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

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

A study to assess the safety and efficacy of Alefacept in de novo kidney transplant patients.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: tacrolimus; Drug: basiliximab; Drug: mycophenolate mofetil; Drug: Corticosteroids; Drug: Alefacept

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 323
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Los Angeles, California, United States, 90033
      • University of Southern California - University Hospital
    • Los Angeles, California, United States, 90057
      • St. Vincent/National Institute of Transplantation
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
    • San Diego, California, United States, 92103
      • UCSD
    • San Diego, California, United States, 92123
      • California Institute of Renal Research/Sharp Memorial Hospital
    • San Francisco, California, United States, 94143
      • University of California - San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Health Science Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida, Shands Hospital, Gainesville
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
  • Georgia
    • Augusta, Georgia, United States, 30921
      • Medical College of Georgia, Augusta
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
    • Chicago, Illinois, United States, 60612
      • Rush - Presbyterian - St. Lukes Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • St. Barnabas Medical Center
  • New York
    • Buffalo, New York, United States, 14203
      • Buffalo General Hospital
    • New York, New York, United States, 10029
      • Mt. Sinai School of Medicine
    • New York, New York, United States, 10065
      • New York Presbyterian Hospital - Cornell
    • Valhalla, New York, United States, 10595
      • Westchester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospital of Cleveland
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
    • Portland, Oregon, United States, 97210
      • Legacy Transplant Services
  • Pennsylvania
    • Harrisburg, Pennsylvania, United States, 17101
      • Pinnacle Health at Harrisburg
    • Philadelphia, Pennsylvania, United States, 19104
      • UNIVERSITY of PENNSYLVANIA
  • Tennessee
    • Memphis, Tennessee, United States, 38104
      • Methodist University Hospital - Memphis
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • Methodist Hospital Research Institute of Houston
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Medical Center
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University School of Medicine
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tacrolimus/MMF/Basiliximab; 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; 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.; Other Names: Prograf, FK506; Drug: basiliximab; Administered as a 20 mg bolus injection within 2 hours prior to transplantation and a 20 mg bolus injection on Day 3.; Other Names: Simulect; Drug: mycophenolate mofetil; 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.; Other Names: CellCept, MMF; Drug: Corticosteroids; 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.
Experimental: Alefacept QW/Tacrolimus/MMF; 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: tacrolimus; 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.; Other Names: Prograf, FK506; Drug: mycophenolate mofetil; 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.; Other Names: CellCept, MMF; Drug: Corticosteroids; 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.; Drug: Alefacept; 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.; Other Names: Amevive, ASP0485
Experimental: Alefacept QW/Tacrolimus; 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: tacrolimus; 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.; Other Names: Prograf, FK506; Drug: Corticosteroids; 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.; Drug: Alefacept; 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.; Other Names: Amevive, ASP0485
Experimental: Alefacept QOW/Tacrolimus/MMF; 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: tacrolimus; 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.; Other Names: Prograf, FK506; Drug: mycophenolate mofetil; 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.; Other Names: CellCept, MMF; Drug: Corticosteroids; 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.; Drug: Alefacept; 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.; Other Names: Amevive, ASP0485

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

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc
• Investigators: Principal Investigator: Principal Investigator, University of Michigan

Publications and helpful links

Helpful Links

• Link to results on JAPIC

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (Actual): February 1, 2011
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: October 11, 2007
• First Submitted That Met QC Criteria: October 12, 2007
• First Posted (Estimate): October 15, 2007

Study Record Updates

• Last Update Posted (Estimate): December 11, 2015
• Last Update Submitted That Met QC Criteria: November 6, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: kidney transplant; alefacept
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Basiliximab; Alefacept
• Other Study ID Numbers: 0485-CL-U201