Decrease in the Severity of Painful Sickle Cell Crises with Oral Pglg

Abstract Background: Our earlier work suggested an enhancement of nicotinamide adenine dinucleotide (NAD) in sickled Red Blood Cells (sRBC) by administering a precursor of NAD, L-glutamine. We hypothesized that L-glutamine would decrease the incidence of painful sickle cell crises (PSCC). Small proof of concept studies led to the development of a multi-center Phase 2 placebo-controlled trial where oral pharmaceutical grade L-glutamine (PGLG) suggested benefit when measuring PSCC incidence at 24 weeks. A large multi-center Phase 3 trial further demonstrated that there was a reduction in the incidence of PSCC by administering PGLG compared to placebo. Additional analyses on the data from this trial were conducted and we are reporting our evaluation on the severity of crises between treatment arms. Methods: A randomized (2:1), double-blind, placebo-controlled, parallel-group Phase 3 study was conducted at 31 sites in the United States. Subjects were stratified by hydroxyurea usage. This study included subjects 5 years of age and older that had at least 2 PSCC during the year prior to enrollment. The primary endpoint for the Phase 3 trial was the number of PSCC between treatment arms. Since PSCC events were adjudicated by a blinded third party committee and data were collected as an adverse event ranked as "None"(0), "Mild" (1), "Moderate" (2) and "Severe" (3), the difference in "Severity" of PSCC between treatment arms using Cochran Mantel Haenszel (CMH) Ranked Scores statistics was evaluated post-hoc. Each patient was counted only once at the highest level of severity. Results; A total of 230 patients were enrolled; ages 5-58; 53.9 % female; 152 were assigned to PGLG and 78 to placebo; and the groups were well balanced for baseline clinical characteristics. The comparison of Severity for PGLG vs. Placebo indicated that at (0) was 24% vs. 10% respectively; at (1) was 6% vs. 8%; at (2) was 36% vs. 35%; and at (3) was 34% vs. 47%. Summary statistics for the cohort taken as a whole indicated a treatment difference benefit for the PGLG treatment (p = 0.0167). Other adverse events in the PGLG arm were similar to those observed in the placebo arm. Conclusion: PGLG therapy may be providing clinical benefit over placebo in adult and pediatric patients with a history of two or more crises per year by reducing the "Severity" of painful crises. Difference appeared to be driven by (0) or "None" PSCC events and by a decrease in (3) "Severe" PSCC events. PGLG was administered without difficulty and did not require special monitoring. Disclosures Niihara: Emmaus Medical, Inc: Employment, Equity Ownership. Tran:Emmaus Medical, Inc: Employment, Equity Ownership. Razon:Emmaus Medical, Inc: Employment. Stark:Emmaus Medical, Inc: Employment, Equity Ownership. Macan:Emmaus Medical, Inc: Employment.

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A Phase 3 Randomized Placebo (PBO)-Controlled Double-Blind Trial of Darbepoetin Alfa in the Treatment of Anemia in Patients with Low or Intermediate-1 (Int-1) Risk Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v128.22.2010.2010 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2010-2010

Author(s):

Uwe Platzbecker ◽

Argiris Symeonidis ◽

Esther N. Oliva ◽

Jeroen S. Goede ◽

Michel Delforge ◽

...

Keyword(s):

Darbepoetin Alfa ◽

Research Funding ◽

Controlled Trial ◽

Dose Frequency ◽

Open Label ◽

Employment Equity ◽

Phase 3 ◽

Double Blind ◽

Pharmaceutical Industries ◽

Equity Ownership

Abstract Background: Although erythropoiesis-stimulating agents (ESAs) are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, ESAs are not widely approved for this indication due to a lack of PBO-controlled trials. Aim: To evaluate the use of darbepoetin alfa (DAR) to treat anemia in patients with IPSS low / int-1 risk MDS in a phase 3 randomized controlled trial (EudraCT2009-016522-14, NCT01362140). Methods: Patients, enrolled from 12/2011 to 8/2014 in 9 European countries, had MDS per WHO 2008 criteria with IPSS low/int-1 risk, anemia [hemoglobin (Hb) ≤10 g/dL], low transfusion burden [<4 units in 2 consecutive 8-week (wk) periods prior to randomization], no previous treatment with ESAs or biologic-response modifiers, and serum EPO ≤500 mU/mL. Patients were randomized 2:1 to 24 wk of SC DAR 500 µg or PBO every 3 wk (Q3W), stratified by IPSS risk, followed by 48 wk of open-label (OL) DAR (dose frequency could be increased to Q2W during that time), and follow-up to assess survival and AML progression for 3 years (ongoing). The dose was withheld for Hb >12 g/dL and decreased if Hb increased by >1.5 g/dL in 3 wk without transfusions. Key endpoints were transfusion incidence from wk 5-24 and erythroid response (HI-E) per IWG 2006 criteria (≥1.5 g/dL Hb increase from baseline sustained for 8 wk without transfusions). Results: Randomized patients [N = 147, 55% male, all Caucasian, median age 74 (min-max: 28-88) years] had median Hb of 9.3 (min-max: 5.5-10.6) g/dL and median baseline EPO level of 69 (min-max: 4.3-497) mU/mL; 50.7% were IPSS low risk and 49.3% int-1 risk, IPSS-R rates were very low: 10%, low: 61%, intermediate: 23%, and high: 3%, IPSS karyotype rates were good: 91% and intermediate: 9%, and WHO classification was RA: 15%, RARS: 14%, RCMD: 44%, del5q: 9%, RAEB-1: 16%, and MDS-U/unknown: 2%. Completion rates for the 24-wk double-blind portion were DAR: 89% (87/98) and PBO: 80% (39/49). Transfusion incidence from wk 5-24 was significantly reduced with DAR [DAR: 36.1% (35/97) vs. PBO: 59.2% (29/49), p = 0.008]. In the 48-wk OL DAR period, 50.8% (64/126) of patients had transfusions. More DAR patients achieved HI-E in the double-blind period [DAR: 14.7% (11/75 evaluable) vs. PBO: 0% (0/35 evaluable), p = 0.016]. All 11 patients with HI-E had baseline EPO ≤100 mU/mL, 4/11 had a dose withheld for Hb >12 g/dL, and 10/11 had no transfusions in the 16 wk prior to randomization (none had transfusions in the 8 wk prior). In the 48-wk OL DAR period, 34.7% (34/98) of patients achieved HI-E; 11/38 (29%) prior PBO arm, 23/87 (26%) prior DAR arm (10 of the prior DAR had HI-E in the 24-wk portion); 6/34 had transfusions in the 16 wk prior to randomization, 30/34 received Q2W dosing at some point, 30/34 had baseline EPO ≤100 mU/mL, and 26/34 had doses withheld. Improved HI-E and transfusion responses were seen with more favorable status for IPSS-R but not IPSS (Figure). In the 48-wk OL DAR period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; doses were held or reduced frequently (Table). Safety results from this trial (Table) were consistent with the previous DAR phase 2 MDS trial (Gabrilove BJH 2008, 142:379-393), with similar AML rates observed in PBO and DAR arms. Conclusion/Summary: In this phase 3, randomized, double-blind, PBO-controlled trial in anemic IPSS low/int-1 risk MDS patients, 24 wk of darbepoetin alfa Q3W significantly reduced transfusions and increased HI-E rates with no new safety signals. Most patients met criteria to change to Q2W dosing during the 48-wk OL period, suggesting that Q2W dosing may offer more benefit. The true clinical benefit of darbepoetin alfa may have been underestimated in this trial due to the nature of IWG 2006 HI-E criteria and the trial design (Hb measured Q3W, dose held if Hb >12 g/dL and decreased if Hb increased by >1.5 g/dL); additional ad hoc analyses are underway. Disclosures Platzbecker: Novartis: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Symeonidis:Amgen Inc.: Research Funding. Oliva:Amgen Inc.: Honoraria; Celgene: Honoraria, Speakers Bureau; La Jolla: Honoraria; Novartis: Speakers Bureau. Goede:Amgen Inc.: Honoraria. Delforge:Amgen Inc.: Honoraria. Mayer:Amgen Inc.: Research Funding. Badre:Amgen Inc.: Employment, Equity Ownership. Gasal:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership.

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Consistent Benefit of L-Glutamine Observed across Patients with Low, Medium, and High Number of Crises Reported in the Year Prior to Screening -- Analysis from the Phase 3 Study of L-Glutamine in Sickle Cell Anemia

Blood ◽

10.1182/blood-2018-99-119720 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1065-1065 ◽

Cited By ~ 2

Author(s):

Yutaka Niihara ◽

Charles William Stark ◽

Rafael Razon ◽

Lan T Tran ◽

Joseph M Becerra ◽

...

Keyword(s):

Sickle Cell ◽

Treatment Effect ◽

Rate Ratio ◽

Negative Binomial ◽

The United States ◽

Acute Chest Syndrome ◽

Employment Equity ◽

Phase 3 ◽

Equity Ownership ◽

Rate Ratios

Abstract Background: A Phase 3, double-blind, randomized, placebo-controlled trial of L-glutamine in 230 patients (ages 5-58) over 48 weeks was conducted at 31 centers in the United States. Twice daily oral L-glutamine or placebo was administered, based on body weight approximating 0.3 g/kg/dose. The primary endpoint was the number of sickle cell crises pain (SCCs) during 48 weeks of treatment. The treatment effect measured was the difference of the median number of SCCs between two arms at week 48. To qualify as an SCC, the patient had to have received treatment with I.V. narcotics/ketorolac at an emergency department or during hospitalization in patients with a history of ≥2 crisis from the previous year. Splenic sequestration, acute chest syndrome and priapism were also considered to be SCCs. Patients stabilized on hydroxyurea (HU) treatment for at least 3 months prior to study screening (66% in both arms of the study) remained on HU for the duration of the study. The primary analysis via a Cochran-Mantel-Haenszel (CMH) test statistic showed a highly significant treatment effect (p=0.005). There was a median of 3 crises for the L-glutamine treatment arm and 4 for the placebo arm (25% difference). There were no concerning adverse events from the treatment compared with the placebo arm. In this abstract, we reported the results from additional analyses of times to first and second crisis as well as cumulative recurrent events, which further demonstrated the clinically meaningful treatment effect of L-glutamine. Although not pre-specified as part of the study nor the drug approval process, external and internal reviewers of the data were interested in examining any differential effects of L-glutamine on patients that had either low, moderate or high frequencies of SCCs prior to study screening. Methods: An evaluation of the data was performed based on patients by three categories of crises; 2 crises (low), 3 - 5 (moderate) and ≥6 crises (high) as collected from their medical records at entry into the phase 3 study. The negative binomial regression (NBR) model was used to ascertain the rate ratios (rate of crises of L-glutamine assignment arm divided by the rate of crises on placebo). The NBR model was utilized to generate an estimate of treatment effect and treatment by subgroup interactions for the three subgroups. A rate ratio < 1.0 favored L-glutamine treatment effect. A significant interaction could be seen if the treatment arm is better than placebo for one category but worse than placebo for another. Subgroups with corresponding sample sizes were as follows: 2 SCCs in year prior: L-glutamine (n = 53) and placebo (n = 26). 3-5 SCCs in year prior: L-glutamine (n = 76) and placebo (n = 36). ≥6 SCCs in year prior: L-glutamine (n = 22) and placebo (n = 16). Results: Rate ratios (bolded) as shown in Table 1 were similar between all categories (2 crises, 3 to 5 crises, and ≥ 6 crises; 0.87, 0.74, and 0.82, respectively). There was no difference in treatment effect among the categories. These findings are confirmed by the lack of treatment by the prior year SCCs interaction; p = 0.8397. Numerically and graphically (Figure 1), there is an apparent lower rate ratio in those that had 3 to 5 SCCs in the year prior to screening. Discussion: The number of crises in the year prior to study screening is viewed as an indicator of disease severity, although this may not always be true due to the intra-patient variability in disease presentation. The apparent lower rate ratio in those that had 3 to 5 SCCs in the year prior to screening may be due to having the largest sample size of the three categories., The analysis indicates that the benefit of L-glutamine treatment observed in the phase 3 trial is consistent regardless of the history (one year) of SCCs prior to the initiation of L-glutamine therapy. Reference:A Phase 3 Trial of l-Glutamine in Sickle Cell Disease | NEJM. New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa1715971. Published 2018. Accessed July 24, 2018. Disclosures Niihara: Emmaus Medical, Inc: Employment, Equity Ownership. Stark:Emmaus Medical, Inc: Employment, Equity Ownership. Razon:Emmaus Medical, Inc: Employment, Equity Ownership. Tran:Emmaus Medical, Inc: Employment, Equity Ownership. Becerra:Emmaus Medical, Inc: Employment.

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A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s dementia

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00795-7 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Shifu Xiao ◽

Piu Chan ◽

Tao Wang ◽

Zhen Hong ◽

Shuzhen Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trial ◽

Controlled Trial ◽

Drug Effects ◽

Disease Assessment ◽

Phase 3 ◽

Double Blind ◽

Double Blind Placebo ◽

The Difference

Abstract Background New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China. Methods We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. Results A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was − 2.15 points (95% confidence interval, − 3.07 to − 1.23; p < 0.0001; effect size 0.531) after 36 weeks of treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group. Conclusions GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated. Trial registration ClinicalTrials.gov, NCT02293915. Registered on November 19, 2014

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Apixaban Reduces Hospitalization In Patients With Venous Thromboembolism: An Analysis Of The AMPLIFY-EXT Trial

Blood ◽

10.1182/blood.v122.21.3638.3638 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3638-3638 ◽

Cited By ~ 3

Author(s):

Xianchen Liu ◽

John Thompson ◽

Hemant Phatak ◽

Jack Mardekian ◽

Anthony R. Porcari ◽

...

Keyword(s):

Placebo Group ◽

Venous Thromboembolism ◽

Controlled Trial ◽

Anticoagulation Therapy ◽

Cox Proportional Hazards ◽

Employment Equity ◽

Double Blind ◽

Significant Difference ◽

Equity Ownership

Abstract Introduction Venous thromboembolism (VTE) is associated with a considerable risk for morbidity and recurrence and related hospitalizations. In the Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy-Extended Treatment (AMPLIFY-EXT) trial, a double-blind placebo-controlled trial with 12 months of treatment, two doses of apixaban (2.5 mg and 5 mg, twice daily) versus placebo significantly reduced symptomatic recurrent VTE or all-cause death without increasing the rate of major bleeding among 2,482 VTE patients who had completed 6-12 months of anticoagulation therapy. In this study, the effects of apixaban therapy versus placebo on medical hospitalization during AMPLIFY-EXT trial were evaluated. Methods A total of 2,477 patients who received study drugs were included in the analysis. All-cause hospitalizations during the trial were captured by dedicated case report forms. Outcomes of interest were; rate of hospitalizations and time from randomization to the first hospitalization. Patients were censored at either death, loss to follow-up, or end of study, whichever came first. Effects of treatment with apixaban versus placebo on the rates of hospitalization were assessed using Cox proportional hazards regression models. Results During a mean follow-up of 12.3 months, 138 patients were hospitalized at least once, 62 (7.5%/year) in the placebo group (n=826), 42 (4.8%/year) in the apixaban 2.5 mg group (n=840), and 34 (4.0%/year) in the apixaban 5 mg group (n=811). Compared with placebo, apixaban 2.5 mg [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.44–0.96; p=0.030] and 5 mg (HR 0.54, 95%CI 0.36–0.83, p=0.004) were both associated with significant reduction in hospitalization. There was no significant difference in hospitalizations between the 2 doses of apixaban (5 mg vs. 2.5 mg: HR 0.84, 95%CI 0.53–1.32, p=0 .445). The mean time to first hospitalization was 153.7 days in the placebo group, 196.9 days in the apixaban 2.5 mg group, and 202.4 days in the apixaban 5 mg group (Figure). Conclusions Extended anticoagulation with apixaban at either a dose of 5 mg or 2.5 mg significantly reduced the risk of hospitalization, possibly due to the reduction in VTE recurrence. Disclosures: Liu: Pfizer: Employment, Equity Ownership. Thompson:Pfizer: Employment, Equity Ownership. Phatak:BMS: Employment, Equity Ownership. Mardekian:Pfizer: Employment, Equity Ownership. Porcari:Pfizer: Employment, Equity Ownership. Johnson:Pfizer: Employment, Equity Ownership.

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Placebo-Controlled, Double-Blind, First-In-Human, Ascending Single Dose and Multiple Dose, Healthy Subject Study Of Intravenous-Administered SelG1, a Humanized Anti-P-Selectin Antibody In Development For Sickle Cell Disease

Blood ◽

10.1182/blood.v122.21.970.970 ◽

2013 ◽

Vol 122 (21) ◽

pp. 970-970 ◽

Cited By ~ 4

Author(s):

Jonathan W. Stocker ◽

Debra Mandarino ◽

Ziad Kawar ◽

Richard Alvarez ◽

David Falconer ◽

...

Keyword(s):

Single Dose ◽

Sickle Cell ◽

Multiple Dose ◽

Study Drug ◽

Cell Disease ◽

Employment Equity ◽

Double Blind ◽

Equity Ownership ◽

Clinically Significant ◽

Dose Dependent

Abstract SelG1 is a humanized anti-P-selectin monoclonal antibody being developed as a treatment for sickle cell disease (SCD). Extensive data have been published that suggest a pivotal role for P-selectin in the pathophysiology of SCD. Much of this work has been conducted in mice engineered to express human β hemoglobin S (sickle cell hemoglobin). These mice have a remarkably similar disease pathology to that observed in human SCD including vasoocclusion. Using these mice, investigators have demonstrated P-selectin interactions between the endothelium and sickled red blood cells, leukocytes and platelets. Additional studies have demonstrated direct P-selectin mediated binding of leukocytes with platelets. All of these cell-cell interactions have been implicated in SCD vasoocclusion. Further, blockade or genetic absence of P-selectin decreases or eliminates these cell-cell interactions and vasoocclusion. A Phase I clinical study was conducted to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of SelG1. This was a single-center, double-blind, placebo-controlled, first-in-human, ascending single dose and multiple dose study of intravenous (IV)-administered SelG1 in healthy adult male and female subjects. There were 5 dosing cohorts in the study (A through E): Ascending single dose cohorts: Cohort A:0.2 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort B:0.5 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort C:1.0 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort D:5.0 mg/kg IV dose of SelG1 (n=6) or placebo (n=2). Multi-dose cohort: Cohort E:two 8.0 mg/kg IV doses of SelG1 (n=5) or placebo (n=2); the doses were given 2 weeks apart. In Cohorts A through D, SelG1 was slowly eliminated (mean t1/2 = 75.6 to 500 hours). Mean t1/2 values increased in a dose dependent manner. The exposure to SelG1 (mean Cmax, AUC0-t, and AUC0-∞) increased in a greater than proportional manner over the dose range. In Cohort E, SelG1 was slowly eliminated (mean t1/2 = 363 hours for the second infusion). The mean Cmax and AUC0-336values were 1.6- and 1.7-fold higher, respectively, after the second infusion relative to the first infusion. The PD data demonstrate that P-selectin function was completely blocked for a minimum of 28 days in Cohort D and at least 56 days in Cohort E. Twenty-six of the 27 subjects who received study drug completed the study, with 1 placebo subject in Cohort D withdrawing himself from the study due to the required travel commitment. There were no deaths, serious adverse events, or severe AEs reported in any subject. There were no increases in the number or severity of AEs with increasing dosages or with multi-dose administration. The percentage of subjects experiencing an AE was similar between the SelG1-treated subjects and the placebo-treated subjects; in Cohorts A-D, 66.7% of SelG1-treated subjects and 60.0% of placebo subjects reported at least 1 AE, while in Cohort E, 60.0% of SelG1-treated subjects and 50.0% of placebo-treated subjects reported at least 1 AE. Only 1 AE occurred in more than 1 subject; vessel puncture site hematoma occurred in 1 subject of Cohort A, 1 subject of Cohort C, and 2 subjects of Cohort E. All other AEs occurred in only 1 subject and were mild to moderate in severity. No AEs in any subject were deemed “related” to study drug. No clinically significant findings were noted from vital sign measurements, physical examinations, or 12-lead ECGs for this study. No biochemistry, hematology, or other laboratory data were reported as clinically significant or were reported as AEs; there were no trends that indicated increases or decreases in mean or median values over time, and there were no dose-dependent increases or decreases in mean or median values. There were no demonstrable changes in coagulation parameters or increased bleeding tendencies. No specific antibody response to SelG1 occurred in any of the subjects. In summary, the administration of SelG1 was well tolerated in this group of healthy male and female subjects. A Phase II clinical study to evaluate the clinical efficacy of SelG1 in SCD patients is currently underway. Disclosures: Stocker: Selexys Pharmaceuticals: Employment, Equity Ownership. Mandarino:Selexys Pharmaceuticals: CRO Other. Kawar:Selexys Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Alvarez:Selexys Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Falconer:Selexys Pharmaceuticals: Employment, Equity Ownership. Rollins:Selexys Pharmaceuticals: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Rother:Selexys Pharmaceuticals: Employment, Equity Ownership.

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Correlation of Voxelotor Exposure with Hemoglobin Response and Measures of Hemolysis in Patients from the HOPE Study

Blood ◽

10.1182/blood-2019-130802 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1020-1020 ◽

Cited By ~ 2

Author(s):

Jo Howard ◽

Elliott Vichinsky ◽

Jennifer Knight-Madden ◽

Margaret Tonda ◽

Carla Washington ◽

...

Keyword(s):

Sickle Cell ◽

Research Funding ◽

Organ Damage ◽

Advisory Board ◽

Pharmacodynamic Modeling ◽

Employment Equity ◽

Double Blind ◽

Hydroxyurea Treatment ◽

Travel Grant ◽

Equity Ownership

Background: Sickle cell disease (SCD) is an inherited disorder in which pathology is driven by hemoglobin (Hb) polymerization and red blood cell sickling, leading to chronic hemolysis and anemia as well as episodic vaso-occlusion. These manifestations of SCD contribute to the cumulative organ damage that leads to disability and accelerated mortality. Voxelotor is a first-in-class therapy in development for the treatment of SCD that has been shown to increase Hb levels and reduce markers of hemolysis, consistent with inhibition of sickle Hb polymerization. The objective of this analysis was to evaluate the association between Hb response and markers of hemolysis in voxelotor-treated patients. Methods: The HOPE trial is a phase 3, randomized, placebo-controlled, double-blind, multicenter study comparing the efficacy and safety of voxelotor (1500 mg and 900 mg daily) versus placebo for ≥24 weeks in patients aged 12 to 65 years with SCD. The primary endpoint is the percentage of patients with a Hb response at week 24, defined as a >1.0 g/dL increase in Hb. Secondary endpoints include change in markers associated with hemolysis: absolute reticulocyte count and percentage of reticulocytes, indirect bilirubin level, and lactate dehydrogenase (LDH) level. The per-protocol population was defined as those who completed the week 24 visit of the assigned treatment regimen and who did not initiate hydroxyurea treatment between baseline and week 24. Pharmacokinetic/pharmacodynamic modeling was used to correlate voxelotor exposure with Hb response and measures of hemolysis. Results: A total of 229 patients (n=74, voxelotor 1500 mg; n=79, voxelotor 900 mg; n=76, placebo) were included in the per-protocol analysis. Among patients receiving voxelotor 1500 mg, all measures of hemolysis were consistently lower for those with changes in Hb of >1 g/dL compared with those with changes of ≤1 g/dL (Table 1). In the 900 mg group, percentage of reticulocytes, bilirubin, and LDH were lower for those with changes in Hb of >1 g/dL compared with those with changes of ≤1 g/dL; this pattern was not seen for absolute reticulocytes in this cohort. Generally, the degree of reduction in hemolysis markers was greater in the 1500 mg arm compared with the 900 mg arm. Linear relationships between voxelotor exposure and Hb and LDH response were observed. In addition, saturable relationships between reticulocytes and bilirubin were also observed. Conclusions: Among patients treated with voxelotor, those with Hb changes of >1.0 g/dL had the greatest reductions in the markers of hemolysis. In addition, patients with Hb changes of >1 g/dL and who received voxelotor 1500 mg had lower hemolytic markers than those who received voxelotor 900 mg, suggesting that exposure to a higher dose of voxelotor results in a greater decrease in hemolysis markers. Taken together, these results suggest that the mechanism by which voxelotor raises Hb is related to a reduction in hemolysis, which may modify the morbidity of SCD by improving hemolytic anemia. Disclosures Howard: Imara: Consultancy, Other: Travel grant; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Resonance Health: Other: Travel grant. Vichinsky:Global Blood Therapeutics: Consultancy; Agios: Research Funding; Pfizer: Research Funding. Knight-Madden:Global Blood Therapeutics: Research Funding; Nova Laboratories: Advisory Board on SCD 2017, Research Funding; Global Blood Therapeutics: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Addmedica: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; BlueBird Bio: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Abbott Nutrition: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Abbot International: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Nova Laboratories: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Pfizer: Other: Advisory Board on SCD 2017. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Washington:Global Blood Therapeutics: Employment, Equity Ownership. Tong:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Gordeuk:Emmaus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Imara: Research Funding; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Ironwood: Research Funding; Inctye: Research Funding; Pfizer: Research Funding; Inctye: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Modus Therapeutics: Consultancy, Honoraria; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; Emmaus: Consultancy, Honoraria; Ironwood: Research Funding; Modus Therapeutics: Consultancy, Honoraria; Imara: Research Funding; Pfizer: Research Funding.

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A 36-week Multicenter, Randomised, Double-blind, Placebo-controlled, Parallel-group, Phase 3 Clinical Trial of Sodium Oligomannate for Mild-to-Moderate Alzheimer's Dementia

10.21203/rs.3.rs-108812/v1 ◽

2020 ◽

Author(s):

Shifu Xiao ◽

Piu Chan ◽

Tao Wang ◽

Zhen Hong ◽

Shuzhen Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trial ◽

Controlled Trial ◽

Drug Effects ◽

Disease Assessment ◽

Phase 3 ◽

Double Blind ◽

Double Blind Placebo ◽

The Difference

Abstract Background: New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide which reconstitutes gut microbiota, reduces neuroinflammation, decreases amyloid deposition, and improves cognition in AD animal models. The first phase 3 clinical trial of GV-971 has been completed in China. Methods: We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. Results: 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time-point, measurable at the week 4 visit and continuing throughout the trial. The difference between groups in change from baseline was −2.15 points (95% confidence interval, −3.07 to −1.23; P<0.0001; effect size 0.531) after 36 weeks treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group.Conclusions: GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well tolerated. Trial registration: ClinicalTrials.gov, NCT02293915. Registered on November 19, 2014.

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Phase 3 Study of L-Glutamine in Sickle Cell Disease: Analyses of Time to First and Second Crisis and Average Cumulative Recurrent Events

Blood ◽

10.1182/blood.v130.suppl_1.685.685 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 685-685

Author(s):

Yutaka Niihara ◽

Rafael Razon ◽

Suvankar Majumdar ◽

Brian Claggett ◽

Onyinye C. Onyekwere ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Treatment Effect ◽

Recurrent Events ◽

Recurrent Event ◽

Cell Disease ◽

Employment Equity ◽

Phase 3 ◽

Hazard Ratios ◽

Equity Ownership

Abstract Background A Phase 3, double-blind, randomized, placebo-controlled trial of L-glutamine in 230 patients (ages 5-58) over 48 weeks was conducted at 31 centers in the United States. Twice daily oral administration of L-glutamine or placebo was based on body weight approximating 0.3 g/kg/dose. The primary endpoint was the number of sickle cell crises (SCCs) during 48 weeks of follow-up. The treatment effect measured was the difference of two median numbers of SCCs between two arms by week 48. The SCCs required treatment with I.V. narcotics/ketorolac at an emergency department or during hospitalization in patients with a history of ≥ 2 crisis from the previous year. Splenic sequestration, acute chest syndrome and priapism were also considered to be SCCs. Patients stabilized on hydroxyurea (HU) treatment for at least 3 months prior to study screening (66% in both arms of the study) remained on HU for the duration of the study. The primary analysis via a Cochran-Mantel-Haenszel (CMH) test statistic showed a highly significant treatment effect (p=0.005). There was a median of 3 crises for the L-glutamine treatment arm and 4 for the placebo arm (25% difference). There were no concerning adverse events from the treatment compared with the placebo arm. In this abstract, we reported the results from additional analyses of times to first and second crisis as well as cumulative recurrent events, which further demonstrated the clinically meaningful treatment effect of L-glutamine. Methods The Kaplan-Meier estimates are constructed with the data from the times to the first and second SCC for both arms. The corresponding estimates of the hazard ratios with confidence intervals and p-values are obtained to evaluate the relative merit of two groups. The 50% quartile (median) of the curve and the 95% confidence interval were reported by treatment. Furthermore, recurrent event time analysis was also performed using the Andersen-Gill procedure as well as the robust method by Lin, Wei, Yang and Ying to estimate the intensity rates. Results L-glutamine therapy significantly prolonged the time to first and the time to second SCCs. The median time to first crisis was delayed by 30 days (84 days vs. placebo 54 days; p=0.0152) and the median time to second crisis was delayed by 79 days (212 days vs. placebo 133 days; p=0.0260). Hazard ratios for the time to first and second crisis were similar (0.69 and 0.68 respectively), suggesting an approximately 30% hazard reduction from the treatment (Figures 1 and 2). Both cumulative recurrent event analyses models for SCCs yielded an intensity rate ratio of 0.75 with 95% confidence intervals based on the Andersen-Gill of (0.62, 0.90) and Lin, Wei, Yang and Ying of (0.55, 1.01), respectively (Figure 3). This suggested that the average cumulative crisis count was reduced by approximately 25% over the entire 48-week period. Cumulative event curve separation was clear by day 30 of treatment and was maintained over the 48-week study period. Conclusion The results of the primary endpoint using time to event analytical methods substantiated the original CMH test result that L-glutamine treatment provided clinical benefit in reducing crises, and other acute complications of sickle cell disease, in patients 5 years of age and older irrespective of hydroxyurea use. EndariTM (L-glutamine oral powder) is now FDA-approved to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older. Disclosures Niihara: Emmaus Medical, Inc: Employment, Equity Ownership. Razon: Emmaus Medical, Inc: Employment. Wood: Emmaus Medical, Inc: Employment, Equity Ownership. Singh: Emmaus Medical, Inc: Employment. Tran: Emmaus Medical, Inc: Employment, Equity Ownership. Stark: Emmaus Medical, Inc: Employment, Equity Ownership.

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A Randomized, Double-Blind, Adaptive Phase 2 Multi-Center Study of Prasugrel Compared to Placebo in Adults with Sickle Cell Disease

Blood ◽

10.1182/blood.v118.21.847.847 ◽

2011 ◽

Vol 118 (21) ◽

pp. 847-847 ◽

Cited By ~ 1

Author(s):

Ted Wun ◽

Denis Soulieres ◽

Lakshmanan Krishnamurti ◽

Abdullah Kutlar ◽

Kenneth Ataga ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Research Funding ◽

Study Drug ◽

Medical Attention ◽

Phase 2 ◽

Cell Disease ◽

Employment Equity ◽

Double Blind ◽

Equity Ownership

Abstract Abstract 847FN2 Introduction: Platelet activation may play a role in the pathogenesis of various complications related to sickle cell disease (SCD). Older studies of antiplatelet agents in reducing the frequency and severity of pain in SCD have been inconclusive. Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndrome undergoing percutaneous coronary intervention. We undertook a study to determine the safety, pharmacodynamics and possible efficacy of prasugrel in adult patients with SCD. Methods: This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo randomization ratio. Study drug was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Secondary endpoints included pain frequency and severity assessed by pain diary and pharmacodynamic effects measured by VerifyNow” P2Y12 reactivity units (VN PRU) and vasodilator stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). If interim analysis of pharmacodynamic data revealed insufficient platelet inhibition in the first 16 patients randomized to 5 mg daily prasugrel, the dose was to be escalated to 7.5 mg. Results: Forty-one patients were randomized to the prasugrel arm and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients (44%) in the prasugrel and 9 (43%) in the placebo arm were on hydroxyurea prior to study drug initiation. These characteristics were balanced between the treatment arms, as was baseline pain intensity (average pain score on a scale of 0 to 9 over 7 days prior to study drug). No hemorrhagic event required medical attention. Eight (20%) of patients in the prasugrel arm had hemorrhagic adverse events of which 6 (15%) were possibly related to study drug versus 1 (5%) in the placebo arm; all were mild except one moderate menorrhagia in a prasugrel-treated patient. There were numerical decreases in median and mean pain rate (% of days with pain) and intensity in the prasugrel arm compared to placebo but this did not reach statistical significance (Figure 1). The proportion of pain episodes requiring medical attention was also numerically lower: 23% prasugrel versus 37% placebo. There was measurable platelet inhibition as assessed by both VerifyNow” PRU and VASP PRI such that no dose escalation was necessary (Figure 2). Conclusions: Prasugrel, 5 mg once daily for 30 days, had anticipated pharmacodynamic effect on platelets in adult patients with SCD, was well tolerated, and was not associated with serious hemorrhagic events. Despite the small size and short duration of this phase 2 study, there was a suggestion of decreased days with pain. These data provide a rationale for a Phase 3 study of prasugrel adequately powered to determine effects on relevant clinical outcomes such as pain rate, severity, and frequency of vaso-occlusive crisis. Disclosures: Wun: Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Krishnamurti:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Kutlar:Celgene: Research Funding; Novartis: Research Funding; Hemaquest: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Ataga:Adventrx: Consultancy; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership.

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Efficacy and Safety of Lenalidomide (LEN) Versus Placebo (PBO) in RBC-Transfusion Dependent (TD) Patients (Pts) with IPSS Low/Intermediate (Int-1)-Risk Myelodysplastic Syndromes (MDS) without Del(5q) and Unresponsive or Refractory to Erythropoiesis-Stimulating Agents (ESAs): Results from a Randomized Phase 3 Study (CC-5013-MDS-005)

Blood ◽

10.1182/blood.v124.21.409.409 ◽

2014 ◽

Vol 124 (21) ◽

pp. 409-409 ◽

Cited By ~ 8

Author(s):

Valeria Santini ◽

Antonio Almeida ◽

Aristoteles Giagounidis ◽

Stephanie Gröpper ◽

Anna Jonasova ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Efficacy And Safety ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Double Blind ◽

Equity Ownership ◽

Grade 3

Abstract Background: Treatment options for RBC-TD pts with lower-risk MDS without del(5q) who are unresponsive or refractory to ESAs are very limited. In a previous phase 2 study, MDS-002 (CC-5013-MDS-002), LEN was associated with achievement of RBC-transfusion independence (TI) ≥ 56 days in 26% of pts with IPSS Low/Int-1-risk MDS without del(5q) (Raza et al. Blood 2008;111:86-93). This international phase 3 study (CC-5013-MDS-005) compared the efficacy and safety of LEN versus PBO in RBC-TD pts with IPSS Low/Int-1-risk MDS without del(5q) unresponsive or refractory to ESAs. Methods: This multicenter, randomized, double-blind, parallel-group phase 3 study included RBC-TD pts (≥ 2 units packed RBCs [pRBCs]/28 days in the 112 days immediately prior to randomization) with IPSS Low/Int-1-risk MDS without del(5q), who were unresponsive or refractory to ESAs (RBC-TD despite ESA treatment with adequate dose and duration, or serum erythropoietin [EPO] > 500 mU/mL). Pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40–60 mL/min) or PBO. Pts with RBC-TI ≥ 56 days or erythroid response by Day 168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was RBC-TI ≥ 56 days (defined as absence of any RBC transfusions during any 56 consecutive days). Secondary endpoints included time to RBC-TI, duration of RBC-TI, RBC-TI ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety. Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of LEN response. Clinical trial identifier: CT01029262. Results: The intent-to-treat population comprises 239 pts (LEN, n = 160; PBO, n = 79). Baseline characteristics were comparable across treatment groups; median age 71 years (range 43–87), 67.8% male, and median time from diagnosis 2.6 years (range 0.1–29.6). Pts received a median of 3.0 pRBC units/28 days (range 1.5–9.8) and 83.7% received prior therapy, including ESAs (78.7%). Significantly more LEN pts achieved RBC-TI ≥ 56 days versus PBO (26.9% vs 2.5%; P < 0.001; Table). The majority (90%) of pts with RBC-TI ≥ 56 days responded within 16 weeks of treatment. Median duration of RBC-TI ≥ 56 days was 8.2 months (range 5.2–17.8). Baseline factors significantly associated with achievement of RBC-TI ≥ 56 days with LEN were: prior ESAs (vs no ESAs; P = 0.005), serum EPO ≤ 500 mU/mL (vs > 500 mU/mL; P = 0.015), < 4 pRBC units/28 days (vs ≥ 4 pRBC units/28 days; P = 0.036), and female sex (vs male; P = 0.035). RBC-TI ≥ 168 days was achieved in 17.5% and 0% of pts in the LEN and PBO groups, respectively. The incidence of AML progression (per 100 person-years) was 1.91 (95% CI 0.80–4.59) and 2.46 (95% CI 0.79–7.64) for LEN and PBO pts, respectively, with median follow-up 1.6 and 1.3 years. Death on treatment occurred in 2.5% of pts on either LEN or PBO. The follow-up period was insufficient to permit OS comparison between the 2 groups. Myelosuppression was the main adverse event (AE); in the LEN versus PBO groups, respectively, grade 3–4 neutropenia occurred in 61.9% versus 11.4% of pts, and grade 3–4 thrombocytopenia in 35.6% versus 3.8% of pts. Discontinuations due to AEs were reported in 31.9% LEN and 11.4% PBO pts; among the 51 LEN pts who discontinued due to AEs, 14 discontinuations were due to thrombocytopenia and 8 due to neutropenia. In the subset of pts evaluated for the Ebert signature (n = 203), the predictive power of the signature was not confirmed. Conclusions: LEN therapy was associated with a significant achievement of RBC-TI ≥ 56 days in 26.9% of pts with a median duration of RBC-TI of 8.2 months; 90% of pts responded within 16 weeks of treatment. These data were consistent with response rates seen in the MDS-002 trial. The overall safety profile was consistent with the known safety profile of LEN and these data suggest LEN can be safely and effectively used in this patient population. Figure 1 Figure 1. Disclosures Santini: Celgene Corporation: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria. Off Label Use: Trial of Lenalidomide in non-del5q MDS. Almeida:Celgene Corporation: Consultancy, Speakers Bureau. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Vey:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Research Funding. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Shpilberg:Celgene Corporation: Consultancy, Honoraria. del Canizo:Celgene Corporation: Consultancy, Research Funding. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ozawa:Celgene: Consultancy, not specified Other. Zhong:Celgene: Employment, Equity Ownership. Séguy:Celgene: Employment, Equity Ownership. Hoenekopp:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

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