A randomized open-label study of darbepoetin alfa administered every 3 weeks with or without parenteral iron in anemic subjects with nonmyeloid malignancies receiving chemotherapy

8612 Background: Patients (pts) with cancer receiving chemotherapy often have chemotherapy-induced anemia (CIA) and reduced quality of life. Darbepoetin alfa (DA) is an erythropoiesis-stimulating agent (ESA) that can effectively treat CIA when administered once every 3 weeks (Q3W). In patients with CIA, limited data in the literature suggest that administration of intravenous (IV) iron with ESA therapy may increase clinical response. Methods: This randomized, multicenter, open-label, 16-week study evaluated the safety and efficacy of DA 500 mcg administered Q3W using the SureClick injection device in pts with CIA (Hb < 11 g/dL) who received either IV iron or standard practice for iron administration (oral iron or no iron). The dose of IV iron was 200 mcg administered either Q3W with DA Q3W or, if required, as 2 doses (200 mcg total) within a 3-week period. Pts who received ≥ 1 dose of DA and who completed the 16-week study period by October 19, 2005 are included in this interim analysis (planned sample size = 400 pts). Accrual will have finished by conference time. Randomization was stratified by tumor type and baseline (BL) Hb (< 10 or ≥ 10 g/dL). The incidence of adverse events and serious adverse events, in particular embolic/thrombotic events, was summarized. Efficacy endpoints were estimated using the crude % of pts (95% CI). Hb values within 28 days of a transfusion were not included in any efficacy analysis. Results: Of the 114 pts included in this interim analysis, 65% were women, 99% were Caucasian, the mean (SD) age was 60 years (12), and 26% had lung or gynecological tumors; study endpoints are shown in the table. Conclusions: Based on the interim results, the safety profile for pts receiving DA 500 mcg Q3W with IV iron appears to be comparable to pts receiving DA 500 mcg Q3W with oral iron or no iron. The % pts who achieved the target Hb (≥ 11 g/dL) appeared higher, and the % pts who required transfusions appeared lower, in the group receiving IV iron. [Table: see text] [Table: see text]

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Effects of intravenous (IV) iron supplementation on responses to every-3-week (Q3W) darbepoetin alfa (DA) by baseline hemoglobin in patients (pts) with chemotherapy-induced anemia (CIA)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.9106 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 9106-9106 ◽

Cited By ~ 4

Author(s):

T. Pinter ◽

T. Mossman ◽

T. Suto ◽

J. Vansteenkiste

Keyword(s):

Clinical Outcomes ◽

Darbepoetin Alfa ◽

Iron Supplementation ◽

Oral Iron ◽

Tumor Type ◽

Open Label ◽

Phase Iiib ◽

Iv Iron ◽

To Receive ◽

Hematopoietic Response

9106 Background: Pts with CIA receiving erythropoiesis-stimulating agents (ESAs) may benefit from IV iron supplementation. This randomized, multicenter, open-label, 16-week, phase IIIb study evaluated the safety and efficacy of darbepoetin alfa in pts with CIA who also received IV iron versus oral iron/no iron. This exploratory analysis presents the clinical outcomes by subgroups based on baseline (BL) hemoglobin (Hb). Methods: Eligible pts were of legal age, had a non-myeloid malignancy, and had CIA (BL Hb < 11g/dL). All pts received DA 500 mcg administered Q3W using the Aranesp (darbepoetin alfa) prefilled SureClick autoinjector. Patients were randomly allocated 1:1 to receive either DA plus 200 mg IV iron (200 mg Q3W with DA Q3W or two 100 mg doses within 3 weeks) or DA plus oral iron/no iron. Randomization was stratified by tumor type and BL Hb category (< 10 or = 10 g/dL). The primary endpoint was the percentage of pts achieving a hematopoietic response (Hb = 12 g/dL or an increase = 2 g/dL). Results: A total of 396 pts were randomized and received = 1 dose of DA (IV iron arm = 200; oral iron/no iron arm = 196). Mean (SD) age was 61.0 (11.5) years; 61% (n = 240) were women; 28% (n = 111) had lung or gynecological tumors; and 45% (n = 178) had BL Hb < 10 g/dL. Pt demographics were similar between arms. Clinical outcomes are shown in the table by BL Hb. Conclusions: DA 500 mcg Q3W with IV iron supplementation appeared to improve clinical outcomes in this study, especially in pts with BL Hb < 10 g/dL; more pts achieved a hematopoietic response, fewer received transfusions, and more achieved the target Hb (= 11 g/dL) compared with those receiving oral iron/no iron. Also, in both treatment arms, pts with BL Hb = 10 g/dL demonstrated better clinical outcomes than pts with BL Hb < 10 g/dL. Benefits associated with initiating ESA treatment on time, ie before pts Hb falls < 10 g/dL, have been suggested previously (Lyman and Glaspy, Cancer 2006). [Table: see text] No significant financial relationships to disclose.

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Changes in iron parameters in patients (pts) with chemotherapy-induced anemia (CIA) receiving darbepoetin alfa (DA) every 3 weeks with and without intravenous iron supplementation

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.19621 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 19621-19621

Author(s):

T. Suto ◽

J. F. Vansteenkiste ◽

T. Mossman ◽

T. Pinter

Keyword(s):

Iron Deficiency ◽

Serum Ferritin ◽

Darbepoetin Alfa ◽

Serum Iron ◽

Iron Supplementation ◽

Binding Capacity ◽

Tumor Type ◽

Open Label ◽

Iv Iron ◽

Iron Parameters

19621 Background: There is growing interest in the use of intravenous (IV) iron supplementation in pts receiving erythropoiesis- stimulating agents (ESAs). We present an exploratory analysis of iron parameters in pts with CIA enrolled in a phase IIIb, randomized, open- label, study of DA administered with either IV iron or oral/no iron. Methods: Eligible pts had a non-myeloid malignancy and CIA (baseline Hb < 11g/dL). Pts received DA 500 mcg every 3 weeks (Q3W) using the Aranesp (darbepoetin alfa) prefilled SureClick autoinjector. Pts were randomly allocated (1:1) to receive either DA + 200 mg IV iron (200 mg Q3W with DA Q3W or two 100 mg doses within 3 weeks) or DA + oral/no iron. Randomization was stratified by tumor type and baseline Hb (< or = 10 g/dL). The primary endpoint was % pts achieving a hematopoietic response (Hb = 12 g/dL or increase = 2 g/dL). Results: 396 randomized pts received 1 dose of DA (IV-iron arm = 200; oral/no-iron arm = 196). Mean (SD) age was 61.0 (11.5) yrs; 61% (n = 240) were women; 28% (n = 111) had lung/gynecological tumors. Pt demographics were similar between arms. 44 (11%) pts had baseline iron deficiency (TSAT < 15%; serum ferritin < 100 μg/L); 5 (2%) in the IV iron arm and 23 (12%) in the oral/no-iron arm developed it. 141 (36%) pts had baseline functional iron deficiency (serum iron < 60 μg/dL; serum ferritin > 20 μg/L; TSAT < 20%); 54 (27%) in the IV arm and 67 (35%) in the oral/no-iron arm developed it. See table for iron parameters. Improved Hb-based responses in the IV-iron arm will be presented. Conclusions: Pts who received DA Q3W + IV iron appeared less likely to develop iron deficiency; iron deficiency may reduce responsiveness to ESAs. These pts also appeared to have a larger increase in mean serum ferritin levels. In contrast, mean serum iron, %TSAT, total iron binding capacity, and reticulocytes appeared to be similar in the 2 arms for most of the study period, suggesting that these iron parameters are not influenced by IV iron. No significant financial relationships to disclose. [Table: see text]

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Effectiveness of Darbepoetin alfa Administered Every 3 Weeks on Clinical Outcomes in Patients with Hematologic Malignancies and Chemotherapy-Induced Anemia.

Blood ◽

10.1182/blood.v106.11.3767.3767 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3767-3767 ◽

Cited By ~ 1

Author(s):

Ralph Vincent Boccia ◽

Peter T. Silberstein ◽

Simon Tchekmedyian ◽

Dianne Tomita ◽

Greg Rossi ◽

...

Keyword(s):

Solid Tumors ◽

Darbepoetin Alfa ◽

Hematologic Malignancy ◽

Hematologic Malignancies ◽

Target Range ◽

Tumor Type ◽

Open Label ◽

Serious Adverse Events ◽

The Mean ◽

Tumor Types

Abstract Patients (pts) with cancer receiving chemotherapy commonly have chemotherapy-induced anemia (CIA), often resulting in reduced quality of life. The primary objective of this analysis was to summarize the effectiveness of darbepoetin alfa (DA) administered at 300mcg every 3 weeks (Q3W), in achieving and maintaining a hemoglobin (Hb) target range of 11–13g/dL in pts with hematologic malignancies and CIA, versus pts with solid tumors and CIA. Data for all 1493 pts enrolled in this multicenter, open-label, 16-week study who received at least one dose of DA are included in this exploratory analysis stratified by tumor type. Pts ≥18 years of age receiving multicycle chemotherapy and with Hb <11g/dL were eligible for this study. Hb-based endpoints were adjusted for red blood cell transfusions and analyzed with and without imputing missing Hb values. Pt-reported outcomes were assessed using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scale. Most pts were white (79%), 61% were female, and the median age was 64 years (range, 19 to 97). At baseline (BL), 31% of pts had Hb <10g/dL and 61% had Hb ≥10g/dL; the mean (SD) was 10.1 (0.7)g/dL. Hematologic malignancy (14%) was the third most common tumor type after breast (29%) and gastrointestinal (24%); 45% of the hematologic malignancies were non-Hodgkin’s lymphoma (NHL) pts. Hb, transfusion, and FACT-F endpoints are shown in the table. A slightly lower percent of NHL pts achieved the Hb target range recommended by current guidelines (11–13g/dL), compared to pts with other hematologic malignancies or with solid tumors. Similar proportions of pts with hematologic malignancies or solid tumors maintained Hb within the target range. The proportion of pts receiving RBC transfusions from week 5 to the end of study (EOS) was similar for pts with hematologic malignancies and for pts with solid tumors. Improvements in FACT-F scores were seen in all groups, although the mean change was lower in NHL pts compared with other tumor types. Serious adverse events were as expected for this patient population. DA Q3W appears to be effective in achieving and maintaining Hb between 11 to 13g/dL in pts with CIA and hematologic malignancies. Since chemotherapy is often administered Q3W, synchronizing DA treatment with pts’ chemotherapy schedules may simplify the treatment of CIA in these pts. Hematologic - NHL N=98 Hematologic - non-NHL N=118 Solid N=1277 All Tumor Types N=1493 *For pts who achieved target. **For pts available at day 29. K-M=Kaplan Meier. CL=confidence limits Mean (95%CL) BL Hb (g/dL) 10.1 (9.9, 10.2) 10.0 (9.8, 10.1) 10.1 (10.1, 10.2) 10.1 (10.1, 10.2) Pts who achieved ≥ Hb 11g/dL. Crude % (95% CL) 74 (66, 83) 82 (75, 89) 79 (77, 81) 79 (77, 81) Proportion of pts maintaining Hb between 11 and 13g/dL after achieving target - n (%)* 51 (70) 68 (70) 739 (73) 858 (73) Time to target Hb (weeks). K-M Median (95% CL) 7 (6, 8) 6 (4, 7) 4 (4, 5) 4 (4, 5) Transfusions from week 5 to EOS. Crude % (95% CL)** 21 (13, 30) 20 (13, 27) 18 (16, 20) 18 (16, 20) Mean change in FACT-F from BL to week 16 (95% CL) 2.8 (−0.9, 6.5) 5.2 (1.8, 8.6) 4.8 (3.9, 5.7) 4.7 (3.9, 5.6)

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The Safety and Efficacy of Ferumoxytol in the Treatment of Iron Deficiency: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2018-99-114146 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4894-4894

Author(s):

Jameel Abdulrehman ◽

Grace Tang ◽

Michael Auerbach ◽

Michelle Sholzberg

Keyword(s):

Systematic Review ◽

Adverse Events ◽

Research Funding ◽

Meta Analysis ◽

Risk Of Bias ◽

Oral Iron ◽

Serious Adverse Events ◽

Safety And Efficacy ◽

Iv Iron ◽

Quality Evidence

Abstract Background Iron deficiency (ID) is one of the most common nutritional deficiencies worldwide, with an increased prevalence in pathological states such as end stage renal disease and inflammatory bowel disorders. Iron stores can be replenished by either oral or intravenous (IV) formulations, however IV formulations are known to raise iron stores more quickly and reliably. Ferumoxytol is an IV iron formulation used in the treatment of ID that, advantageously, can be given in large doses over a short period of time. Despite the initial large quantity of post-marketing reports of serious adverse events (SAEs), multiple clinical trials have failed to demonstrate a significant safety signal. Objectives To determine the safety and efficacy of ferumoxytol in the treatment of ID compared to other IV and oral iron formulations, and placebo. Methods This systematic review and meta-analysis was conducted following the Cochrane Handbook, and was reported as per Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the Cochrane Library, Medline, and EMBASE from inception until February 2018 as well as trial registries and reference lists of relevant articles. All randomized or quasi-randomized controlled trials comparing ferumoxytol to alternate IV iron, oral iron, or placebo were included. Outcomes included treatment emergent adverse events (TEAEs), treatment related adverse events (TRAEs), SAEs, related serious adverse events (RSAEs), hypotension or hypersensitivity reactions (HHR) and composite cardiovascular outcomes (CCO). Two review authors independently extracted data and assessed included studies for risk of bias. If required, additional data was sought from trial authors. Meta-analysis was performed using the Review Manager 5.3. Data was pooled using random-effects models. Risk of bias was assessed using the Cochrane Collaboration tool Risk of Bias. The GRADE approach was used to assess quality of evidence. Results The review included nine studies, one of which was a cross-over trial. These included 5691 participants (mean age 54.3, study mean range 30 to 65.1 years). Ferumoxytol was compared to alternate IV iron in three studies, to oral iron in two, and to placebo in four. Overall, studies were at low risk of bias (see figure 1). There was high quality evidence that relative to other IV iron formulations, ferumoxytol has little to no increase in the achievement of a minimum 1g/dL increase in hemoglobin (Relative Risk [RR] 1.04, 95%Confidence Interval [CI] 0.96 to 1.12; 767 participants pooled (pp) from 2 trials)), low quality evidence that it has little to no decrease in TEAE (RR 0.88, 95%CI 0.80 to 0.97; 2764 pp from 3 trials), little to no decrease in TRAEs (RR 0.73, 95%CI 0.61 to 0.88; 2764 pp from 3 trials), little to no increase on SAEs (RR 1.13, 95%CI 0.77 to 1.67; 2764 pp from 3 trials), and little to no decrease in RSAEs (RR 0.58, 95%CI 0.13 to 2.55; 2764 pp from 3 trials), very low quality evidence that it has little to no decrease in HHR (RR 0.58, 95%CI 0.31 to 1.09; 2764 pp from 3 trials) and moderate quality evidence that it has little to no decrease on CCO (RR 0.56, 95% CI 0.24 to 1.29; 2602 pp from 2 trials). Compared to oral iron, ferumoxytol had less TEAEs (RR 0.78, 95%CI 0.61 to 0.98; 515 pp from 2 trials), but compared to placebo ferumoxytol had more (RR 1.62, 95%CI 1.01 to 2.61; 2348 pp from 3 trials). Publication bias was not assessed due to the limited number of studies included. Conclusions Upon review of the available evidence, ferumoxytol is probably as efficacious as alternative IV iron formulations with no clear safety concerns. In addition, ferumoxytol had less TEAEs compared to oral iron formulations, but more compared to placebo. Disclosures Auerbach: AMAG Pharmaceuticals: Research Funding; Pharmacosmos A/S: Research Funding.

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Comparison of Safety and Tolerability of Deutetrabenazine During Titration and Maintenance in Patients with Tardive Dyskinesia

CNS Spectrums ◽

10.1017/s1092852920002643 ◽

2021 ◽

Vol 26 (2) ◽

pp. 164-180

Author(s):

Amanda Wilhelm ◽

Karen E. Anderson ◽

Hubert H. Fernandez ◽

Hadas Barkay ◽

Nayla Chaijale ◽

...

Keyword(s):

Suicidal Ideation ◽

Adverse Events ◽

Tardive Dyskinesia ◽

Dry Mouth ◽

Fixed Dose ◽

Open Label ◽

Serious Adverse Events ◽

Open Label Extension ◽

Pharmaceutical Industries ◽

Flexible Dose

AbstractBackgroundDeutetrabenazine is approved to treat tardive dyskinesia (TD) in adults and is titrated weekly by 6 mg/day, from 12 to 48 mg/day, based on dyskinesia control and tolerability. This analysis compared the safety of deutetrabenazine during titration versus maintenance.MethodsSafety was assessed during titration versus maintenance using integrated data from two 12-week placebo-controlled studies (ARM-TD and AIM-TD) and the open-label extension study. Rates were compared for overall and serious adverse events (AEs), AEs leading to discontinuation, treatment-related AEs, common AEs (≥4%), and specific AEs (parkinsonism, suicidal ideation, akathisia, restlessness).ResultsIn titration versus maintenance, AE rates with placebo (n=130) were: overall, 43.1% vs 25.4%; serious, 4.6% vs 2.3%; leading to discontinuation, 3.1% vs 0; treatment-related, 26.9% vs 10.0%. For placebo, common AEs during titration were somnolence, headache, nausea, fatigue, and dry mouth; none occurred during maintenance. In titration versus maintenance, AE rates in fixed-dose deutetrabenazine 12–36 mg (n=216) were: overall, 33.3–38.9% vs 22.2–29.2%; serious, 2.8–6.9% vs 0–1.4%; leading to discontinuation, 2.8–5.6% vs 0; treatment-related, 8.3–16.7% vs 8.3–13.9%. For fixed-dose deutetrabenazine, common AEs during titration were headache, diarrhea, nasopharyngitis, depression, hypertension, and dry mouth; headache was the only common AE during maintenance. In titration versus maintenance, AE rates with flexible-dose deutetrabenazine (n=168) were: overall, 49.4% vs 32.7%; serious, 3.6% vs 2.4%; leading to discontinuation, 2.4% vs 0.6%. For flexible-dose deutetrabenazine, the only common AE during titration was somnolence; none occurred during maintenance. Rates of parkinsonism, suicidal ideation, akathisia, and restlessness were low and comparable in titration and maintenance.ConclusionsDeutetrabenazine was well-tolerated, with AE rates similar to placebo during both phases; AE rates were higher during titration and decreased during maintenance.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel

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Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-211873 ◽

2017 ◽

Vol 76 (12) ◽

pp. 2065-2070 ◽

Cited By ~ 33

Author(s):

Lisa K Stamp ◽

Peter T Chapman ◽

Murray Barclay ◽

Anne Horne ◽

Christopher Frampton ◽

...

Keyword(s):

Adverse Events ◽

Dose Escalation ◽

Controlled Trial ◽

Serum Urate ◽

Extension Study ◽

Open Label ◽

Serious Adverse Events ◽

Open Label Extension ◽

Randomised Controlled ◽

Kidney Impairment

ObjectivesTo determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout.MethodsPeople, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue current dose for the first 12 months began allopurinol DE at month 12 if SU was ≥6 mg/dL (control/DE). Immediate DE participants who achieved target SU maintained allopurinol dose (DE/DE). The primary endpoints were reduction in SU and adverse events (AEs) at month 24.ResultsThe mean (SE) change in SU from month 12 to 24 was −1.1 (0.2) mg/dL in control/DE and 0.1 (0.2) mg/dL in DE/DE group (p<0.001). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to months 12 and 24 compared with baseline in both groups and in mean tophus size over 24 months, but no difference between randomised groups. There were similar numbers of AEs and serious adverse events between groups.ConclusionsThe majority of people with gout tolerate higher than creatinine clearance-based allopurinol dose and achieve and maintain target SU. Slow allopurinol DE may be appropriate in clinical practice even in those with kidney impairment.Trial registration numberACTRN12611000845932

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Achieving blood pressure control targets in hypertensive patients of rural China – A pilot randomized trial

10.21203/rs.2.12264/v3 ◽

2020 ◽

Author(s):

Xiao Huang ◽

Lishun Liu ◽

Yun Song ◽

Lan Gao ◽

Min Zhao ◽

...

Keyword(s):

Adverse Events ◽

Randomized Trial ◽

Real World ◽

Large Scale ◽

Rural China ◽

Standard Group ◽

Open Label ◽

Target Groups ◽

Serious Adverse Events ◽

Hypertensive Patients

Abstract Background This study aimed to test the feasibility and titration methods to achieve specific BP control targets in hypertensive patients of rural China. Methods A randomized, controlled, open-label trial was conducted in Rongcheng, China. We enrolled 105 hypertensive participants aged over 60 years, and who had no history of stroke and cardiovascular disease. The patients were randomly assigned to one of three systolic BP target groups: standard: 140 - < 150mmHg; moderately intensive: 130 - < 140mmHg; and intensive: <130mmHg. Patients were followed for 6 months. Discussion The optimal target for SBP lowering is still uncertain worldwide and such information is critically needed, especially in China. However, in China the rates of awareness, treatment and control are only 46.9%, 40.7% and 15.3%, respectively. It is challenging to achieve BP control in the real world and it is very important to develop population-specific BP control protocols that fully consider the population’s characteristics, such as age, sex, socio-economic status, compliance, education level and lifestyle. This randomized trial showed feasibility and safety of the titration protocol to achieve desirable SBP targets (<150, <140, and <130mmHg) in a sample of rural Chinese hypertensive patients. The three BP target groups had similar baseline characteristics. After 6 months of treatment, the mean SBP measured at an office visit was 137.2mmHg, 131.1mmHg, and 124.2mmHg in the three groups. Home BP and central aortic BP measurements were also obtained. At 6 months, home BP measurements (2 hours after drug administration) showed a mean SBP of 130.9 mmHg in the standard group, 124.9 mmHg in the moderately intense group, and 119.7 mmHg in the intensive group. No serious adverse events were recorded over the 6-month study period. Rates of adverse events including dry cough, palpitations, and arthralgia were low and showed no significant differences between the three groups. This trial gained real world experience and laid the foundation for a future large-scale BP target study.

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Effect of Patiromer in Hyperkalemic Patients Taking and Not Taking RAAS Inhibitors

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248418788334 ◽

2018 ◽

Vol 23 (6) ◽

pp. 524-531 ◽

Cited By ~ 5

Author(s):

Robert A. Kloner ◽

Coleman Gross ◽

Jinwei Yuan ◽

Ansgar Conrad ◽

Pablo E. Pergola

Keyword(s):

Adverse Events ◽

Serum Potassium ◽

Common Adverse Event ◽

Open Label ◽

Serious Adverse Events ◽

End Point ◽

The Mean ◽

Baseline Characteristics ◽

Raas Inhibitors ◽

Post Hoc

Introduction: Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin–angiotensin–aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi. Methods: Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi. Results: Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was −0.67 (0.08) mEq/L in patients taking RAASi and −0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer. Conclusions: Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.

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Abstract 19503: Durability of Antiplatelet Effect of a Novel Extended-release Formulation of Acetylsalicylic acid, Durlaza in Patients With Diabetes

Circulation ◽

10.1161/circ.132.suppl_3.19503 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Paul A Gurbel ◽

Kevin Blide P. P Bliden ◽

Jeff Patrick Patrick ◽

Katayoon Saadin Saadin ◽

Udaya Tantry

Keyword(s):

Adverse Events ◽

Extended Release ◽

Platelet Reactivity ◽

Cvd Risk ◽

Open Label ◽

Serious Adverse Events ◽

Release Formulation ◽

Antiplatelet Effect ◽

Immature Platelet Fraction ◽

Induced Aggregation

Background: High platelet turnover (HPT) is implicated in incomplete platelet inhibition and high platelet reactivity (HPR) during immediate release aspirin therapy in type II diabetes patients (T2DM). Durlaza is a new, extended-release orally administered aspirin formulation developed to provide 24-hour antithrombotic effects with once-daily dosing. Methods: In this open-label, single-center study, T2DM patients (n=40) and a history of cardiovascular disease (CVD) or multiple CVD risk factors were treated with daily 162.5 mg Durlaza for 14±4 days and adverse events were collected. Antiplatelet effects were determined by conventional aggregation (LTA), Multiplate analyzer, thrombelastography with PlateletMapping, PlateletWorks ,VerifyNow Assay, and serum thromboxane B2 (TxB2) at 1, 12, 16, and 24 hrs after the last dose. HPT was defined as immature platelet fraction of ≥3.0% or MPV≥11.0 fl. Patients exhibiting HPT and/or HPR (based on previously published cutpoints in ≥2 assays) were treated with Durlaza at 325mg for 14± 4 days and platelet function testing was repeated. Results: Prevalence of HPT and HPR was 47% and 27%, respectively. There was no loss of antiplatelet effect at 12, 16 and 24 h versus 1 h by all assays (Table 1). All patients responded to 162.5mg Durlaza as measured by arachidonic acid-induced aggregation with LTA and platelet reactivity levels were low at all timepoints (Table). Serum TxB2 was lower at 12 h (p<0.03) as compared to 1 h after 162.5mg and was lower at all times with the 325 mg vs. the 162.5 mg Durlaza (p < 0.05). HPT did not affect the PD profile of Durlaza (Pts with HPT vs. no HPT, p=NS for all). Patients had no serious adverse events and low treatment related AE rate (<5%). Conclusion: In this first comprehensive assessment, a new, extended-release 162.5 Durlaza provided sustained antiplatelet effects over 24 h in T2DM patients with a favorable safety profile. Doubling the dose further lowered serum TxB2 in pts with HPT and/or HPR.

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A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

BMC Pharmacology and Toxicology ◽

10.1186/s40360-020-00446-x ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Fabian Lang ◽

Lydia Wunderle ◽

Susanne Badura ◽

Eberhard Schleyer ◽

Monika Brüggemann ◽

...

Keyword(s):

Adverse Events ◽

Acute Leukemia ◽

Phase I ◽

Mtor Inhibitor ◽

Prolonged Treatment ◽

Small Subset ◽

Open Label ◽

Serious Adverse Events ◽

Efficient Treatment ◽

Link Type

Abstract Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300–400 mg BID (cohort − 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. Results Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. Trial registration ClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.

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