A Phase 2 Open-Label, Sequential-Cohort, Dose-Escalation Study of AMG 531 in Japanese Patients with Chronic Immune Thrombocytopenic Purpura (ITP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1308-1308
Author(s):  
Yukari Shirasugi ◽  
Kiyoshi Ando ◽  
Satoshi Hashino ◽  
Toshiro Nagasawa ◽  
Yoshiyuki Kurata ◽  
...  
Keyword(s):  
Platelet Count ◽  
Dose Escalation ◽  
Japanese Patients ◽  
Phase 2 ◽  
Platelet Response ◽  
Phase 3 ◽  
Continuation Phase ◽  
Platelet Counts ◽  
Starting Dose ◽  
The Mean

Abstract AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin (TPO) receptor. This phase 2 study was conducted to identify the appropriate starting dose of AMG 531 for treatment of chronic ITP in adult Japanese patients. The study consisted of 2 phases: a 2-week cohort dose-escalation phase to determine the starting dose for subsequent phase 3 evaluation, and a treatment continuation phase (that lasted until completion of the dose-escalation phase) which provided continuation of treatment for those with a platelet response. Patients in the continuation phase received the dose of AMG 531 they had received in the dose-escalation phase with the option for subsequent dose adjustments. Twelve patients were enrolled with a mean platelet count of 11.8x109/L and a median age of 60.5 years (range 32 to 63); 8 were female. Four patients enrolled into each of 1μg/kg, 3μg/kg, or 6μg/kg dose cohorts and received AMG 531 by subcutaneous injection on days 1 and 8 with no dose adjustments. Cohort dose escalation was to be stopped in the event of an observed platelet count >1000x109/L. Comparison of dose cohorts showed that the proportion of patients achieving a platelet response (doubling of baseline counts and ≥50x109/L) was greater in cohorts receiving higher doses of AMG 531 (see Table). A dose response was also observed in the mean peak platelet counts, the mean fold changes from baseline in peak platelet counts, and the maximum platelet count. Because one patient in the 6μg/kg cohort had an excessively high platelet count (980x109/L), this dose was eliminated from consideration as the starting dose in phase 3 and further dose escalation to 10μg/kg dose cohort was stopped. Five of 7 eligible patients (3μg/kg, 1/4; 6μg/kg, 4/4) elected to enter the treatment continuation phase. There were no study withdrawals, and no serious adverse events (AEs) were reported during the study in either phase. The most common treatment-related AE in the cohort phase was headache (25%), and in the treatment continuation phase were arthralgia, contact dermatitis, and malaise (each 20%). No patients received rescue medications during the entire treatment period. No antibodies against either AMG 531 or endogenous TPO were detected. AMG 531 was well-tolerated and produced a dose-responsive increase in platelet counts. The phase 3 study in Japanese patients with ITP will be initiated with a starting dose of 3μg/kg based on the outcome of this study. Key Measures of Platelet Response

Evaluation of AMG 531 Efficacy in Splenectomized Patients with Chronic Immune Thrombocytopenic Purpura (ITP) in a Randomized Placebo-Controlled Phase 3 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2-2 ◽  
Author(s):  
Terry B. Gernsheimer ◽  
Vinod Pullarkat ◽  
Francis M. Senecal ◽  
Louis M. Aledort ◽  
Craig M. Kessler ◽  
...  
Keyword(s):  
Platelet Count ◽  
Neutralizing Antibodies ◽  
Study Endpoint ◽  
Primary Study ◽  
Platelet Response ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Platelet Counts ◽  
Starting Dose

Abstract AMG 531 is a novel thrombopoiesis-stimulating peptibody that acts by stimulating the thrombopoietin (TPO) receptor. We report efficacy data in splenectomized patients from a randomized, double blind, placebo-controlled Phase 3 study designed to evaluate the efficacy and safety of AMG 531 in patients with chronic ITP. Sixty-three splenectomized patients were enrolled (placebo, 21; AMG 531, 42), with a median age of 52 years (range 26 to 88) and a mean baseline platelet count 14.7x109/L. Subcutaneous AMG 531 or placebo was administered weekly for 24 weeks at a starting dose of 1μg/kg, and adjusted to maintain a target platelet count of 50–200x109/L. The primary study endpoint was the incidence of a durable platelet response, defined as a platelet count ≥50x109/L for ≥6 weeks during the last 8 weeks of the 24 week treatment period in the absence of rescue medications. Sixteen of the 42 splenectomized patients (38.1%) receiving AMG 531 achieved a durable platelet response compared to 0/21 (0.0%) receiving placebo (p=0.0013). Overall response, defined as either durable or transient platelet response (≥4 weekly platelet responses), was observed in 33/42 (78.6%) patients receiving AMG 531, compared to 0/21 (0%) placebo patients. The mean number of weekly platelet responses (platelet count ≥50x109/L) was significantly greater in patients receiving AMG 531 (12.3/24 weeks, 51%) compared to placebo (0.2/24 weeks, 1%) (p<0.0001). AMG 531 reduced the proportion of patients requiring ITP rescue medications, defined as either increase from baseline in dose of concurrent medication or use of new medication to increase platelet counts. Twelve of 21 (57.1%) placebo-treated patients received rescue medications compared to just 11/42 (26.2%) AMG 531-treated patients (p=0.0175). In addition, 12/12 (100.0%) AMG 531-treated patients compared to 1/6 (16.7%) placebo-treated patients either discontinued or reduced by >25% their concurrent ITP medications. AMG 531 was well-tolerated. There were 2 treatment-related serious adverse events; 1 patient with elevated bone marrow reticulin that returned to baseline 3 months after withdrawal of AMG 531, and 1 patient experienced thrombosis that was successfully treated allowing study continuation. No patient developed neutralizing antibodies against either AMG 531 or endogenous TPO. In summary, AMG 531 was well-tolerated, and effectively increased and sustained platelet counts in splenectomized patients with ITP. AMG 531-treated patients required less frequent rescue medications in comparison to those receiving placebo, and were able to reduce their use of concurrent therapies.

Single Oral Doses of a Novel Thrombopoietin Mimetic ONO-7746 Increase Platelet Counts In Healthy Subjects

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4827-4827
Author(s):  
Thomas L Hunt ◽  
Ming Q. Lu ◽  
Yasushi Kawasaki ◽  
John P. Hall ◽  
Junji Komaba ◽  
...  
Keyword(s):  
Adverse Event ◽  
Platelet Count ◽  
Single Dose ◽  
Dose Escalation ◽  
Healthy Subjects ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Stopping Rules ◽  
Platelet Counts ◽  
The Mean

Abstract Abstract 4827 Objective: A novel orally administered small-molecule thrombopoietin receptor (c-Mpl) agonist, ONO-7746, was investigated in a double-blind, placebo-controlled single dose escalation study for its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy subjects. Methods: A total of 48 subjects were enrolled into 6 cohorts of 8 subjects each. For each cohort, subjects were randomly assigned to receive ONO-7746 or placebo in a 3:1 ratio. After a single dose of study drug on Day 1 of each cohort, all subjects in a cohort were assessed on Day 21 for their overall safety, tolerability and changes in platelet count prior to proceeding to the next higher dose. The doses of ONO-7746 applied for each successive cohort were adjusted per Dose-Escalation and Stopping Rules, i.e. the successive dose was only a 1.5-fold increase from the previous dose if either of the following were observed: Two subjects had a platelet count increase greater than 400 × 109/L, or had a platelet count doubling from Baseline. Further dose escalation was terminated if 50% of the subjects in a cohort (4 subjects) demonstrated a platelet count increase > 400 × 109/L or doubling from Baseline. This study completed a total of 6 cohorts including 5, 10, 20, 50, 100, and 150 mg. Intensive safety, tolerability, PK, and PD assessments were made throughout the study. Safety assessments included 12-lead ECGs, vital signs, serum chemistry, hematology, urinalysis and adverse event (AE) reporting. Plasma samples for ONO-7746 concentration-time analysis were collected at several time points. PD parameters included platelet count, platelet activation, and aggregation. Results: Dose escalation was only increased 1.5-fold after the 100-mg cohort because of increases in platelet count, and dose escalation was ultimately terminated after the 150-mg cohort because 50% of subjects had a platelet count increase to > 400 × 109/L or doubling from Baseline. The mean platelet counts in the ONO-7746 cohorts increased from Baseline beginning on Days 3 or 4, peaked between Days 9 and 11, decreased from Days 11 or 13, and returned to baseline levels by Day 28. Maximum platelet count, change from Baseline values increased with ascending ONO-7746 dose level. The largest percent change from Baseline in platelet count (117.0%) was observed in the 150-mg cohort, compared with 14.7% in the placebo cohort. Platelet function as measured by the exploratory platelet aggregation and activation tests was not affected by administration of ONO-7746. The PK profile of ONO-7746 showed that the plasma concentrations reached Cmax at a median Tmax of 3.0 to 4.0 hours. The mean T1/2 ranged from 22 to 27 hours. The PK of ONO-7746 was linear in the dose range of 5 to 100 mg. In the dose range of 100 to 150 mg, Cmax and AUCinf increased greater than dose proportionally. One subject in the 150-mg cohort had an adverse event of special interest (AESI) of increased platelet count > 500 × 109/L that was considered mild in severity. There were no deaths, serious AEs, severe AEs, or AEs that led to study discontinuation. No treatment- or dose-related trends were observed in AEs, clinical laboratory results, vital sign measurements, 12-lead ECG and telemetry results. Conclusion: The above observations indicate that ONO-7746 could increase platelet count even with a single dose. ONO-7746 is a potent once-daily oral c-Mpl agonist with demonstrated thrombopoietic activity in human subjects, safe and well tolerated at all the tested dose levels (5, 10, 20, 50, 100 and 150 mg). Observed Platelet Count by Study Day Disclosures: Hunt: ONO Pharma USA: Research Funding. Lu:ONO Pharma USA: Employment. Kawasaki:Ono Pharmaceutical Co., Ltd.: Employment. Hall:ONO Pharma USA: Employment. Komaba:ONO Pharma USA: Employment. Takeuchi:Ono Pharmaceutical Co., Ltd.: Employment. Imamura:ONO Pharma USA: Employment. Kuter:ONO Pharma USA: Consultancy.

Long-Term Hematologic Response to Eliglustat in Patients with Gaucher Disease Type 1: Results from a Phase 2 and Two Phase 3 Trials

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 884-884
Author(s):  
Neal J. Weinreb ◽  
Timothy M Cox ◽  
Elena Lukina ◽  
Pramod Mistry ◽  
Jennifer Angell ◽  
...  
Keyword(s):  
Platelet Count ◽  
Gaucher Disease ◽  
Hemoglobin Level ◽  
Mononuclear Phagocytes ◽  
Phase 2 ◽  
Spleen Volume ◽  
Phase 3 ◽  
Lysosomal Acid ◽  
Platelet Counts ◽  
Grant Support

Introduction: Gaucher disease is caused by a deficiency in lysosomal acid β-glucosidase, which leads to accumulation of glucosylceramide primarily in macrophages. These pathogenic macrophages (Gaucher cells) deposit in the spleen, liver, bone marrow and lungs and lead to hepatosplenomegaly, pancytopenia and skeletal disease. As thrombocytopenia, anemia and splenomegaly are common presenting symptoms of Gaucher patients, hematologists are often the healthcare provider to identify, evaluate and manage the disease. The current standard of care is biweekly intravenous enzyme replacement therapy (ERT) that supplements lysosomal acid β-glucosidase in mononuclear phagocytes. Eliglustat, a ceramide analogue, is a novel oral substrate reduction therapy (SRT) that was recently approved as a first-line treatment of adults with Gaucher disease type 1 (GD1) who have a compatible CYP2D6 metabolizer phenotype (>90% of patients). Rather than supplement lysosomal acid β-glucosidase in mononuclear phagocytes, eliglustat partially inhibits glucosylceramide synthase and reduces glucosylceramide production to offset the attenuated rate of degradation. Methods: We report on improvements in hemoglobin level and platelet counts in adults with GD1 from 3 ongoing clinical trials of eliglustat sponsored by Genzyme, a Sanofi company. Two trials are in treatment-naïve patients: an open-label Phase 2 trial (N=26, NCT00358150) for which 4-year data are available and a randomized, placebo-controlled Phase 3 trial (ENGAGE, N=40, NCT00891202) for which 18-month data are available. The third trial (ENCORE, Phase 3 imiglucerase-controlled, N=159, NCT00943111) involved patients previously stabilized on ≥3 years of ERT and 24-month data are available. Results: In the Phase 2 study, the primary endpoint was met after 1 year, with 77% of patients improving in at least 2 of 3 main efficacy parameters (spleen volume, hemoglobin level and platelet count) (Lukina et al. Blood 2010;116:816). After 4 years, mean hemoglobin level had increased by 2.3±1.5 g/dL from the baseline mean of 11.3±1.5 g/dL, and mean platelet count had increased by 95% from the baseline mean of 69±21x109/L. In the ENGAGE study, all primary and secondary endpoints were met after 9 months, with statistically significant improvements in spleen volume, hemoglobin level, liver volume and platelet counts seen in eliglustat-treated but not placebo patients (Mistry et al. JAMA 2015;313;695). Improvements continued in patients who received eliglustat for 18 months in the trial extension; mean hemoglobin level increased by 1.02±0.84 g/dL from a baseline of 12.1±1.8 g/dL, mean platelet count increased by 58%±41 from a baseline of 75±14x109/L, and mean spleen volume decreased by 44.6%±10 from a baseline of 13.9±6.0 multiples of normal (MN). For the 20 patients who switched from placebo to eliglustat, mean hemoglobin increased by 0.79±0.82 g/dL from a baseline of 12.2±2.0 g/dL, mean platelet count increased by 40%±37 from a baseline of 71.5±25.2 x109/L and mean spleen volume decreased by 31.1%±10 from a baseline of 12.5±6.0 MN, after 9 months of eliglustat. In the ENCORE study, eliglustat was found to be non-inferior to imiglucerase in maintaining stability with respect to hemoglobin concentration, platelet count, spleen volume and liver volume after 12 months (Cox et al. Lancet 2015;385:2355). Stable hemoglobin was defined as not decreasing by more than 1.5 g/dL from baseline and stable platelet count as not decreasing by more than 25% from baseline. For patients who received eliglustat for 24 months in the ENCORE extension, hemoglobin levels remained stable in 97% of patients (mean change: -0.10±0.77 g/dL) and platelet count remained stable in 94% of patients (mean change: 2.27±17.6x109/L). In former imiglucerase patients who received eliglustat for 12 months in the ENCORE extension, hemoglobin levels remained stable in 100% of patients at 12 months and platelet counts remained stable in 90%. In all 3 trials, eliglustat was generally well tolerated with 90% of patients overall electing to continue on eliglustat. Most AEs were non-serious, considered unrelated to eliglustat, and either mild or moderate in severity. Conclusions: Long-term use of eliglustat in adults with GD1 is associated with continued improvements over time in hematologic parameters in previously untreated patients and hematologic stability in patients previously stabilized on ERT. Disclosures Weinreb: Genzyme, a Sanofi company: Consultancy, Honoraria, Other: Grant Support, Speakers Bureau; Shire: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Cox:Genzyme, a Sanofi company: Consultancy, Honoraria, Other: Grant Support, Speakers Bureau; Shire: Consultancy, Honoraria, Other: Grant support, Speakers Bureau; Actelion: Consultancy, Honoraria, Speakers Bureau. Lukina:Shire: Honoraria, Other: Travel Reimbursement; Genzyme, a Sanofi company: Honoraria, Other: Travel Reimbursement. Mistry:Genzyme, a Sanofi company: Consultancy, Honoraria, Other: Grant Support, Speakers Bureau; Shire: Consultancy, Honoraria, Other: Grant Support, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Synageva: Honoraria, Speakers Bureau; NIH NIMS: Other: Grant Support. Angell:Genzyme, a Sanofi company: Employment. Gaemers:Genzyme, a Sanofi company: Employment. Peterschmitt:Genzyme, a Sanofi company: Employment.

Evaluation of AMG 531 Safety in Splenectomized (S) and Nonsplenectomized (NS) Patients with Chronic Immune Thrombocytopenic Purpura (ITP) in Two Randomized Placebo-Controlled Phase 3 Studies

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1300-1300 ◽  
Author(s):  
Roger Lyons ◽  
James N. George ◽  
Francois Lefrere ◽  
Alan E. Lichtin ◽  
Michael D. Tarantino ◽  
...  
Keyword(s):  
Platelet Count ◽  
Adverse Events ◽  
Safety Data ◽  
Weekly Dose ◽  
Platelet Response ◽  
Bleeding Events ◽  
Phase 3 ◽  
Platelet Counts ◽  
Clinically Significant ◽  
Adjusted Incidence

Abstract AMG 531 is a novel platelet-stimulating peptibody that stimulates the thrombopoietin (TPO) receptor, and is being studied for its ability to increase production of platelets. We report safety data in both S and NS patients (pts) from 2 randomized, double blind, placebo-controlled Phase 3 studies designed to evaluate the efficacy and safety of AMG 531 in adult pts with chronic ITP. All pts that received at least 1 dose of AMG 531 were counted as AMG 531-treated pts in this safety analysis. Of the 125 pts enrolled, 63 were S (placebo, 21; AMG 531, 42), and 62 were NS (placebo, 21; AMG 531, 41) with a median age of 52 years (range 21 to 88) and a mean baseline platelet count of 16.5x109/L. Subcutaneous AMG 531 or placebo was administered weekly for 24 weeks at a starting dose of 1μg/kg, and adjusted to maintain a target platelet count of 50–200x109/L. Among AMG 531 pts, the mean weekly dose was 3.3±2.7 μg/kg, with most pts (54/84, 64%) receiving a dose between 1 and 4μg/kg. There was no difference in the safety profile between S and NS pts treated with AMG 531; therefore safety data were pooled. Adverse events were reported in 39/41 (95%) placebo and in all (100%) AMG 531 pts. The most frequently reported adverse events (AEs) were: headache (placebo vs AMG 531; 32% vs 35%), fatigue (29% vs 33%), epistaxis (24% vs 32%), arthralgia (20% vs 26%), and contusion (24% vs 25%). There were 2 AMG 531-related serious AEs, both in S pts; 1 pt with elevated bone marrow reticulin after 4 weeks of receiving AMG 531 that returned to baseline 3 months after drug withdrawal, and 1 pt experienced thrombosis (right transfemoral popliteal embolectomy) that was successfully treated allowing study continuation. One (2.4%) placebo and 3 (3.6%) AMG 531 pts withdrew from the study due to AEs. Three placebo pts died of cerebral hemorrhage, atypical pneumonia, and pulmonary embolism. One AMG 531 pt died of intracranial hemorrhage 2 weeks after discontinuation of AMG 531. The total number of bleeding events in the 42 placebo pts and 83 AMG 531 pts were 76 and 152, respectively, corresponding to an exposure-adjusted incidence of 7.9 and 7.8 per 100 Patient-Weeks, reduced to 5.2 per 100 Patient-Weeks in AMG 531-treated pts when their platelet counts were ≥50x109/L (platelet response). Clinically significant bleeding events (MedDRA 9.0 defined severity grade ≥3) did not occur in responding pts, and were reported only when platelet counts were <20x109/L. Among non-responders, there were 5 significant bleeding events in placebo pts and 10 in AMG 531 pts, corresponding to an exposure-adjusted incidence of 0.5 per 100 Patient-Weeks in each group. Blood chemistry and complete blood counts remained stable, with no clinically significant changes occurring except for platelet counts. No pts tested positive for neutralizing antibodies against either AMG 531 or endogenous TPO. In summary, AMG 531 appeared to be well-tolerated in ITP pts and reduced the incidence of bleeding events among pts exhibiting a platelet response.

Evaluation of AMG 531 Efficacy in Nonsplenectomized Patients with Chronic Immune Thrombocytopenic Purpura (ITP) in a Randomized Placebo-Controlled Phase 3 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 565-565 ◽  
Author(s):  
David J. Kuter ◽  
James B. Bussel ◽  
Francis M. Senecal ◽  
Louis M. Aledort ◽  
Craig M. Kessler ◽  
...  
Keyword(s):  
Platelet Count ◽  
Neutralizing Antibodies ◽  
Study Endpoint ◽  
Primary Study ◽  
Platelet Response ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Platelet Counts ◽  
Efficacy Analysis

Abstract AMG 531 is a novel platelet-stimulating peptibody that stimulates the thrombopoietin (TPO) receptor, and is being studied for its ability to increase production of platelets. Here we report efficacy data in nonsplenectomized patients from a randomized, double blind, placebo-controlled Phase 3 study designed to evaluate the efficacy and safety of AMG 531 in patients with chronic ITP. Sixty-two nonsplenectomized patients were enrolled (placebo, 21; AMG 531, 41) with a median age of 52 years (range 21 to 88) and a mean baseline platelet count of 18.3x109/L. Subcutaneous AMG 531 or placebo was administered weekly for 24 weeks at a starting dose of 1μg/kg, and adjusted to maintain a target platelet count of 50-200x109/L. One patient randomized to placebo received 3 doses of AMG 531 in error and was included in the efficacy analysis as a placebo. The primary study endpoint was the incidence of a durable platelet response, defined as a platelet count ≥50x109/L for ≥6 weeks during the last 8 weeks of the 24-week treatment period in the absence of rescue medications. Starting at a low dose of AMG 531 and gradually increasing it, as well as reducing the dose of steroids in certain patients, contributed to lower platelet counts early in the study. Twenty-five of the 41 patients (61.0%) receiving AMG 531 achieved a durable platelet response compared to 1/21 (4.8%) receiving placebo (p<0.0001). Overall response, defined as either durable or transient platelet response (≥4 weekly platelet responses), was observed in 36/41 (87.8%) patients receiving AMG 531, but was observed in only 3/21 (14.3%) placebo patients. The mean number of weekly platelet responses (platelet count ≥50x109/L) was significantly greater in patients receiving AMG 531 (15.2/24 weeks, 63%) compared to placebo (1.3/24 weeks, 5%) (p<0.0001). AMG 531 reduced the proportion of patients requiring ITP rescue medications, defined as either increase from baseline in dose of concurrent ITP medication or use of new medication to increase platelet counts. Thirteen of 21 (61.9%) placebo-treated patients received rescue medications compared to just 7/41 (17.1%) AMG 531-treated patients (p=0.0004). There were no treatment-related serious adverse events and no patients tested positive for neutralizing antibodies against either AMG 531 or endogenous TPO. In summary, as in previous studies, AMG 531 was well-tolerated while effectively increasing and sustaining platelet counts in nonsplenectomized patients with ITP. When compared to placebo, AMG 531 administration resulted in a higher mean platelet count, and was associated with less frequent use of rescue medications.

Evaluation of Romiplostim In a Randomized Placebo-Controlled Phase 3 Study of a Japanese Population with Chronic Immune Thrombocytopenia (ITP).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3704-3704
Author(s):  
Koji Miyazaki ◽  
Yukari Shirasugi ◽  
Kiyoshi Ando ◽  
Yoshiaki Tomiyama ◽  
Shinichiro Okamoto ◽  
...  
Keyword(s):  
Platelet Count ◽  
Placebo Group ◽  
Adverse Events ◽  
Target Range ◽  
Platelet Response ◽  
Employment Equity ◽  
Phase 3 ◽  
Platelet Counts ◽  
Equity Ownership ◽  
H Pylori

Abstract Abstract 3704 Introduction: Chronic immune thrombocytopenia (ITP) is an autoimmune disorder characterized by both increased platelet destruction and decreased platelet production. Romiplostim increases platelet counts by binding and activating the thrombopoietin receptor. Romiplostim has been approved for the treatment of adult ITP in the United States, Europe, Canada, and Australia. This study evaluated dosing, efficacy, and safety in a Japanese population of adults with ITP. Methods: This phase 3 study was placebo-controlled, double-blind, and randomized 2:1 (romiplostim:placebo). Patients were eligible for the study if they were Japanese patients with ITP diagnosed at least 6 months before the initial screening, were aged ≥ 20 years, and were H pylori negative or had received at least 1 treatment for H pylori eradication. Patients were stratified by splenectomy status (yes or no). After a 3-week evaluation period, patients were treated for 12 weeks with a weekly subcutaneous injection of either romiplostim or placebo. The starting dose was 3 mcg/kg with dose adjustments to a maximum of 10 mcg/kg to achieve a platelet count within the target range of ≥ 50 to ≤ 200 × 109/L. Patients were monitored posttreatment until their platelet count dropped to ≤ 50 × 109/L or for a maximum of 12 weeks. The primary endpoint was number of weeks with platelet response (platelet count ≥ 50 × 109/L). Results: Thirty-four patients enrolled (22 romiplostim, 12 placebo), 24 (71%) were female, the median (range) age was 55 (44 - 64) years, and the median (range) baseline platelet count was 19 (3 – 32) × 109/L. Patients had received a median of 4 (1 – 19) prior ITP therapies, and 15 (44%) had previously undergone a splenectomy; 23 (68%) patients were receiving concurrent ITP therapy at baseline. All patients completed the study. Romiplostim demonstrated superiority to placebo on weekly platelet response, incidence of increase in platelet count ≥ 20 × 109/L from baseline, change from baseline in mean of last 4 platelet counts during week 2 to week 13, and number of weeks with platelet counts within the target range (Table 1), and 16 (73%) romiplostim patients had platelet counts ≥ 200 × 109/L. Twenty-one (95%) patients in the romiplostim group had a platelet response with a median time of 1 week until first response. Results for weekly platelet response were comparable irrespective of splenectomy status and baseline concurrent ITP therapy. Two (17%) patients in the placebo group achieved a platelet response. In romiplostim-treated patients, posttreatment platelet counts remained > 50 × 109/L for 8 weeks in one and for 12 weeks in another. The mean weekly dose of romiplostim for the study was 2.6 mcg/kg compared with the dose range of 3–4 mcg/kg in prior phase 3 studies (Kuter et al. Lancet. 2008;371:395–403). There was a low incidence of rescue medication use in the study (Table 1). The adverse events profile was comparable to that seen in non-Japanese studies. Patients in both treatment groups experienced similar proportions of adverse events (91% romiplostim, 92% placebo). Adverse events with > 10% higher frequency in the romiplostim group than placebo group) were (romiplostim, placebo) nasopharyngitis (41%, 17%), headache (32%, 17%), peripheral edema (18%, 0%), back pain (14%, 0%), and pain in extremity (14%, 0%). Significant (≥ grade 3) bleeding events occurred in 1 patient in the romiplostim group (subarachnoid hemorrhage) and 1 patient in the placebo group (subarachnoid hemorrhage, cerebral hemorrhage, and gastrointestinal hemorrhage). There were no adverse events of bone marrow reticulin, thrombosis, or detection of neutralizing antibodies. Conclusion: Romiplostim significantly increased and maintained platelet counts and was well-tolerated in a Japanese ITP population. Disclosures: Tomiyama: Kyowa Hakko Kirin Co.: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Kurokawa:Novartis: Consultancy; Shionogi & Co., Ltd.: Consultancy. Wei:Amgen Inc.: Employment, Equity Ownership. Lizambri:Amgen Inc.: Employment, Equity Ownership.

scholarly journals MP09: Canadian Community Utilization of Stroke Prevention Pilot Study-Emergency Department (C-CUSP ED)

CJEM ◽  
2017 ◽  
Vol 19 (S1) ◽  
pp. S68 ◽  
Author(s):  
R. Parkash ◽  
K. Magee ◽  
M. McMullen ◽  
M.B. Clory ◽  
M. D’Astous ◽  
...  
Keyword(s):  
Stroke Prevention ◽  
Phase 1 ◽  
Retrospective Chart Review ◽  
Phase 2 ◽  
Phase 3 ◽  
Three Phase ◽  
Rigorous Study ◽  
The Mean ◽  
Prior Risk

Introduction: Atrial fibrillation (AF) is the most common sustained arrhythmia affecting 1-2% of the population. Oral anticoagulation (OAC) reduces stroke risk by 60-80% in AF patients, but only 50% of indicated patients receive OAC. Many patients present to the ED with AF due to arrhythmia symptoms, however; lack of OAC prescription in the ED has been identified as a significant gap in the care of AF patients. Methods: This was a multi-center, pragmatic, three-phase before-after study, in three Canadian sites. Patients who presented to the ED with electrocardiographically (ECG) documented, nonvalvular AF and were discharged home were included. Phase 1 was a retrospective chart review to determine OAC prescription of AF patients in each ED; Phase 2 was a low-intensity knowledge translation intervention where a simple OAC-prescription tool for ED physicians with subsequent short-term OAC prescription was used, as well as an AF patient education package and a letter to family physicians; phase 3 incorporated Phase 2 interventions, but added immediate follow-up in a community AF clinic. The primary outcome of the study was the rate of new OAC prescriptions at ED discharge in AF patients who were OAC eligible and were not on OAC at presentation. Results: A total of 632 patients were included from June, 2015-November, 2016. ED census ranged from 30000-68000 annual visits. Mean age was 71±15, 67±12, 67±13 years, respectively. 47.5% were women, most responsible ED diagnosis was AF in 75.8%. The mean CHA2DS2-VASc score was 2.6±1.8, with no difference amongst groups. There were 266 patients eligible for OAC and were not on this at presentation. In this group, the prescription of new OAC was 15.8% in Phase 1 as compared to 54% and 47%, in Phases 2 and 3, respectively. After adjustment for center, components of the CHA2DS2-VASc score, prior risk of bleeding and most responsible ED diagnosis, the odds ratio for new OAC prescription was 8.0 (95%CI (3.5,18.3) p&lt;0.001) for Phase 3 vs 1, and 10.0 (95%CI (4.4,22.9) p&lt;0.001), for Phase 2 vs 1). No difference in OAC prescription was seen between Phases 2 and 3. Conclusion: Use of a simple OAC-prescription tool was associated with an increase in new OAC prescription in the ED for eligible patients with AF. Further testing in a rigorous study design to assess the effect of this practice on stroke prevention in the AF patients who present to the ED is indicated.

scholarly journals Long Term Discontinuation of Eltrombopag after Remission in Primary Immune Thrombocytopenia: 8-Year Follow-up Data from 15 Spanish Centers

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2352-2352
Author(s):  
Tomas Jose Gonzalez-Lopez ◽  
Fernando Fernandez-Fuertes ◽  
Maria Cristina Pascual Izquierdo ◽  
Isabel Caparros ◽  
Silvia Bernat ◽  
...  
Keyword(s):  
Platelet Count ◽  
Median Time ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Previous Treatment ◽  
Complete Response ◽  
Platelet Response ◽  
Platelet Counts

Background: Successful discontinuation of eltrombopag in certain immune thrombocytopenia (ITP) patients after complete response has already been demonstrated. However, the frequency of this phenomenon and type of candidate patients are still matter of discussion. Moreover, possibility of long term discontinuation responses is not clearly established. Methods: Here we retrospectively evaluated our whole cohort of 508 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry with a focus on the patients who achieved a durable (at least six months) platelet response after stopping eltrombopag. Successful discontinuation of eltrombopag (SDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 6 months in absence of eltrombopag or any rescue therapies administered. Long term discontinuation of eltrombopag (LTDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 36 months in the absence of eltrombopag or any rescue therapies administered. The study was approved by the Hospital Universitario de Burgos Ethics Committee and fulfilled Helsinki declaration standards. Results: While 37.4% of our patients relapsed of ITP with subsequent platelet count drop sometime during first six months of discontinuation of eltrombopag, a total of 74 patients (14.6%) were able to achieve SDOE. The median age of SDOE patients was 62 [range, 47-79] years. There were 47 women and 27 men. According to the standard definition, patients were allocated to newly diagnosed (n=17), persistent (n=15) and chronic (n=42) ITP groups. The median time from diagnosis to eltrombopag initiation was 31 [range, 4-104] months. The median number of previous therapies was 2 [range, 1-2], including splenectomy (14%), rituximab (18%) and romiplostim (12%). As expected, all patients but 1 achieved a complete response (platelet count ≥100 x 109/L) prior to eltrombopag discontinuation The median duration of eltrombopag treatment was 7 [range, 2-19] months. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=43), platelet count >400x109/L (n=16), aspartate aminotransferase elevation (n=5), diarrhea (n=4), thrombosis (n=3), patient's request (n=2) and other reasons (n=1). Analysis of these SDOE discontinued patients show that with a median follow-up of 55 [range, 29-79] months, 38 patients (51.3%) maintained treatment-free response 36 months after stopping eltrombopag with no need of additional ITP therapies (median time of eltrombopag discontinuation was 70 [range, 50-77] months).This condition is what we define now as LTDOE. Nevertheless, 36 patients relapsed beyond 6 months but before 36 months of eltrombopag discontinuation (median time of eltrombopag discontinuation was 10 [range,7 -22] months). Characteristics of LTDOE population were a median time since ITP diagnosis of 32 [range, 5-88] months with 15/38 patients having ITP <1 year. 9 patients (24%) were male and their median age was 50 [range, 37-64] years. They had received a median of only two previous treatment lines [range: 1-2 lines]. The median platelet count before starting eltrombopag was 19 x 109/L [range, 8-40]. Meanwhile, platelet count before eltrombopag stop was 218 x 109/L [range, 123-356]. The main characteristics (age, gender, duration of ITP, prior ITP lines, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 38 patients with LTDOE were compared with those of the SDOE cohort who did not achieve a LTDOE. Unfortunately, no predictive factors of LTDOE could be identified. Conclusion: Durable platelet response following eltrombopag cessation may be observed in only 15% of primary ITP patients treated with this drug. On the contrary, half of patients who achieve a sustained response after eltrombopag withdrawal will get a long term discontinuation. However, we are lacking predictor factors for successful and long-term discontinuation of eltrombopag in primary ITP. Disclosures Gonzalez-Lopez: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy. Sánchez-González:Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Jarque:Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

scholarly journals Efficacy and safety of tolvaptan in patients with malignant ascites: a phase 2, multicenter, open-label, dose-escalation study

2020 ◽  
Author(s):  
Toshihiro Kudo ◽  
Yoshiyuki Murai ◽  
Yoshitsugu Kojima ◽  
Kenji Uehara ◽  
Taroh Satoh
Keyword(s):  
Body Weight ◽  
Ascitic Fluid ◽  
Dose Escalation ◽  
Urine Volume ◽  
Fluid Volume ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Open Label ◽  
Dose Escalation Study ◽  
The Mean

Abstract Objective This phase 2 study examined the efficacy and safety of tolvaptan, an aquaretic drug, in the treatment of ascites associated with cancer. Methods In the dose-escalation phase, oral tolvaptan was initiated at a dose of 3.75 mg/day, and the dose was increased daily to 7.5, 15 and 30 mg/day. Dose escalation was terminated once the increase from baseline in the daily urine volume reached 500 ml, at which point the patient proceeded to the maintenance phase of 5–7 days. Improvement of ascites was determined primarily by reduction in body weight and ascitic fluid volume. Results The mean change from baseline in body weight was maintained below 0 kg throughout the study. The mean change (±standard deviation) from baseline in ascitic fluid volume at the end of treatment (EOT) was 237.45 ± 868.14 ml in 33 evaluable patients. Although an increase from baseline in ascitic fluid volume at the EOT was observed in 23 of 33 patients (maximum: 1589.3 ml, minimum: 3.83 ml), a reduction in ascitic fluid volume was observed in the remaining 10 patients (maximum: −2304.3 ml, minimum: −27.5 ml). The common treatment-emergent adverse events included vomiting (5 of 43 patients, 11.6%), abdominal distension, constipation, thirst, blood osmolarity increased and renal impairment (3 of 43 patients, 7.0% each). Conclusions Tolvaptan seemed to have no definitive effect on reducing ascites; however, it might be effective in at least some cancer patients. No new safety concerns were identified at doses of 3.75–30 mg/day.

Long-Term Dosing of AMG 531 in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura: 48-Week Update.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 476-476 ◽  
Author(s):  
David Kuter ◽  
James Bussel ◽  
James George ◽  
Louis Aledort ◽  
Alan Lichtin ◽  
...  
Keyword(s):  
Platelet Count ◽  
Neutralizing Antibodies ◽  
Sinus Thrombosis ◽  
Therapeutic Option ◽  
Subcutaneous Administration ◽  
Transverse Sinus ◽  
Platelet Response ◽  
Open Label ◽  
The Mean

Abstract AMG 531 is a novel thrombopoiesis-stimulating peptibody that increases platelet production by targeting the TPO receptor. The study described here is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, subcutaneous administration of AMG 531 in ITP patients who have completed a previous AMG 531 study. Patients previously treated with AMG 531 receive the same starting dose as the final dose given in the previous study; placebo-treated patients begin the extension with a 1 μg/kg dose. Doses may be skipped, decreased, maintained, or increased based on platelet response. Patients who achieve a stable dose for at least 3 weeks (later amended to 4 weeks) may be allowed to self-administer the drug. A total of 104 patients have been enrolled; the longest AMG 531 treatment duration is 96 weeks. This planned interim analysis includes 36 patients (safety subset) whose previous study was a phase 2 trial. Data for patients previously enrolled in a phase 3 trial are still blinded. The 25 women and 11 men have a mean age of 50±13 (SD) years; 30 (83%) have had a splenectomy. Twelve patients entered the study using concurrent corticosteroids, which were tapered when the platelet count was &gt;50x109/L. Adverse event (AE) profiles were similar for the intervals of weeks 1–24 vs 25–48 and beyond. The most frequent were headache (incidence of 2.0 per 100 weeks of subject exposure for weeks 1–24 vs 1.7 for weeks 25–48), upper respiratory infection (1.3 vs 0.8), and fatigue (0.9 vs 1.0). Four patients had serious treatment-related AEs: vaginal hemorrhage/anemia (withdrawn from treatment), diffuse reticulin formation in the bone marrow (withdrawn), bone pain (continues on treatment), and transverse sinus thrombosis with papilledema and temporary decrease in visual acuity (64-year-old patient with diabetes mellitus and a platelet count of 293x109/L at the time of the AE; this patient continues on treatment). No neutralizing antibodies have been detected to date. The efficacy subset consists of 27 patients who completed week 48 or beyond. Both the mean platelet count and the mean dose of AMG 531 have remained stable between weeks 24–48. The mean platelet count was 100x109/L ± 4.4 (SE) during weeks 1–24 and 131x109/L ± 5.3 (SE) during weeks 25–48. Eleven patients (41%) have had at least one platelet count &gt;450x109/L, excluding counts associated with ITP rescue medication. Six of 12 patients were able to discontinue concurrent corticosteroids, and 2 had a &gt;25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for ITP. Most patients have been able to maintain a safe platelet count and to decrease or discontinue concurrent corticosteroid therapy.

Sign in / Sign up

Export Citation Format

Share Document