1 to 7, with lower scores indicating a better quality of life with respect to gastrointestinal symptoms. | Months 1, 3, 6, and 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
kidney transplant, alefacept