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Background and Key Results From the EPIC 1-Year Cardiac Substudy

This 1-year prospective, open-label, multicenter, single-arm study of a subgroup of patients (N=192) with β-thalassemia enrolled in the EPIC (Evaluation of Patients' Iron Chelation with EXJADE) trial was conducted to evaluate the efficacy of EXJADE in removing cardiac iron and preventing cardiac iron loading. Myocardial iron was assessed by T2*.1

Patient eligibility1

Eligible patients were 10 years or older and had a serum ferritin ≥2500 µg/L, a LIC >10 mg Fe/g dry weight, a lifetime minimum of 50 transfused blood units, and a left ventricular ejection fraction of at least 56%, as measured by cardiac MRI.

The patient population was assigned to 2 study arms: a cardiac iron reduction group (n=114) and a prevention group (n=78). Subjects were assigned to the cardiac iron reduction group if screening revealed a T2* between 5 ms and <20 ms, reflecting mild or moderate (T2* >10-<20 ms) to severe (T2* <10 ms) cardiac iron toxicity. Patients assigned to the prevention arm included those who met all eligibility criteria but had a myocardial T2* ≥20 ms. Change from baseline to 12 months in myocardial T2* constituted the primary end point of the study.

Patient stratification1

Of the patients enrolled in the study, all 114 patients in the cardiac iron reduction group and 76/78 in the prevention arm had received another chelator (either deferoxamine monotherapy or deferoxamine +deferiprone).1 The mean EXJADE dosage over the study year was 32.6 (±4.0) mg/kg/day and was 31.8 (± 4.5) mg/kg/day for those with a T2* <10 ms, and 33.2 (±3.6) mg/kg/day for those with a T2* from 10 to <20 ms (cardiac iron reduction arm). For the 78 patients in the prevention arm (T2* ≥20 ms), treatment was initiated at a dosage of 20 mg/kg/day in 63 patients and at 30 mg/kg/day in 15 patients. The mean dosage over 1 year was 27.6 (±6.0) mg/kg/day.

Measures of efficacy1

Cardiovascular MRI measured myocardial T2* at baseline and at 12 months of therapy.

The secondary efficacy measures, serum ferritin and LIC, were evaluated for changes from baseline to 12 months. LIC was assessed by MRI measurements of the transverse relaxation parameter R2 at baseline and 6 months (cardiac iron reduction group only) and 12 months after treatment. Serum ferritin was assessed at baseline and every 4 weeks over the course of the study.

In the cardiac iron reduction arm at 12 months1

  • Myocardial T2* increased significantly from a baseline of 11.2 ms to 12.9 ms, (P<0.001), for an improvement from baseline of 16%
  • Significant increases from baseline in the groups of patients with T2* measurements of <10 ms and from 10 to <20 ms of 7.4 ms to 8.2 ms (P<0.001) and 14.6 to 17.4 (P<0.001)
  • 69.5% of all patients experienced an improvement in T2* values, 14.3% experienced no change, and 16.2% experienced a worsening of cardiac iron
  • Twenty-four percent of patients had a normal myocardial T2* of >20 ms at the end of 12 months of treatment
  • LIC values were significantly reduced from baseline (P<0.001)
  • The reduction in median serum ferritin of –1257 µg/L was also significant (P<0.001)

In the prevention arm (normal myocardial iron), after 12 months1

T2* was 32.5 ms compared with 32.0 at baseline. Moreover, none of the patients in this arm with a myocardial T2* >20 ms at baseline had a value <20 ms at 1 year.

In this group, LIC also significantly decreased by –7.2 mg Fe/g dry weight (P<0.001), for a 30% reduction, as did serum ferritin from 4367 µg/Lto 3145 µg/L (P<0.001), for a relative reduction of 20%.

EPIC Cardiac Study Extension2

Seventy-one patients completed two years of treatment and entered the third year of the above study. The mean EXJADE dosage increased from a mean of 33.3 ± 3.9 in the initial 1-year study to 33.6 ±9.8 in the extension phase.

Continued improvements in T2* and clinical parameters2

Improvement in myocardial T2* continued and after 3 years had increased from a baseline geometric mean of 11.9 ms to 17.1 ms (P<0.001). Increases from 7.7 ms to 10.5 ms (P<0.001) were also significant for patients with a baseline T2* of <10 ms and from 14.9 to 22.3 (P<0.001) for those with a T2* of 10 to 20 ms.

Median LIC and median serum ferritin reductions from baseline were also significant (28.4 to 15.5 mg Fe/g dry weight and 5575 µg/L to 2794 µg/L, respectively; P<0.001 for both) on the basis of last observation carried forward.

Summary

In the cardiac substudy of the EPIC trial, reductions in serum ferritin were seen as early as 3 months with EXJADE. Moreover, the reductions continued, as witnessed by the 3-year results, in which liver iron concentration and median serum ferritin levels were reduced by 47% and 46%, respectively (P<0.001 for both). After 3 years, 68.1% of patients with mild-moderate cardiac iron levels normalized to T2* ≥20 ms, and 50% of patients with severe cardiac iron levels improved above the 10-ms threshold.1,2