Phase III Evaluation of Once-Daily, Oral Therapy with ICL670 (Exjade®) Versus Deferoxamine in Patients with β-Thalassemia and Transfusional Hemosiderosis.
Authors: Cappellini Maria , Bejaoui Mohamed , Perrotta Silverio , Agaoglu Leyla , Kattamis Antonios , Giardina Patricia , Janka-Schaub Gritta , Opitz Herbert , Ressayre-Djaffer Catherine , Alberti Daniele 
Published: October 2019

ICL670 (deferasirox) is an investigational once-daily oral iron chelator that has demonstrated the ability to induce sustained, clinically relevant reductions in liver iron content (LIC) in heavily transfused patients with β-thalassemia and iron overload. The efficacy and safety of ICL670 is being assessed in a multicenter, randomized, open-label Phase III study in comparison with deferoxamine (DFO) in patients aged ≥2 years with β-thalassemia and transfusional hemosiderosis. Between March and November 2003, 587 patients began treatment (296 on ICL670; 291 on DFO) in the following 12 countries : Italy (200), Turkey (87), Tunisia (68), US (48), Greece (46), Germany (27), Argentina (24), Belgium (24), Brazil (20), UK (18), Canada (13) and France (12). Based on LIC at baseline (2–3, >3–7, >7–14 and >14 mg Fe/g dw), patients were randomized in a 1:1 ratio to receive either oral ICL670 once daily at doses of 5, 10, 20 or 30 mg/kg, respectively, or subcutaneous DFO at doses of 20–60 mg/kg/day for 5 days/week. Treatment was for one year initially, to be followed by an extension phase during which patients randomized to DFO may switch to ICL670. LIC, the primary outcome variable, was assessed at baseline by liver biopsy or, in some children, non-invasively by magnetic susceptometry using a Superconducting QUantum Interference Device (SQUID). LIC will be reassessed after 12 months of therapy in each patient using the same methodology as at baseline. Liver biopsies are analyzed at a single center (Rennes, France) and SQUID assessments are performed in 3 centers (Turin, Italy; Hamburg, Germany; Oakland, US). At baseline, median (25–75th percentiles) LIC was 13.0 mg Fe/g dw (7.2–21.0) by biopsy and 5.6 (4.0–7.7) in those patients assessed by SQUID. Total body iron balance will be assessed to determine the relative chelation efficacies of ICL670 and DFO. A summary of patient demographics and baseline characteristics (median values or no. of pts) is given in the table. ICL670 has been well tolerated with mild, transient gastrointestinal complaints as the main AEs with a suspected relationship to study drug. As of May 2004, 8 patients on ICL670 and 2 on DFO had discontinued therapy due to AEs. The key efficacy and safety data from the initial 12 months of therapy for all randomized patients will be available late November 2004.

Treatment group (by initial dose) ICL670 (n=296) Deferoxamine (n=291) 10 mg/kg n = ≤ 94 20 mg/kg n = 83 30 mg/kg n = 119 <35 mg/kg n = 51 35-<50 mg/kg n = 119 ≥ 50 mg/kg n = 121 Age (yrs) median 15 15 15 15 14 17 No. of pts 2 - <16 years 49 44 60 26 63 56 No. of ≥ pts 16 yrs 45 39 59 25 56 65 No. of males/females 44/50 41/42 54/65 32/19 50/69 61/60 LIC (mg Fe/g dry weight) 4.7 10.6 21.8 4.5 9.1 19.5 No. of pts with biopsy/SQUID* 60/34 69/14 117/0* 36/15 93/26 119/2 Serum ferritin (ng/ml) 1881 1954 3250 1546 2037 2383