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

プラセボコンパレーター：Placebo

Participants received placebo administered intra-operatively as an intravenous (IV) bolus on Day 0, another IV bolus on Day 3 and weekly subcutaneous injections thereafter for 12 weeks. Participants also received tacrolimus, mycophenolate mofetil (MMF) and steroid treatment.

薬：placebo

IV and subcutaneous injection

薬：Tacrolimus

The initial daily dose was 0.2 mg/kg orally given in 2 doses commencing 24 hours after completion of surgery.

薬：Mycophenolate Mofetil

Mycophenolic mofetil was administered as 750 mg twice per day orally

薬：Steroids

Methylprednisolone or equivalent:

Day 0: 500 - 1000 mg IV bolus Day 1: 125 - 250 mg IV bolus

Prednisone or equivalent:

Days 2 - 14: 20 - 30 mg orally Days 15 - 28: 10 - 20 mg orally Days 29 - 60: 10 - 15 mg orally Days 61 onwards: 5 - 10 mg orally

実験的：Alefacept

Participants received 7.5 mg alefacept administered intra-operatively as an IV bolus on Day 0, another 7.5 mg IV bolus on Day 3, and weekly subcutaneous injections of 15 mg alefacept thereafter for 12 weeks. Participants also received tacrolimus, MMF and steroid treatment.

薬：Tacrolimus

The initial daily dose was 0.2 mg/kg orally given in 2 doses commencing 24 hours after completion of surgery.

薬：Mycophenolate Mofetil

Mycophenolic mofetil was administered as 750 mg twice per day orally

薬：Steroids

Methylprednisolone or equivalent:

Day 0: 500 - 1000 mg IV bolus Day 1: 125 - 250 mg IV bolus

Prednisone or equivalent:

Days 2 - 14: 20 - 30 mg orally Days 15 - 28: 10 - 20 mg orally Days 29 - 60: 10 - 15 mg orally Days 61 onwards: 5 - 10 mg orally

薬：Alefacept

IV and subcutaneous injection

他の名前：

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Percentage of Participants With Biopsy-confirmed Acute T-cell Mediated Rejection at Month 6 Assessed by Local Review

Biopsies were graded by the clinical site pathologist.according to the Banff 97/05 updated histological classification:

• Grade IA: significant interstitial infiltration (>25% parenchyma affected) and foci of moderate tubulitis;
• Grade IB: significant interstitial infiltration (>25% parenchyma affected) and foci of severe tubulitis;
• Grade IIA: mild to moderate intimal arteritis;
• Grade IIB: severe intimal arteritis comprising >25% of the luminal area;
• Grade III: "transmural" arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocyte inflammation.

A biopsy confirmed acute rejection was an event of suspected acute rejection confirmed by a graft biopsy result of Banff grade ≥ 1.

The Kaplan-Meier estimate of biopsy-confirmed acute T-cell mediated rejection within the first 6 months following transplantation is reported. Participants lost to follow-up or with missing outcomes were censored at their last follow up visit.

Percentage of Participants With Biopsy Confirmed Antibody-Mediated Acute Rejection at Month 6

Biopsies were graded by the clinical site pathologist.according to the Banff 97/05 updated histological classification:

Acute antibody-mediated rejection - documented anti-donor antibody ('suspicious for' if antibody not demonstrated):

• Grade I: acute tubular necrosis-like - complement split product positive (C4d+), minimal inflammation;
• Grade II: capillary-margination and/or thromboses, C4d+
• Grade III: arterial - v3, C4d+.

A biopsy confirmed acute rejection was an event of suspected acute rejection confirmed by a graft biopsy result of Banff grade ≥ 1.

The Kaplan-Meier estimate of biopsy-confirmed antibody-mediated acute rejection within the first 6 months following transplantation is reported. Participants lost to follow-up or with missing outcomes were censored at their last follow up visit.

Percentage of Participants With Biopsy Confirmed Acute Rejection (T-Cell Mediated or Antibody Mediated) at Month 6

Biopsies were graded by the clinical site pathologist.according to the Banff 97/05 updated histological classification. A biopsy confirmed acute rejection was an event of suspected acute rejection confirmed by a graft biopsy result of Banff grade ≥ 1.

The Kaplan-Meier estimate of biopsy-confirmed acute T-cell mediated or antibody-mediated rejection within the first 6 months following transplantation is reported. Participants lost to follow-up or with missing outcomes were censored at their last follow up visit.

Percentage of Participants With Biopsy Confirmed Acute Mixed T-Cell Mediated and Antibody-Mediated Rejection at Month 6

Biopsies were graded by the clinical site pathologist.according to the Banff 97/05 updated histological classification. A biopsy confirmed acute rejection was an event of suspected acute rejection confirmed by a graft biopsy result of Banff grade ≥ 1.

The Kaplan-Meier estimate of biopsy-confirmed acute mixed T-cell mediated and antibody-mediated rejections within the first 6 months following transplantation is reported. Participants lost to follow-up or with missing outcomes were censored at their last follow up visit.

Percentage of Participants With Acute Rejection Diagnosed by Signs and Symptoms at Month 6

Acute rejection diagnosed by signs and symptoms, including biopsy-confirmed or suspected (not confirmed by biopsy - i.e. no biopsy was performed or biopsy did not confirm an acute T-cell mediated rejection). The Kaplan-Meier estimate of acute rejection diagnosed by signs and symptoms within the first 6 months following transplantation is reported. Participants lost to follow-up or with missing outcomes were censored at their last follow up visit.

Percentage of Participants With Clinically Treated Acute Rejection at Month 6

Patients who received immunosuppressive medications for the treatment of suspected or biopsy-confirmed acute rejections were considered to have a clinically-treated acute rejection. The Kaplan-Meier estimate of clinically treated acute rejection within the first 6 months following transplantation is reported. Participants lost to follow-up or with missing outcomes were censored at their last follow-up visit.

Percentage of Participants With Steroid-resistant Acute Rejection at Month 6

A steroid-resistant acute rejection is defined as a rejection episode which did not resolve following treatment with corticosteroids. In the case that a rejection episode was not treated with corticosteroids first but only with antibodies, it was included in this category.

The Kaplan-Meier estimate of steroid-resistant acute rejection within the first 6 months following transplantation is reported. Participants lost to follow-up or with missing outcomes were censored at their last follow up visit.

Percentage of Participants With Biopsy-Confirmed Acute T-cell Mediated Rejection as Assessed by Central Review at Month 6

Biopsies were graded by the central reviewer according to the Banff 97/05 updated histological classification. A biopsy confirmed acute rejection was an event of suspected acute rejection confirmed by a graft biopsy result of Banff grade ≥ 1.

The Kaplan-Meier estimate of biopsy-confirmed acute T-cell mediated rejection within the first 6 months following transplantation is reported. Participants lost to follow-up or with missing outcomes were censored at their last follow up visit.

Patient Survival

Patient survival is any participant known to be alive at Month 6. The Kaplan-Meier estimate of patient survival within the first 6 months following transplantation is reported. Participants lost to follow-up were censored at the time of last assessment.

Graft Survival

Graft survival was defined as any participant who was known to have a functioning graft (i.e., not graft loss) at 6 months. Graft loss is defined as re-transplantation, nephrectomy, death or as dialysis ongoing at end of study or at discontinuation of the participant unless superseded by follow-up information.

The Kaplan-Meier estimate of graft survival within the first 6 months following transplantation is reported. Participants lost to follow-up were censored at the time of last assessment.

Maximum Histological Grade of All Biopsies After Local Review

The grade of acute rejection was classified according to Banff 97/05 updated version. If a patient had more than 1 rejection episode, the episode with the most severe grade was used.

Acute T-cell mediated rejection:

• Grade IA: significant interstitial infiltration (>25% parenchyma affected) and foci of moderate tubulitis;
• Grade IB: significant interstitial infiltration (>25% parenchyma affected) and foci of severe tubulitis;
• Grade IIA: mild to moderate intimal arteritis;
• Grade IIB: severe intimal arteritis comprising >25% of the luminal area;
• Grade III: "transmural" arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocyte inflammation.

Acute antibody-mediated rejection:

• Grade I: acute tubular necrosis-like - complement split product positive (C4d+), minimal inflammation;
• Grade II: capillary-margination and/or thromboses, C4d+
• Grade III: arterial - v3, C4d+.

Percentage of Participants With Anti-Lymphocyte Antibody Therapy for Treatment of Rejection at Month 6

The Kaplan-Meier estimate of anti-lymphocyte antibody therapy for acute rejection (clinically-treated or biopsy-confirmed) within the first 6 months following transplantation is reported. Participants lost to follow-up or with missing outcomes were censored at their last follow-up visit.

Change From Month 1 in Serum Creatinine

Change From Month 1 in Glomerular Filtration Rate (GFR)

The GFR was calculated using the Modification of Diet in Renal Disease (MDRD) formula.

Change From Month 1 in Creatinine Clearance

The creatinine clearance was calculated according to the Cockcroft-Gault formula.

GFR Measured by Iothalamate Clearance at Month 6

GFR measured using the iothalamate clearance method and determined by a central laboratory.

Percentage of Participants With Efficacy Failure at Month 6

Efficacy failure is defined as death, graft loss, biopsy-confirmed acute T-cell mediated rejection assessed by local reading or lost to follow-up.

The Kaplan-Meier estimate of efficacy failure within the first 6 months following transplantation is reported.

Percentage of Participants With Delayed Graft Function

Delayed graft function was defined as the requirement for dialysis within the first week post-transplant.

Percentage of Participants With Treatment Failure at Month 6

Treatment failure is defined as efficacy failure (death, graft loss, biopsy-confirmed acute T-cell mediated rejection assessed by local reading, lost to follow-up) or early discontinuation of alefacept/placebo at any time (during the 12-week administration period) for any reason. The Kaplan-Meier estimate of treatment failure within the first 6 months following transplantation is reported. Participants lost to follow-up or with missing outcomes were censored at their last follow-up visit.

Number of Participants With Adverse Events

Causally related was defined as adverse events (AEs) assessed by the Investigator as possibly or probably related to study drug or records where the relationship was missing.

A serious adverse event (SAE) was any untoward medical occurrence that, at any dose:

• Resulted in death.
• Was life-threatening.
• Resulted in persistent or significant disability/incapacity.
• Resulted in congenital anomaly or birth defect.
• Required patient hospitalization or led to prolongation of hospitalization
• Was considered a medically important event.

All rejections and any BK virus, Epstein Barr virus and/or cytomegalovirus infection had to be reported as an SAE