14 CLINICAL STUDIES
14.1 Renal Allograft Rejection
Renal Transplant Rejection
The effectiveness of ATGAM for treatment of acute allograft rejection was evaluated in three different treatment applications: as a substitute for standard therapy, in conjunction with standard therapy at the time of diagnosis of the first rejection episode, and in conjunction with standard therapy in steroid resistant rejection episodes.
A randomized controlled trial of the use of ATGAM as a substitute for standard therapy for treatment of the first acute rejection episode was conducted at one transplant center in recipients of living related renal allografts. A total of 22 patients were studied; 11 in each of the two treatment groups [ATGAM versus standard therapy (bolus doses of Solu-Medrol®)]. Patients randomized to the ATGAM group received 14–21 doses of ATGAM therapy, starting on the day the rejection was diagnosed. ATGAM was administered daily according to a dose-by-rosette regimen which resulted in a mean daily dose of approximately 15 mg/kg. Patients randomized to the control group received Solu-Medrol® at a dosage of 15 mg/kg starting on the day the rejection was diagnosed, administered either daily or on alternate days for 3 to 7 doses to complete a maximum total dose of 5,000 mg for the course of the rejection episode. In this study, ATGAM was at least effective as standard therapy for treatment of acute allograft rejection. All 11 ATGAM treated patients achieved resolution of first rejection compared with 10/11 control patients. At one year, the functional graft survival rate was 91% in the ATGAM group (10/11) and 64% in the control group (7/11). Patient survival was similar in the two treatment groups (11/11 ATGAM patients versus 10/11 control patients).
The effect of ATGAM when administered in conjunction with standard therapy at the time of diagnosis of the first rejection episode was studied under two different protocols with cadaveric and living related renal transplant patients. The results from these studies demonstrate the efficacy associated with the addition of ATGAM to standard therapy for treatment of the first rejection episode in renal allograft recipients. In Study 1, a randomized controlled, two center trial of ATGAM use for treatment of acute rejection in cadaveric renal transplant patients, the addition of ATGAM to standard rejection therapy (methylprednisolone sodium succinate) resulted in an increased frequency of resolution of the first acute rejection episode which was statistically significant (p <0.01). ATGAM-treated patients achieved a rejection resolution rate of 80% (36/45) compared with 54% (25/46) in the control group. There was a statistically significant improvement in functional graft survival favoring the ATGAM group (p <0.01), and a statistically significant steroid sparing effect during the first rejection episode among patients in the ATGAM group. There was no difference in the patient survival rate between the two treatment groups. Study 2 was a randomized controlled trial conducted at five different transplant centers. In this study, the addition of ATGAM to standard rejection therapy (bolus doses of Solu-Medrol®) for treatment of acute rejection in recipients of living related renal transplants resulted in an increased frequency of rejection resolution and improvement in functional graft survival. Due to the small sample size, the difference between the ATGAM group and the control group in functional graft survival rate did not achieve statistical significance. Marginal statistical significance was demonstrated in rejection reversal rate and intravenous steroid sparing among ATGAM patients (p=0.10 and p=0.07). Patient survival rates were similar in the two treatment groups.
Results from randomized controlled trials in patients with first acute renal allograft rejection episodes refractory to conventional steroid therapy have demonstrated that ATGAM, when administered in conjunction with standard therapy, yields efficacy results superior to those of standard therapy alone. One study investigated two different regimens of ATGAM; immediate and delayed therapy. Patients were enrolled at the time of first rejection episode and randomized among three treatment groups: control (no ATGAM), immediate ATGAM, and delayed ATGAM. Patients in all three treatment groups received standard rejection therapy in the form of bolus doses of Solu-Medrol® 15 mg/kg/day IV, while patients in the two ATGAM groups received ATGAM therapy in addition to Solu-Medrol®. In the immediate ATGAM group, ATGAM administration started at the time of diagnosis of rejection (concurrent with standard therapy). In the delayed ATGAM group, ATGAM administration started on rejection day 4 (following the first three doses of Solu-Medrol®). Patients in both of the treated groups received from 10 to 21 doses of ATGAM. Results favored the two ATGAM groups (and particularly the immediate ATGAM group) in both outcome of first rejection and functional graft survival. The improvement in functional graft survival was statistically significant (p=0.05). There was also a statistically significant difference in patient survival rate favoring the ATGAM-treated groups (p=0.02).
The effectiveness of ATGAM for reversal of acute renal allograft rejection was also demonstrated in other controlled studies performed in various medical centers. In these studies, ATGAM was administered at time of diagnosis of the first rejection episode at a range of 10 to 15 mg/kg per day for 14 to 15 days, followed by alternate day therapy for a total of 21 doses in 28 days.
14.2 Aplastic Anemia
The use of ATGAM for the treatment of moderate to severe aplastic anemia in patients who are unsuitable for bone marrow transplantation is based on data from three controlled studies.
The effectiveness of the ATGAM therapy in the studies described below was evaluated by the hematological response and survival rates (Table 3).
10 to 20 mg/kg daily for 8 to 14 days
A total of 41 patients with moderate or severe aplastic anemia ages 6 to 69 years, who were not candidates for bone marrow transplantation were enrolled in a randomized controlled study. The objective of this study was to determine the efficacy of ATGAM as a single agent, in restoring hematopoiesis in patients with moderate to severe aplastic anemia. Twenty-one (n=21) patients in the ATGAM treatment group received 20 mg/kg/day for 8 days, while control patients (n=20) were observed for 3 months. All patients were given oral prednisone (40 mg/m2/day) starting on day 8 then tapered over 1 to 2 weeks.
At 3 months post-study enrollment, 11 patients in the supportive care group who showed no improvement became eligible and were crossed over to receive ATGAM therapy. Efficacy was evaluated as sustained improvement in peripheral blood counts within 3 months of entry into the study. A statistically significant (p<0.01) difference was observed between the two treatment groups in hematological improvement based on the investigator's evaluation; 11 of 21 (52%) patients in the ATGAM group responded, compared with no patients (0 of 20) in the control group. Six of the 11 crossover patients from the control group showed improvement after 3 months of therapy. Overall, of 32 patients in both the ATGAM group and the control group who crossed over to receive ATGAM, 17 patients (53%) had a hematological improvement. Estimated 1-year survival rate was 62% for all 32 patients treated with ATGAM. The 2-year survival rate was 100% among the ATGAM responders [17 of the 32 patients (53%) compared to 14% for the nonresponders].
Fever, chills, and erythematous or urticarial rash were seen in all ATGAM treated patients. Platelet counts decreased during ATGAM infusion and daily platelet transfusions were necessary. Serum sickness occurred in all patients within 6 to 18 days of ATGAM initiation and was well-controlled with standard therapy. Three patients experienced transient hypotension.
A randomized double-blind, placebo prospective, controlled study was conducted to compare the safety and efficacy of ATGAM and androgen (oxymetholone; OXY) immunosuppressive therapy with the combination of ATGAM, androgen (OXY) and an infusion of HLA mismatched bone marrow in patients with severe aplastic anemia who were not candidates for bone marrow transplantation. Allocation to treatment group was based on the availability of mismatched bone marrow donors. A total of 42 patients, ages 1 to 69 years were treated. Eighteen patients received ATGAM at a dose of 16 mg/kg/day for 10 doses with concomitant androgens (OXY) at a dose of 3 mg/kg/day for a minimum of 3 months, and 24 patients received an infusion of bone marrow from an HLA-mismatched donor 48 hours after the completion of ATGAM treatment.
At 3 months after entry into the study, 51% of patients with disease of idiopathic etiology (21 of the 41 evaluable patients from both groups) showed improvement based on investigator's evaluation of transfusion requirements and peripheral blood counts. Hematological response rate (complete/moderate based on sponsor's evaluation) at 3 months for the ATGAM and androgen group was 44% compared with 43% for the group receiving ATGAM, androgen and bone marrow infusion. The group of patients who received mismatched bone marrow infusion had better estimated 1-year survival rate, although the difference between these estimates was not statistically significant (p=0.14); 83% at 12 months for the group receiving bone marrow infusion versus 59% for the ATGAM and androgen alone group. Estimated 1-year survival rate for both groups combined was 73%.
The most commonly reported adverse events were rash, fever, arthralgias, chills, headache, myalgia and pruritus.
A pooled analysis of data from Studies 1 and 2 revealed an overall estimated 1-year survival rate of 69% in ATGAM-treated patients.
A total of 53 patients (3 to 76 years of age) participated in this randomized, placebo-controlled, double-blind study to determine if androgens add to the efficacy of ATGAM in providing favorable hematologic response rates in patients with moderate to severe aplastic anemia. All patients were treated with ATGAM 20 mg/kg/day IV for 8 days, and were randomized to receive the oral androgen (oxymetholone 4 mg/kg/day or fluoxymesterone 25 mg/m2/day) (n=26), or a matched placebo (n=27). Both groups received oral prednisone (40 mg/m2/day) beginning on Day 8 which was tapered and discontinued in 1 to 2 weeks. A group of historical controls from previous studies (n=68; 1 to 72 years of age) who received ATGAM (20 mg/kg/day IV for 8 days) without androgens were included for treatment results comparison. The proportions of subjects who presented complete or partial response at 6 months were 42% in the ATGAM plus androgen group, 44% in the ATGAM plus placebo group, and 51% in the historical controls. The difference in response rates was not significant (p>0.9). Survival at 2 years was also comparable in the two groups for patients with severe aplastic anemia; 55% in the ATGAM plus androgen group compared with 50% in the ATGAM plus placebo group (p=0.65), and 56% for the historical controls. In patients with moderate aplastic anemia, two-year survival for the ATGAM plus androgen group was 63% compared with 100% in those receiving ATGAM plus placebo and 72% in the historical controls who received ATGAM alone.
Adverse reactions in both groups were comparable and included rash, chills, gastrointestinal disturbances, and joint pain during ATGAM infusion, as well as symptoms of serum sickness in all patients. Five patients had asymptomatic sinus bradycardia; six patients required antihypertensive therapy. Alanine transaminase or alkaline phosphatase levels increased to >2 times the upper limits of normal in 7 patients receiving ATGAM plus androgen, and in nine patients receiving ATGAM plus placebo.
|Study||ATGAM + comparator or other therapy||No. of Subjects||Response rate %|
|P Value||Survival rate %|
|P Value (or 95% CI)|
|10 to 20 mg/kg/day for 8 to 14 days|
|Study 1||ATGAM||21||47†/ 52‡ (3 mo)||<0.01†/<0.01‡||62§ (12 mo)||NA|
|Control||20||6†/ 0‡ (3 mo)|
|Study 2||ATGAM + Bone marrow infusion||24||43 (3 mo)||Not reported||83 (12 mo)||=0.14|
|ATGAM||18||44 (3 mo)||59 (12 mo)|
|Study 3||ATGAM + Androgen||26||42 (6 mo)||>0.9||55¶ (24 mo)||=0.65|
|ATGAM + Placebo||27||44 (6 mo)||50¶ (24 mo)|
|ATGAM historical controls||68||51 (6 mo)||NA||56 (24 mo)|