Epoetin Delta, Erythropoietin Produced in a Human Cell Line, Is as Effective as Epoetin Alfa in the Treatment of Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1296-1296
Author(s):  
Michael Smyth ◽  
Raymond D. Pratt
Keyword(s):  
Adverse Events ◽  
Hematological Parameters ◽  
Human Cell Line ◽  
Target Range ◽  
Epoetin Alfa ◽  
Open Label ◽  
Double Blind ◽  
Open Label Phase ◽  
The Difference ◽  
Average Hemoglobin

Abstract Epoetin therapy for anemia in patients with chronic kidney disease (CKD) is widespread and effective. Currently available erythropoietins are produced in Chinese hamster ovary (CHO) cell lines. Epoetin delta (Dynepo®, Shire plc) is the only erythropoietin synthesized in a human cell line. We report data from a 24-week, double-blind, active-comparator study, followed by a 28 week open-label phase, designed to test whether epoetin delta was as effective as epoetin alfa in the treatment of anemia in patients receiving hemodialysis. Patients with hemoglobin levels of 9.6–12.4 g/dL who had been receiving epoetin therapy for at least 90 days were eligible for entry to the study. Patients were randomized to epoetin delta or epoetin alfa in a 3:1 ratio with the first dose of study medication identical to the last dose the patient received before entering the study. Subsequent dosing was adjusted according to a predefined algorithm to maintain hemoglobin within the target range of 10–12 g/dL. Efficacy was evaluated on the basis of weekly determinations of hematological parameters (hemoglobin, hematocrit, red blood cell [RBC] and reticulocyte count). The primary efficacy endpoint was average hemoglobin over Weeks 12, 16, 20 and 24 and to demonstrate that the difference in hemoglobin levels between the two groups was less than 1g/dL (90% CI contained within the range -1 to 1). Other key efficacy measures included the percentage of hemoglobin levels > 10g/dL and hematocrit levels > 30% and profiles of hematological parameters from baseline to Week 52. From the randomized population, 555 patients received epoetin delta and 191 received epoetin alfa. 583 finished the 24-week double-blind phase and all these patients passed into the open-label phase to be treated with epoetin delta. Adjusted average hemoglobin over Weeks 12–24 was 11.57 g/dL for the epoetin delta group and 11.56 g/dL for the epoetin alfa group. The difference between the groups was 0.01g/dL with both 90% CI (-0.13; 0.15) and 95% CI (-0.16; 0.17) within the predefined acceptable range of -1 to 1 g/dL demonstrating equivalence between the agents. 89.5 % of patients receiving epoetin delta had hemoglobin levels > 10 g/dL compared with 91.5% of patients receiving epoetin alfa. Average hemoglobin levels were maintained in the target range until the end of the study with no need to increase mean dose. Overall, treatment with epoetin delta at a mean dose of 63.7 IU/kg maintained hemoglobin levels at an average value of 11.31 g/dL over Weeks 12 through to the end of the study. In the double-blind phase the overall incidence of adverse events was similar between the study groups and at levels expected given the baseline characteristics of the study population. Hypotension, upper respiratory infection, muscle cramps and headache were the most commonly reported events overall and the levels were similar between the groups. Adverse events considered possibly related to treatment occurred in 11.6% of patients receiving epoetin delta compared with 8.4% of patients receiving epoetin alfa. No patient in this study developed neutralizing anti-erythropoietin antibodies to either epoetin alfa or epoetin delta. Epoetin delta was demonstrated to be as effective as epoetin alfa for maintenance of hemoglobin levels in CKD patients requiring hemodialysis. Control of hemoglobin level was maintained over 52 weeks without the need to increase average dose and epoetin delta was well tolerated for up to one year of exposure.

OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial

Cephalalgia ◽  
2010 ◽  
Vol 30 (7) ◽  
pp. 793-803 ◽  
Author(s):  
SK Aurora ◽  
DW Dodick ◽  
CC Turkel ◽  
RE DeGryse ◽  
SD Silberstein ◽  
...  
Keyword(s):  
Adverse Events ◽  
Chronic Migraine ◽  
Primary Endpoint ◽  
Burden Of Illness ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Episode Frequency ◽  
Open Label Phase ◽  
Prophylaxis Therapy

Objectives: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine. Methods: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U–195 U; n = 341) or placebo ( n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24. Results: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (−5.2 vs. −5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days ( p = .006) and migraine days ( p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. Conclusions: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.

scholarly journals 32 Early-Onset Efficacy and Safety Pilot Study of Amphetamine Extended-Release Oral Suspension (AMPH EROS) in the Treatment of Children with Attention-Deficit/Hyperactivity Disorder

CNS Spectrums ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 191-192
Author(s):  
Ann C. Childress ◽  
Antonio Pardo ◽  
Thomas R. King ◽  
Judith C. Kando ◽  
Barry K. Herman
Keyword(s):  
Pilot Study ◽  
Adverse Events ◽  
Extended Release ◽  
Rating Scale ◽  
Upper Respiratory Tract ◽  
Open Label ◽  
Double Blind ◽  
Hyperactivity Disorder ◽  
Laboratory Classroom ◽  
Open Label Phase

ObjectiveTo determine whether amphetamine extended-release oralsuspension (AMPH EROS) has an onset of effect at 30minutes postdose inchildren with ADHD.MethodsThis randomized, double-blind, 2-treatment, 2-sequence, placebo-controlled crossover pilot study enrolled subjects aged 6 to 12 years withattention-deficit/hyperactivity disorder (ADHD) and ADHD-Rating Scale-5 scores of ≥90th percentile for sex and age. A dose of 5 to 20mg/day of AMPH EROS was determined during a 1-week open-label phase based on medication history, symptom control, and tolerability. Subjects completed a practice laboratory classroom then received one day of double-blind active drug or placebo each in random sequence during 2 double-blind laboratory classroom days. Subjects completed the first double-blind laboratory classroom session, returned to open label drug for 5days then crossed over on day 6 during a second double-blind laboratory classroom session. DB dose was fixed at AMPH EROS 15, 17.5, or 20mg . The primary endpoint was change from predose in the Swanson, Kotkin, Agler, M-Flynn, Pelham rating scale-combined score (SKAMP-C) at 30minutes postdose on two DB days. The key secondary endpoint was change from predose in the SKAMP-C score at 3hours postdose for AMPH EROS compared with placebo. Safety assessments included vital signs and adverse events.ResultsEighteen subjects were enrolled in the study (14 males and 4 females) with a mean age of 9 years. At both 30minutes and 3hours postdose, changes from baseline in SKAMP-C for AMPH EROS vs. placebo were statistically significant (p<0.01 and p=0.0002, respectively) with corresponding effect sizes of 0.96 and 1.57. Adverse events (>10%) during the open-label phase included upper respiratory tract infection, fatigue, upper abdominal pain, headache, decreased appetite, and affect lability.ConclusionsAMPH EROS was effective in reducing ADHD symptoms at 30minutes postdose. AEs were mild or moderate and consistent with those of other extended-release amphetamines.Funding Acknowledgements: Support was provided by Tris Pharma, Inc.

OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial

Cephalalgia ◽  
2010 ◽  
Vol 30 (7) ◽  
pp. 804-814 ◽  
Author(s):  
HC Diener ◽  
DW Dodick ◽  
SK Aurora ◽  
CC Turkel ◽  
RE DeGryse ◽  
...  
Keyword(s):  
Adverse Events ◽  
Chronic Migraine ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Efficacy And Safety ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Open Label Phase

Objectives: This is the second of a pair of studies designed to evaluate the efficacy and safety of onabotulinumtoxinA (BOTOX®) for prophylaxis of headaches in adults with chronic migraine. Methods: PREEMPT 2 was a phase 3 study, with a 24-week, double-blind, placebo-controlled phase, followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections of onabotulinumtoxinA (155U–195U; n = 347) or placebo ( n = 358) every 12 weeks for two cycles. The primary efficacy endpoint was mean change in headache days per 28 days from baseline to weeks 21–24 post-treatment. Results: OnabotulinumtoxinA was statistically significantly superior to placebo for the primary endpoint, frequency of headache days per 28 days relative to baseline (−9.0 onabotulinumtoxinA/−6.7 placebo, p < .001). OnabotulinumtoxinA was significantly favoured in all secondary endpoint comparisons. OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few patients (3.5% onabotulinumtoxinA/1.4% placebo) discontinued due to adverse events. Conclusions: The results of PREEMPT 2 demonstrate that onabotulinumtoxinA is effective for prophylaxis of headache in adults with chronic migraine. Repeated onabotulinumtoxinA treatments were safe and well tolerated.

scholarly journals Switching from Epoetin Alfa (Epogen®) to Epoetin Alfa-Epbx (RetacritTM) Using a Specified Dosing Algorithm: A Randomized, Non-Inferiority Study in Adults on Hemodialysis

2018 ◽  
Vol 48 (3) ◽  
pp. 214-224 ◽  
Author(s):  
Ravi Thadhani ◽  
Ruffy Guilatco ◽  
Jeffrey Hymes ◽  
Franklin W. Maddux ◽  
Ajay Ahuja
Keyword(s):  
Standard Of Care ◽  
Target Range ◽  
Maintenance Hemodialysis ◽  
Similar Proportion ◽  
Epoetin Alfa ◽  
Open Label ◽  
Dosing Algorithm ◽  
Significant Difference ◽  
Full Analysis ◽  
The Difference

Background: For patients with anemia undergoing hemodialysis, erythropoiesis-stimulating agents (ESAs) are typically dosed via precise algorithms. Using one such algorithm, we assessed the maintenance of hemoglobin levels in patients switched from epoetin alfa reference product (Epogen®) to epoetin alfa-epbx (RetacritTM; a biosimilar to US-licensed Epogen®/Procrit®). Methods: This randomized, open-label, non-inferiority study was conducted at Fresenius Medical Care North America (FMCNA) hemodialysis centers. Patients with anemia and chronic kidney disease undergoing maintenance hemodialysis and receiving routine intravenous (IV) Epogen® were randomized 1: 1 to switch to IV RetacritTM or continue standard-of-care (Epogen®) for 24 weeks, using analogous versions of the FMCNA ESA-dosing algorithm. The primary endpoint was the proportion of time patients’ hemoglobin was 9–11 g/dL during weeks 17–24. Results: Of 432 randomized patients, 418 received treatment (RetacritTM, n = 212; standard-of-care, n = 206) and comprised the full analysis set. A similar proportion of patients discontinued from each arm. The proportion of time patients’ hemoglobin was within the target range was 61.9% (95% CI 57.5–66.2) in the RetacritTM arm and 63.3% (95% CI 58.7–67.7) in the standard-of-care arm. The difference in proportions between treatment arms was –1.4% (95% CI –7.6 to 4.9), and the lower bound of the confidence interval was within the pre-specified non-inferiority margin of –12.5%. There was no statistically significant difference between arms in the mean change from baseline in the weekly mean ESA dose during weeks 17–24, and no clinically relevant differences in safety outcomes. Conclusions: Switching to RetacritTM was non-inferior to continuing ­Epogen® in maintaining hemoglobin levels in patients receiving hemodialysis, when both ESAs were dosed using a specified algorithm (ClinicalTrials.gov, NCT02504294).

scholarly journals Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Hang Quach ◽  
Simon J Harrison ◽  
Je-Jung Lee ◽  
Nichloas Murphy ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Research Funding ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Biweekly Raltitrexed in Combination with Irinotecan (RIR) as Second-Line Therapy for Patients with Metastatic Colorectal Cancer: A Non-Randomized, Open-Label Phase II Trial.

2020 ◽  
Author(s):  
Ke Cheng ◽  
Yu-Wen Zhou ◽  
Ye Chen ◽  
Zhi-Ping Li ◽  
Meng Qiu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Overall Response Rate ◽  
Progression Free Survival ◽  
Second Line ◽  
Open Label ◽  
Second Line Therapy ◽  
Free Survival ◽  
Common Grade ◽  
Open Label Phase ◽  
Grade 3

Abstract Background Irinotecan-based doublet chemotherapy strategy was standard second-line backbone treatment for patients with oxaliplatin‑refractory metastatic colorectal cancer(mCRC). The aim of this study was to evaluate tolerability and efficacy of raltitrexed combined with irinotecan biweekly administered as the second-line therapy for mCRC patients.Methods The study was a single-center, non-randomized, open-label phase II trial. Patients with mCRC after failure with first-line treatment of oxaliplatin and fluoropyrimidine or its derivatives were enrolled. Irinotecan (180 mg/m2) and raltitrexed (2.5 mg/m2) were given intravenously on day 1. Cycles were repeated every 2 weeks. The primary endpoint was progression-free survival, and the secondary endpoints included overall response rate, disease control rate, overall survival and treatment related adverse events. Results Between December 2012 and October 2016, 35 patients were enrolled. 33 and 35 patients were assessed for response and safety, respectively. The overall response rate (ORR) was 8.6 %, and the disease control rate (DCR) was 71.4%. The median progression-free survival (PFS) was 4.5 months (95% CI 3.8–5.2). The median overall survival was 12.0 months (95% CI 8.5–15.5). Four patients received conversion therapy to no evidence of disease (NED), and 2 patients were still alive with beyond 24 months survival. The most common grade 3/4 hematological adverse events were leukopenia (8.6%), neutropenia (5.7%). The most common grade 3/4 nonhematological adverse events were anorexia (14.3%), vomiting (14.3%), nausea (11.4%) and fatigue (8.6%). Two patients discontinued the protocol treatment because of treatment-related gastrointestinal adverse events. No one died from treatment-related events. The incidence and severity of toxicity was irrelevant to UGT1A1 status.Conclusions The combination of irinotecan with raltitrexed is an active, convenient and acceptable toxic regimen for second-line treatment for mCRC patients, which needs further study as a chemotherapy backbone to be combined with targeted agents in mCRC.Trial registration No. ChiCTR-ONC-12002767. The study was registered with the Chinese Clinical Trial Registry at 29 Octorber 2012, http://www.chictr.org.cn/index.aspx.

scholarly journals Safety and effectiveness of lurasidone in adolescents with schizophrenia: results of a 2-year, open-label extension study

CNS Spectrums ◽  
2020 ◽  
pp. 1-11
Author(s):  
Christoph U. Correll ◽  
Robert L. Findling ◽  
Michael Tocco ◽  
Andrei Pikalov ◽  
Ling Deng ◽  
...  
Keyword(s):  
Body Weight ◽  
Adverse Events ◽  
Rating Scales ◽  
Extension Study ◽  
Open Label ◽  
Double Blind ◽  
Syndrome Scale ◽  
Open Label Extension ◽  
Glycemic Indices

Abstract Background Minimal long-term benefit: Risk data are available regarding antipsychotic treatments for schizophrenia in pediatric populations. This study evaluated the long-term safety, tolerability, and effectiveness of lurasidone in adolescents with schizophrenia. Methods Patients aged from 13 to 17 who completed 6 weeks of double-blind (DB), placebo-controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible dose (20-80 mg/day) lurasidone treatment study. Safety was assessed via spontaneous reporting, rating scales, body weight measurement, metabolic, and prolactin testing. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score. Results About 271 patients completed 6 weeks of DB treatment and entered the 2-year OL extension study. Altogether, 42.4% discontinued prematurely, 10.7% due to adverse events. During OL treatment, the most common adverse events were headache (24.0%); anxiety (12.9%), schizophrenia, and nausea (12.5%); sedation/somnolence (12.2%); and nasopharyngitis (8.9%). Minimal changes were observed on metabolic parameters and prolactin. Mean change from DB baseline in weight at week 52 and week 104 was +3.3 kg and + 4.9 kg, respectively, compared to an expected weight gain of +3.4 kg and + 5.7 kg, respectively, based on the sex- and age-matched US Center for Disease Control normative data. Continued improvement was observed in PANSS total score, with mean change from OL baseline of −15.6 at week 52 and −18.4 at week 104. Conclusion In adolescents with schizophrenia, long-term lurasidone treatment was associated with minimal effects on body weight, lipids, glycemic indices, and prolactin. Continued improvement in symptoms of schizophrenia was observed over 2 years of lurasidone treatment.

scholarly journals Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study of the Penetration of a Monoclonal Antibody Combination (ASN100) Targeting Staphylococcus aureus Cytotoxins in the Lung Epithelial Lining Fluid of Healthy Volunteers

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Zoltan Magyarics ◽  
Fraser Leslie ◽  
Johann Bartko ◽  
Harald Rouha ◽  
Steven Luperchio ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Dose Escalation ◽  
Human Study ◽  
Epithelial Lining ◽  
Open Label ◽  
Double Blind ◽  
Epithelial Lining Fluid ◽  
Double Blind Placebo

ABSTRACT ASN100 is a novel antibody combination of two fully human IgG1(κ) monoclonal antibodies (MAbs), ASN-1 and ASN-2, which neutralize six Staphylococcus aureus cytotoxins, alpha-hemolysin (Hla) and five bicomponent leukocidins. We assessed the safety, tolerability, and serum and lung pharmacokinetics of ASN100 in a randomized, double-blind, placebo-controlled single-dose-escalation first-in-human study. Fifty-two healthy volunteers were enrolled and randomized to receive either ASN-1, ASN-2, a combination of both MAbs (ASN100), or a corresponding placebo. Thirty-two subjects in the double-blind dose escalation portion of the study received ASN-1 or ASN-2 at a 200-, 600-, 1,800-, or 4,000-mg dose, or placebo. Eight subjects received both MAbs simultaneously in a 1:1 ratio (ASN100) at 3,600 or 8,000 mg, or they received placebos. Twelve additional subjects received open-label ASN100 at 3,600 or 8,000 mg to assess the pharmacokinetics of ASN-1 and ASN-2 in epithelial lining fluid (ELF) by bronchoalveolar lavage fluid sampling. Subjects were monitored for 98 days (double-blind cohorts) or 30 days (open-label cohorts) for safety assessment. No dose-limiting toxicities were observed, and all adverse events were mild and transient, with only two adverse events considered possibly related to the investigational product. ASN100 exhibited linear serum pharmacokinetics with a half-life of approximately 3 weeks and showed detectable penetration into the ELF. No treatment-emergent anti-drug antibody responses were detected. The toxin neutralizing potency of ASN100 in human serum was confirmed up to 58 days postdosing. The favorable safety profile, ELF penetration, and maintained functional activity in serum supported the further clinical development of ASN100.

Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years

2000 ◽  
Vol 6 (4) ◽  
pp. 255-266 ◽  
Author(s):  
K P Johnson ◽  
B R Brooks ◽  
C C Ford ◽  
A Goodman ◽  
J Guarnaccia ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Glatiramer Acetate ◽  
Relapse Rate ◽  
Open Label ◽  
Double Blind ◽  
Open Label Study ◽  
Label Study ◽  
Open Label Phase ◽  
Multiple Sclerosis Patients ◽  
To Receive

In a randomized, placebo-controlled, double-blind study, glatiramer acetate (Copaxone®) reduced the relapse rate and slowed accumulation of disability for patients with relapsing-remitting multiple sclerosis. Of the original 251 patients randomized to receive glatiramer acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug. The majority of the original double-blind cohort continues to receive glatiramer acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse. The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg glatiramer acetate were well tolerated. The mean annual relapse rate of the patients who received glatiramer acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34-0.51). The rate per year has continued to drop and for the sixth year is 0.23. Of the group who have received glatiramer acetate without interruption for 5 or more years, 69.3% were neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS). Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out. This study demonstrates the sustained efficacy of glatiramer acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with relapsing forms of multiple sclerosis.

An Open-Label Phase I Pharmacokinetic Study of [14c] Bendamustine in Patients with Relapsed or Refractory Malignancy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2476-2476 ◽  
Author(s):  
Anne-Charlotte Dubbelman ◽  
Hilde Rosing ◽  
Mona Darwish ◽  
Denise D'Andrea ◽  
Mary Bond ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Safety Profile ◽  
Half Life ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3 ◽  
Refractory Malignancy

Abstract Abstract 2476 Background: Bendamustine is a unique alkylating agent which combines a nitrogen mustard moiety of mechlorethamine with a benzimidazole. This study was conducted to characterize the distribution, metabolism, and elimination of [14C] bendamustine and its metabolites (M3, M4, and dihydroxy bendamustine [HP2]) and to assess the roles of renal and hepatic pathways in the drug's metabolism and excretion. A secondary objective was to further characterize the safety profile of single-agent bendamustine. Methods: This open-label, phase I study enrolled 6 patients, age ≥18 years, with confirmed relapsed or refractory malignancy. The study was divided into 2 assessment periods: period A, during which the mass balance and pharmacokinetics of [14C] bendamustine were investigated, and period B, an extended-use period of up to 6 cycles with non-labeled bendamustine, during which safety continued to be assessed. Patients received intravenous (IV) bendamustine (120 mg/m2), containing 80–95 μCi of [14C] bendamustine, on day 1 of cycle 1 and non-labeled IV bendamustine (120 mg/m2) on day 2 of cycle 1 (period A). Pharmacokinetic parameters of bendamustine and metabolites M3, M4, and HP2 were calculated through plasma and urine concentrations, which were determined through 24 hours following administration of bendamustine on day 1. Total radioactivity (TRA) levels were measured in plasma, urine, and feces collected prior to drug administration and at time points through 168 hours after patients received [14C] bendamustine. Collection of excreta could continue (after the 7-day period) on an outpatient basis: if radiolabeled bendamustine ≥1% of dose was measurable in the 144- to 168-hour urine or feces collection, collection continued until the recovery in each 24-hour urine or feces collection was <1% of dose. Results: Six patients (3 males; 3 females) with a median age of 66 (48–75) years were enrolled and completed the pharmacokinetic portion of the study. For bendamustine, the decline from peak plasma concentration was characterized by an initial rapid distribution phase, followed by a somewhat slower intermediate phase. The pharmacologically relevant half-life (t½) was approximately 40 minutes. The plasma concentrations of M3, M4, and HP2 were very low relative to the bendamustine concentrations. Of the TRA dose administered, approximately half of the dose was recovered in the urine and approximately a quarter of the dose was recovered in the feces. Less than 5% of TRA dose was recovered in the urine as unchanged bendamustine. Mean recovery of TRA in excreta was approximately 76% of the radiochemical dose. Total recovery was incomplete due to continued slow excretion of TRA at the end of the collection period. The sustained levels of radioactivity in the plasma as compared with plasma concentrations of bendamustine suggest that, despite the rapid clearance of bendamustine, 1 or more longer-lived [14C] bendamustine-derived materials remain in the plasma. These longer-lived materials likely include by-products of alkylation. As previously noted, bendamustine volume of distribution was small (Vss∼20 L). The steady-state volume of distribution for TRA was ∼50 L. These results confirm previous data and provide evidence that neither bendamustine nor TRA are extensively distributed into the tissues. All 6 patients withdrew prior to completion of period B due to disease progression (n = 4), an adverse event (n = 1), or refusal to continue treatment (n=1). Bendamustine was well tolerated when administered at a dosage of 120 mg/m2 for 2 to 3 cycles. The most frequent treatment-related adverse events were fatigue (50%) and vomiting (50%). A grade 3/4 absolute lymphocyte count decrease occurred in all patients at some point during the study. There were no other grade 3/4 hematologic adverse events. Conclusions: Bendamustine was extensively metabolized via multiple metabolic pathways, with subsequent excretion in both urine and feces. Bendamustine accumulation is not anticipated in cancer patients with renal or hepatic impairment due to the dose administration schedule and short intermediate half-life. Adverse events and hematologic changes were consistent with the known safety profile of bendamustine. This research was sponsored by and conducted by Cephalon, Inc., Frazer, PA. Disclosures: Darwish: Cephalon, Inc.: Employment. D'Andrea:Cephalon, Inc.: Employment. Bond:Cephalon, Inc.: Employment. Hellriegel:Cephalon, Inc.: Employment.

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