P0220EFFECTIVENESS OF SODIUM ZIRCONIUM CYCLOSILICATE (SZC) IN HAEMODIALYSIS PATIENTS WITH SEVERE HYPERKALAEMIA IN THE DIALIZE STUDY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Martin Ford ◽  
Steven Fishbane ◽  
Bruce Spinowitz ◽  
Anjay Rastogi ◽  
Nicolas Guzman ◽  
...  
Keyword(s):  
Rescue Therapy ◽  
Adverse Outcomes ◽  
Dose Titration ◽  
Once Daily ◽  
Sodium Zirconium ◽  
Titration Phase ◽  
Evaluation Phase ◽  
Starting Dose ◽  
Post Hoc ◽  
Sodium Zirconium Cyclosilicate

Abstract Background and Aims Patients with severe hyperkalaemia require urgent intervention to avoid serious adverse outcomes and mortality. The phase 3b DIALIZE study (NCT03303521) showed that sodium zirconium cyclosilicate (SZC) reduces predialysis serum potassium (sK+) after the long interdialytic interval and is well tolerated in haemodialysis patients with hyperkalaemia. This post-hoc analysis of the DIALIZE data assessed the efficacy of SZC in patients with severe hyperkalaemia (defined as sK+ ≥6.0 mmol/L) at baseline. Method The DIALIZE study randomised 196 patients 1:1 to placebo (n=99) or SZC (n=97). The study consisted of an 8-week treatment period, comprising a 4-week SZC dose titration phase followed by a 4-week evaluation phase. The starting dose of SZC was 5 g orally once daily on non-dialysis days (4 days/week) for the 4-week dose titration phase (titrated in 5 g increments to a maximum of 15 g on non-dialysis days) to achieve predialysis sK+ 4.0–5.0 mmol/L. Patients maintained a stable dose of SZC for the 4-week evaluation phase (SZC 5, 10 or 15 g). Here, treatment response was defined as achievement of predialysis sK+ of 4.0–5.5 mmol/L during ≥3 of 4 haemodialysis treatments after the long interdialytic interval during the 4-week evaluation phase and not requiring potassium-lowering rescue therapy. Rates of response were compared between those patients with and without baseline severe hyperkalaemia (sK+ ≥6 mmol/L and <6 mmol/L, respectively). The sK+ measurement on Visit 1 (Day –7) was used as the baseline value. Results At baseline, 88 patients had sK+ ≥6 mmol/L (SZC n=46, placebo n=42) and 106 patients had sK+ <6 mmol/L (SZC n=49, placebo n=57); data were missing for two SZC patients. The overall proportion of treatment responders (irrespective of treatment and dose) in patients with baseline sK+ ≥6 mmol/L and <6 mmol/L was 44.3% and 43.4%, respectively. The proportion of treatment responders was greater with SZC compared with placebo in patients with baseline sK+ ≥6 mmol/L and sK+ <6 mmol/L (Figure). For patients receiving SZC, the proportion of treatment responders was consistent in those with baseline sK+ ≥6 mmol/L (67.4%) compared with those with baseline sK+ <6 mmol/L (71.4%; Figure). Conclusion Our results suggest that SZC is effective in haemodialysis patients with severe hyperkalaemia.

P0242SUBGROUP EFFICACY ANALYSIS OF SODIUM ZIRCONIUM CYCLOSILICATE (SZC) IN HYPERKALAEMIC HAEMODIALYSIS PATIENTS IN THE DIALIZE STUDY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Kieran McCafferty ◽  
Steven Fishbane ◽  
Bruce Spinowitz ◽  
Anjay Rastogi ◽  
Martin Ford ◽  
...  
Keyword(s):  
Rescue Therapy ◽  
Normal Serum ◽  
Dose Titration ◽  
Efficacy Analysis ◽  
Sodium Zirconium ◽  
Titration Phase ◽  
Evaluation Phase ◽  
Baseline Weight ◽  
Sodium Zirconium Cyclosilicate ◽  
Patient Subgroups

Abstract Background and Aims Patients with end-stage renal disease have severely reduced renal potassium excretion and many require haemodialysis (3 days/week) to maintain normal serum potassium (sK+). The phase 3b DIALIZE study (NCT03303521) showed that sodium zirconium cyclosilicate (SZC) reduces predialysis sK+ after the long interdialytic interval and is well tolerated in haemodialysis patients with hyperkalaemia. This post-hoc analysis of the DIALIZE data assessed the efficacy of SZC in patient subgroups. Method The DIALIZE study randomised 196 patients 1:1 to placebo (n=99) or SZC (n=97). The study consisted of an 8-week treatment period, comprising a 4-week SZC dose titration phase followed by a 4-week evaluation phase. The starting dose of SZC was 5 g orally once daily on non-dialysis days (4 days/week) for the 4-week dose titration phase (titrated in 5 g increments to a maximum of 15 g) to achieve predialysis sK+ 4.0–5.0 mmol/L. Patients maintained a stable SZC dose for the 4-week evaluation phase (SZC 5, 10 or 15 g). Here, we assessed the proportion of treatment responders, i.e. those who during the 4-week evaluation phase achieved predialysis sK+ of 4.0–5.5 mmol/L during ≥3 of 4 haemodialysis treatments after the long interdialytic interval and who did not require potassium-lowering rescue therapy. Treatment responders were stratified by patient subgroups: sex, country, race, age (years), baseline weight (kg) and baseline sK+ (mmol/L). Results For patients receiving SZC, at baseline 59% were male, mean age was 55.7 years, 52% were white, 11% were Black or African American and 34% were Asian, and mean predialysis sK+ was 5.8 mmol/L. Using a predialysis sK+ range of 4.0–5.5 mmol/L, 69.1% (n=67/97) of SZC patients and 19.2% (n=19/99) of placebo patients were deemed treatment responders. Response to SZC was generally consistent across patient subgroups vs placebo for sex, country, race, age, baseline weight and baseline sK+, with some variation between subgroup subcategories (Table). Conclusion Our results suggest that SZC is generally effective across all groups of haemodialysis patients with hyperkalaemia. SZC responder rates for some patient subgroup subcategories were limited by low patient numbers.

scholarly journals Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia

2019 ◽  
Vol 14 (6) ◽  
pp. 798-809 ◽  
Author(s):  
Bruce S. Spinowitz ◽  
Steven Fishbane ◽  
Pablo E. Pergola ◽  
Simon D. Roger ◽  
Edgar V. Lerma ◽  
...  
Keyword(s):  
Adverse Events ◽  
Confidence Interval ◽  
Serum Potassium ◽  
Maintenance Phase ◽  
Renin Angiotensin Aldosterone System ◽  
Once Daily ◽  
Renin Angiotensin ◽  
Sodium Zirconium ◽  
Sodium Zirconium Cyclosilicate ◽  
Correction Phase

Background and objectivesOral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via the gastrointestinal tract. Sodium zirconium cyclosilicate–associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial.Design, setting, participants, & measurementsIn the correction phase, adult outpatients with plasma potassium ≥5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24–72 hours until normokalemic (potassium =3.5–5.0 mmol/L). Qualifying participants entered the ≤12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassium values (3.5–5.0 mmol/L) during the correction phase and maintenance of serum potassium ≤5.1 mmol/L during the maintenance phase. Adverse events were assessed throughout.ResultsOf 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium =4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age ≥65 years old; 74% had an eGFR<60 ml/min per 1.73 m2, and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3–12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values ≤5.1 and ≤5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor–naïve participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0–3.4 mmol/L, respectively.ConclusionsAfter achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for ≤12 months.

scholarly journals MO214EVALUATION OF THE EFFECT OF A POTASSIUM BINDER ON ARRHYTHMIA-RELATED CARDIOVASCULAR OUTCOMES IN PATIENTS ON CHRONIC HAEMODIALYSIS WITH RECURRENT HYPERKALAEMIA: DESIGN AND RATIONALE FOR THE SODIUM ZIRCONIUM CYCLOSILICATE DIALIZE-OUTCOMES STUDY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Steven Fishbane ◽  
Michel Jadoul ◽  
Laura M Dember ◽  
Csaba Kovesdy ◽  
Ian Sabir ◽  
...  
Keyword(s):  
Ventricular Tachyarrhythmia ◽  
Composite Endpoint ◽  
Primary Objective ◽  
Controlled Study ◽  
Chronic Haemodialysis ◽  
Double Blind ◽  
Once Daily ◽  
Sodium Zirconium ◽  
Outcomes Study ◽  
Sodium Zirconium Cyclosilicate

Abstract Background and Aims Patients with end-stage renal disease (ESRD) on chronic haemodialysis are at an elevated risk of arrhythmias that can increase the risk of sudden cardiac death (SCD) and stroke, along with the need for hospitalisation and interventions. These arrhythmias may be exacerbated by pre-dialysis hyperkalaemia and rapid serum potassium (sK+) shifts that occur during and after haemodialysis sessions. The DIALIZE study (NCT03303521) demonstrated that sodium zirconium cyclosilicate (SZC) was an effective and well-tolerated treatment for pre-dialysis hyperkalaemia, when administered once-daily on non-dialysis days for 8 weeks in patients with ESRD undergoing chronic haemodialysis. The DIALIZE-Outcomes study (EudraCT 2020-005561-14) will evaluate the effect of SZC treatment on arrhythmia-related cardiovascular (CV) outcomes in patients with ESRD on chronic haemodialysis with recurrent hyperkalaemia. Method The DIALIZE-Outcomes study is an international, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, to be conducted at ∼300 study sites across ∼20 countries. Adults (≥18 years of age) with ESRD on haemodialysis three times weekly and with recurrent pre-dialysis sK+ ≥5.5 mmol/L after the long interdialytic interval (LIDI) will be eligible for enrolment. Approximately 2300 patients will be randomised 1:1 to SZC or placebo (Figure), starting at 5 g orally once daily on non-dialysis days (4 days/week) and uptitrated weekly in 5 g increments (maximum 15 g) to achieve pre-dialysis sK+ 4.0–5.0 mmol/L after the LIDI. Dose adjustments after the uptitration phase will be guided by sK+ monitoring, as per clinical practice. The primary objective is to evaluate the efficacy of SZC versus placebo in reducing the incidence of the primary composite endpoint of time to first occurrence of SCD, stroke or hospitalisation/intervention/emergency department visit due to arrhythmias (atrial fibrillation, bradycardia, asystole, ventricular tachyarrhythmia). Secondary endpoints include the efficacy of SZC versus placebo in maintaining normokalaemia (sK+ 4.0–5.5 mmol/L after the LIDI) and preventing severe hyperkalaemia (sK+ ≥6.5 mmol/L after the LIDI) at 1 year (assessed through measurement of sK+ at the 12-month study visit), and time to occurrence of CV outcomes. Safety and tolerability of SZC versus placebo will also be evaluated. The study is event-driven, with patients remaining on study treatment until a pre-specified number of primary endpoint events (770) has occurred. The anticipated average treatment period is ∼25 months. Conclusion The DIALIZE-Outcomes study is the first evaluation of a K+ binder in improving CV outcomes in patients with ESRD on chronic haemodialysis and with recurrent hyperkalaemia. The study findings will provide valuable information that may help to further our understanding of the relationship between hyperkalaemia and CV morbidity and mortality in patients on chronic haemodialysis, and to optimise treatment regimens in this high CV and SCD risk population.

scholarly journals A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis Hyperkalemia

2019 ◽  
Vol 30 (9) ◽  
pp. 1723-1733 ◽  
Author(s):  
Steven Fishbane ◽  
Martin Ford ◽  
Masafumi Fukagawa ◽  
Kieran McCafferty ◽  
Anjay Rastogi ◽  
...  
Keyword(s):  
Serum Potassium ◽  
Rescue Therapy ◽  
Controlled Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Interdialytic Weight Gain ◽  
Sodium Zirconium ◽  
Efficacy Outcome ◽  
Sodium Zirconium Cyclosilicate

BackgroundPatients with ESRD have minimal renal potassium excretion and, despite hemodialysis, often have persistent predialysis hyperkalemia. The DIALIZE study (NCT03303521) evaluated sodium zirconium cyclosilicate (SZC) in the management of hyperkalemia in hemodialysis patients.MethodsIn the DIALIZE study, a double-blind, placebo-controlled, phase 3b multicenter study, we randomized adults with ESRD who were managed by three-times weekly hemodialysis and had predialysis hyperkalemia to receive placebo or SZC 5 g once daily on non-dialysis days, and titrated towards maintaining normokalemia over 4 weeks, in 5 g increments to a maximum of 15 g. The primary efficacy outcome was proportion of patients during the 4-week stable-dose evaluation period who maintained predialysis serum potassium of 4.0–5.0 mmol/L during at least three of four hemodialysis treatments after the long interdialytic interval and did not require urgent rescue therapy to reduce serum potassium.ResultsIn total, 196 patients (mean [standard deviation (SD)] age =58.1 [13.7] years old) were randomized to sodium zirconium cyclosilicate or placebo. Of 97 patients receiving sodium zirconium cyclosilicate, 41.2% met the primary end point and were deemed treatment responders compared with 1.0% of 99 patients receiving placebo (P<0.001). Rescue therapy to reduce serum potassium during the treatment period was required by 2.1% of patients taking sodium zirconium cyclosilicate versus 5.1% taking placebo. Serious adverse events occurred in 7% and 8% of patients in sodium zirconium cyclosilicate and placebo groups, respectively. The two groups displayed comparable interdialytic weight gain. There were few episodes of hypokalemia.ConclusionsSodium zirconium cyclosilicate is an effective and well-tolerated treatment for predialysis hyperkalemia in patients with ESRD undergoing adequate hemodialysis.

scholarly journals Effects of sodium zirconium cyclosilicate on sodium and potassium excretion in healthy adults: a Phase 1 study

2020 ◽  
Author(s):  
Mats Någård ◽  
Bhupinder Singh ◽  
David W Boulton
Keyword(s):  
Phase 1 ◽  
Vital Signs ◽  
Systemic Absorption ◽  
Phase 1 Study ◽  
Safety Measures ◽  
Once Daily ◽  
Sodium Zirconium ◽  
High K ◽  
K Concentration ◽  
Sodium Zirconium Cyclosilicate

Abstract Background Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a potassium (K+) binder for treatment of hyperkalemia in adults. SZC binds K+ in exchange for sodium (Na+) or hydrogen (H+) in the gastrointestinal tract, conveying potential for systemic absorption of Na+. Methods This single-center Phase 1 study evaluated the effects of SZC on Na+ and K+ excretion in healthy, normokalemic adults. During an initial run-in period (Days 1–2), participants started a high K+/low Na+ diet. After baseline (Days 3–4), SCZ 5 or 10 g once daily (QD) was administered (Days 5–8). The primary endpoint was mean change in urinary Na+ excretion from baseline (Days 3–4) to the treatment period (Days 7–8). Results Of 32 enrolled participants, 30 entered and completed the study; the first 15 received 5 g and the next 15 received 10 g. Nonsignificant changes from baseline in urinary Na+ excretion were observed with SZC 5 g (mean ± SD −0.93 ± 25.85 mmol/24 h) and 10 g (−5.47 ± 13.90 mmol/24 h). Statistically significant decreases from baseline in urinary K+ excretion (mean ± SD −21.17 ± 21.26 mmol/24 h; P = 0.0017) and serum K+ concentration (−0.25 ± 0.24 mmol/L; P = 0.0014) were observed with the 10-g dose. There were few adverse events and no clinically meaningful changes in vital signs or laboratory safety measures. Conclusions Treatment with SZC 5 or 10 g QD reduced serum K+ concentration and urinary K+ excretion, with no significant effect on urinary Na+ excretion, and was well tolerated.

scholarly journals P1299SODIUM ZIRCONIUM CYCLOSILICATE FOR THE TREATMENT OF PERSISTENT HYPERKALAEMIA IN PREVALENT HAEMODIALYSIS PATIENTS: EXPERIENCE FROM CLINICAL PRACTICE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Owain Brooks ◽  
Ashraf Mikhail ◽  
Chris Brown ◽  
Mark Gumbleton ◽  
Justine Jenkins ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Treatment Period ◽  
Controlled Trial ◽  
Previous Treatment ◽  
Sodium Zirconium ◽  
Significant Difference ◽  
The Mean ◽  
Pre Treatment ◽  
Post Hoc ◽  
Sodium Zirconium Cyclosilicate

Abstract Background and Aims Sodium zirconium cyclosilicate (SZC) (Lokelma®) is a new oral potassium binder. In September 2019 the UK National Institute for Health and Care Excellence (NICE) did not recommend SZC for dialysis patients due to a lack of evidence. The recent DIALIZE phase 3b randomised controlled trial concluded that SZC is an effective and well-tolerated treatment for hyperkalemia in haemodialysis (HD) patients. We offer an insight into SZC treatment in HD patients with persistent hyperkalaemia in clinical practice. Method Adult prevalent HD patients prescribed SZC for persistent hyperkalaemia were included for analysis. The highest pre-dialysis serum potassium (sK+) values were recorded each month before (M-6 to M-1) and after (M1 to M5) SZC initiation. The primary efficacy measure was a reduction in sK+ with SZC treatment. Results Sixteen patients (mean age 53.5 years, 56.3% male) were included for analysis. 43.8% (n=7) were diabetic. At the time of SZC initiation 43.8% (n=7) received HD via arteriovenous fistula, 12.4% (n=2) via arteriovenous graft and 43.8% (n=7) via tunnelled central venous catheter. The mean Urea Reduction Ratio [SD] was 68.5% [10.8] and the mean [SD] pre-HD bicarbonate was 22.8mmol/L [2.7]. The dialysate potassium prescription was 2mmol/L for 93.8% of patients (n=15) and 1mmol/L for 6.2% of patients (n=1). The mean [SD] achievement of prescribed dialysis hours over the previous 4 weeks was 93.5% [12.2]. 68.8% (n=11) had previous treatment with calcium polystyrene sulfonate and 12.5% (n=2) with patiromer. 18.8% (n=3) were currently prescribed a renin-angiotensin-aldosterone system inhibitor. 93.8% (n=15) had received dietetic advice. SZC starting doses ranged from 5g four times a week on non-dialysis days to 10g three times a day. Mean [SD] sK+ at month-1 (M-1) (immediate pre-treatment period) was 7.38mmol/L [0.31]. Mean [SD] sK+ at month 1 (M1) was 6.37mmol/L [1.21]. The statistical difference between these groups was p=0.0023 (paired two-tailed T-test). Figure 1 includes mean maximum monthly pre-dialysis sK+ from M-6 to M5. SZC was stopped in two patients (after M1 with sK+ 5.0mmol/L and after M4 with sK+ 4.3mmol/L) as it was no longer clinically indicated. Two patients became non-compliant (clinician-suspected or confirmed by patient) with SZC after M2 (sK+ 6.7mmol/L and sK+ 6.4mmol/L). Subsequent sK+ values would not reflect treatment with SZC in these patients. Figure 2 includes mean maximum monthly sK+ for the 12 patients on SZC from M-3 to M5. ANOVA and post-hoc Dunnett’s tests were undertaken to compare SZC treatment months (M1, 2, 3, 4 and 5) to the immediate pre-treatment period (M-1). ANOVA was close to significance (p=0.058), with post-hoc corrected for multiple comparisons finding the data to be significant for M1 vs. M-1 (p=0.045) and M5 vs. M-1 (p=0.018). The same tests across M1 through M5 revealed no significant difference (p=0.968 ANOVA and p=0.555 Dunnett’s), demonstrating that continued treatment with SZC to M5 did not result in a further decline in sK+. Conclusion Sodium zirconium cyclosilicate is effective in reducing pre-dialysis sK+ in patients with moderate and severe hyperkalaemia undergoing haemodialysis in clinical practice.

scholarly journals Efficacy and Safety of Sodium Zirconium Cyclosilicate for Treatment of Hyperkalemia: An 11-Month Open-Label Extension of HARMONIZE

2019 ◽  
Vol 50 (6) ◽  
pp. 473-480 ◽  
Author(s):  
Simon D. Roger ◽  
Bruce S. Spinowitz ◽  
Edgar V. Lerma ◽  
Bhupinder Singh ◽  
David K. Packham ◽  
...  
Keyword(s):  
Point Of Care ◽  
Efficacy And Safety ◽  
Open Label ◽  
Once Daily ◽  
End Point ◽  
Sodium Zirconium ◽  
Open Label Extension ◽  
Median Daily Dose ◽  
Sodium Zirconium Cyclosilicate ◽  
Secondary Results

Background: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for treatment of hyperkalemia. An open-label extension (OLE) of the ­HARMONIZE study evaluated efficacy and safety of SZC for ≤11 months. Methods: Patients from HARMONIZE with point-of-care device i-STAT K+ 3.5–6.2 mmol/L received once-daily SZC 5–10 g for ≤337 days. End points included achievement of mean serum K+ ≤5.1 mmol/L (primary) or ≤5.5 mmol/L (secondary). Results: Of 123 patients who entered the extension (mean serum K+ 4.8 mmol/L), 79 (64.2%) completed the study. The median daily dose of SZC was 10 g (range 2.5–15 g). The primary end point was achieved by 88.3% of patients, and 100% achieved the secondary end point. SZC was well tolerated with no new safety concerns. Conclusion: In the HARMONIZE OLE, most patients maintained mean serum K+ within the normokalemic range for ≤11 months during ongoing SZC treatment.

Efficacy and Safety of Deferasirox (Exjade®) in Patients with Transfusion- Dependent Anemias: Preliminary Results From the First, Retrospective, Multicenter Brazilian Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5096-5096
Author(s):  
Rodolfo Cancado ◽  
Jose E. Nicolau ◽  
Antonio Fabron ◽  
Ana CCV França ◽  
Ivan L. Angulo ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Iron Overload ◽  
Iron Chelator ◽  
Oral Iron ◽  
Dose Titration ◽  
Efficacy And Safety ◽  
Once Daily ◽  
Subsequent Dose ◽  
Starting Dose ◽  
Oral Iron Chelator

Abstract Abstract 5096 Background Deferasirox is a once-daily oral iron chelator with established dose-dependent efficacy for treating transfusional iron overload. The retrospective multicenter Brazilian trial included patients (pts) from 14 sites of 10 states with a variety of transfusion-dependent anemias and was designed to evaluate the efficacy and safety of fixed starting doses of deferasirox based on transfusion history, with subsequent dose titration based on serum ferritin (SF) trends. Data were available from 105 eligible pts at 6 months of treatment and 73 pts from 1-year follow-up period. Methods Pts (aged ≥ 2 yrs) had transfusion-dependent anemia with a history of multiple transfusions (>20 transfusions) and/or SF levels ≥ 1000 ng/mL and serum creatinine level < the upper limit of normal (ULN). Deferasirox starting dose was 10-30mg/kg/day depending on transfusion requirements and subsequent dose adjustments of 5-10 mg/Kg/day (range 0–35 mg/kg/d) were done every 3 months based on changes in SF and safety parameters. Efficacy was assessed monthly by measuring change from baseline in SF levels. Safety was evaluated on a monthly basis according to the incidence and type of adverse events and measurement of laboratory parameters, including serum creatinine and liver enzyme levels. Results 105 pts (40 M, 65 F; mean age 25.0±16.6 yrs) were enrolled; 46% (n=48) aged <20 yrs; 54% Afro-descendant (n=57). Underlying anemias were: sickle cell disease (n=59), β-thalassemia (n=32), myelodysplastic syndromes (n=6) and other conditions associated with anemia (n=8). Most pts (79%, n=83) had received > 40 units of red blood cell (RBC); 71.5% (n=75) were on regular RBC transfusion, 56% of the pts required < 2 RBC units/month and 44% between 2 and 4 RBC units/month. Only 63% (n=66) had received prior chelation therapy: deferoxamine (DFO; 51.4%) or DFO/deferiprone combination (11.4%). Sixty-four (61%) pts started on 20 mg/kg/d and 41(39%) > 20-30 mg/kg/d, 15.2% of pts had dose increases at a median of 24 weeks after treatment initiation. Mean ± SD SF levels (μg/L) did significantly reduce at 6 months and 12 months compared to baseline (BL) [from 3132.14 ± 2237.47 to 2784.25 ± 1969.7 at 6 months (p=0.0001) and 2327.46 ± 1873.8 at 12 months (p=0.005)]. The proportion of patients with SF levels < 2000, 2000-3000 and > 3000 μg/L from BL to 6 and 12 months by percentage of patients changed from 36% to 47.5% and 52%; from 26% to 26.5% and 24.5%; from 38% to 26% and 23%, respectively. No patient discontinued the treatment. No death was reported by the investigators during the study. The most common drug-related (investigator-assessed) AEs were mild, transient diarrhea (n=15; 14.3%), rash (n=5; 4.7%), nausea (n=9; 8.5%) and headache (n=6; 5.7%). Seven pts (6.6%) had serum creatinine value >33% above BL on two consecutive visits, 3 (2.8%) of whom had creatinine increases above the ULN; there were no progressive increases or renal failure. Eleven (10.5%) pts had an increase in alanine aminotransferase < 5x ULN but no one experience increases ≥ 5x ULN; levels were already elevated in all of them. Conclusions This first multicenter Brazilian study confirms deferasirox efficacy in achieving a reduction of iron load across a wide range of pts with transfusion-related iron overload. It also supports the clinical approach to fixed starting dose of deferasirox based on iron intake from ongoing blood transfusions and current iron burden with subsequent individual dose titration every 3 months according to SF trends and safety markers. Deferasirox was generally well tolerated in pediatric and adult pts with a safety profile consistent with data from previous clinical trials. The availability of deferasirox as a once-daily oral iron chelator would potentially facilitate improved compliance, and thereby reduce morbidity and mortality from iron overload. Disclosures No relevant conflicts of interest to declare.

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