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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc
ClinicalTrials.gov Identifier:
NCT00543569
First received: October 11, 2007
Last updated: November 6, 2015
Last verified: November 2015
  Purpose
A study to assess the safety and efficacy of Alefacept in de novo kidney transplant patients.

Condition Intervention Phase
Kidney Transplantation
Drug: Alefacept
Drug: tacrolimus
Drug: basiliximab
Drug: mycophenolate mofetil
Drug: Corticosteroids
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Astellas Pharma Inc:

Primary Outcome Measures:
  • Percentage of Participants With Biopsy-confirmed Acute Rejection (BCAR) at Month 6 Assessed by Local Review [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Patient Survival at Month 6 and Month 12 [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]

    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.


  • Graft Survival at Month 6 and Month 12 [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]

    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.


  • Percentage of Participants With BCAR at Month 12 Assessed by Local Review [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    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.


  • Percentage of Participants With BCAR at Month 6 and 12 Assessed by Central Review [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]

    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.


  • Percentage of Participants With T-cell Mediated BCAR at Month 6 and 12 Assessed by Local Review [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]

    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.


  • Percentage of Participants With T-cell Mediated BCAR at Month 6 and 12 Assessed by Central Review [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]

    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.


  • Change From Week 4 in Glomerular Filtration Rate Estimated by the MDRD Method at Month 6 and Month 12 [ Time Frame: Week 4, Month 6 and Month 12 ] [ Designated as safety issue: No ]
    The glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease (MDRD) method.

  • Change From Week 4 in GFR by Iothalamate Clearance at Month 6 [ Time Frame: Week 4 and Month 6 ] [ Designated as safety issue: No ]
    The glomerular filtration rate was measured directly using iothalamate clearance.

  • Change From Week 4 in Serum Creatinine at Month 6 and 12 [ Time Frame: Week 4 and Month 6 and 12 ] [ Designated as safety issue: No ]
  • Percentage of Participants With Efficacy Failure at 6 and 12 Months Assessed by Local Review [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Efficacy Failure at 6 and 12 Months Assessed by Central Review [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]
    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.

  • Time to First BCAR Assessed by Local Review [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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.

  • Time to First BCAR Assessed by Central Review [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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.

  • Time to First T-cell Mediated BCAR Assessed by Local Review [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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.

  • Time to First T-cell Mediated BCAR Assessed by Central Review [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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.

  • Maximum Grade of T-cell Mediated Rejection Assessed by Local Review [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]

    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.


  • Maximum Grade of T-cell Mediated Rejection as Assessed by Central Review [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]

    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.


  • Percentage of Participants With Clinically Treated Acute Rejection at Month 6 and Month 12 [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]
    Patients who received immunosuppressive medications for the treatment of suspected or BCAR were considered to have a clinically-treated acute rejection.

  • Percentage of Participants With Anti-lymphocyte-treated Rejection at Months 6 and 12 [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]

    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.


  • Percentage of Participants With Multiple Rejection Episodes at Months 6 and 12 [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Treatment Failure at Month 6 and 12 [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]
    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.

  • Gastrointestinal Quality of Life Index Score Over Time [ Time Frame: Months 1, 3, 6, and 12 ] [ Designated as safety issue: No ]
    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.

  • Gastrointestinal Symptom Rating Scale Scores Over Time [ Time Frame: Months 1, 3, 6, and 12 ] [ Designated as safety issue: No ]
    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.


Enrollment: 323
Study Start Date: February 2008
Study Completion Date: February 2011
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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 Name: 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: 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 Name: Amevive, ASP0485
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 Name: 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 Name: 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
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
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 Name: Amevive, ASP0485
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 Name: 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.
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: 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 Name: Amevive, ASP0485
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 Name: 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 Name: 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.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00543569

  Show 38 Study Locations
Sponsors and Collaborators
Astellas Pharma Inc
Investigators
Study Director: Senior Medical Director Astellas Pharma Global Development
Principal Investigator: Principal Investigator University of Michigan
  More Information

Additional Information:
No publications provided

Responsible Party: Astellas Pharma Inc
ClinicalTrials.gov Identifier: NCT00543569     History of Changes
Other Study ID Numbers: 0485-CL-U201 
Study First Received: October 11, 2007
Results First Received: November 6, 2015
Last Updated: November 6, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Astellas Pharma Inc:
kidney transplant
alefacept

Additional relevant MeSH terms:
Alefacept
Basiliximab
Mycophenolate mofetil
Mycophenolic Acid
Tacrolimus
Antibiotics, Antineoplastic
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on February 08, 2016