Inhibition of Interleukin-6 (IL-6) Reverses Anemia In Patients with Advanced Non Small Cell Lung Cancer (NSCLC): Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 640-640 ◽  
Author(s):  
Michael W. Schuster ◽  
James R Rigas ◽  
Sergey V Orlov ◽  
Branislav Milovanovic ◽  
Kumar Prabhash ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Chemistry ◽  
Controlled Trial ◽  
Safety Data ◽  
Primary Objective ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Reactive Protein ◽  
Grade 3 ◽  
Cancer Related Anemia

Abstract Abstract 640 Background: ALD518 is a humanized, desialyated anti-IL-6 antibody being developed for the treatment of cancer-related anemia, cachexia and fatigue. The primary objective of the study was to determine the efficacy and safety of ALD518 in patients with advanced NSCLC. Secondary objectives examined hematologic parameters. Methods: 124 patients with NSCLC, ECOG 0–3, weight loss in the preceding 3 months of >5% body weight, hemoglobin (Hb) >7g/dL, and C-reactive protein (CRP) >10mg/L were dosed. Patients were randomized to 1 of 4 groups (n~30/group). Placebo or ALD518 80mg, 160mg, or 320mg was administered intravenously every 8 weeks. Pts were followed up for 24 weeks. Data included hematologic parameters, clinical chemistry, CRP, D-dimer, lean body mass and adverse events (AEs). Quality of life data included the FACIT-F, FACT-L, and FAACT questionnaires. Data presented in this abstract relates to the safety and hematology results. Results: 29 pts completed the study treatments and evaluations, 38 failed to complete every visit, 52 died of progressive disease, and 5 withdrew because of adverse events. There were no dose limiting toxicities (DLTs), infusion reactions, or anti-idiotypic antibody responses to ALD518 observed in the study. 84 pts had serious AEs of which 1 was deemed to be possibly related to administration of ALD518 (rectal hemorrhage). The majority of the serious adverse events were due to progression of the NSCLC. Six patients had a CTC grade 4 change in laboratory safety data during the study. Four patients experienced a grade 4 hypercalcemia: 1 (3.6%), 2 (6.1%), and 1 (3.2%) in the ALD518 80mg, 160mg and placebo groups, respectively, and there was 1 patient with grade 4 GGT elevation (placebo) and 1 patient with grade 4 hypokalemia (ALD518 160mg). There were no treatment related differences in vitals sign or 12-lead ECG data. The mean (±SD) values for Hb, hematocrit (Hct), mean corpuscular Hb (MCH) and platelet counts are listed below: 38/93 pts treated with ALD518 and 10/31 given placebo had a pre-dose Hb =< 11g/dL. 24 of these pts on ALD518 and 7 of these pts on placebo remained in the study at week 4. 14/24 pts on ALD518 and 0/7 on placebo had raised their Hb from =< 11g/dL to >= 12g/dL. Conclusions: ALD518 increased Hb, Hct, MCH in NSCLC pts and raised Hb to >= 12g/dL in 58% of pts with a Hb =< 11g/dL at baseline. There was also a modest fall in platelet count observed in patients treated with ALD518 but no patients had a CTC grade 4 thrombocytopenia and only one patient (ALD518 160mg group) had a grade 3 thrombocytopenia at one time point. There were no major safety signals related to the administration of ALD518. Further study of ALD518 as a novel non-erythropoietic stimulating agent for cancer-related anemia is warranted. Disclosures: Schuster: Alder Biopharmaceuticals Inc: Honoraria. Rigas: Alder Biopharmaceuticals inc: Honoraria. Smith:Alder Biopharmaceuticals Inc: Employment.

A randomized phase II trial with gemcitabine with or without pertuzumab (rhuMAb 2C4) in platinum-resistant ovarian cancer (OC): Preliminary safety data

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13001-13001 ◽  
Author(s):  
D. Glenn ◽  
F. Ueland ◽  
A. Bicher ◽  
D. Dizon ◽  
M. Gold ◽  
...  
Keyword(s):  
Adverse Events ◽  
Controlled Trial ◽  
Single Agent ◽  
Safety Data ◽  
Study Drug ◽  
Hematological Toxicity ◽  
Serious Adverse Events ◽  
Platinum Resistant ◽  
Platinum Based Chemotherapy ◽  
Grade 3

13001 Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs). P inhibits dimerization of HER2 with EGFR, HER3 and HER4, and subsequently inhibits signaling through MAP and PI3 kinases. Single agent P has demonstrated clinical benefit in advanced OC (ASCO 2005 abstract #5051). Methods: 40 pts with platinum-resistant OC (progressed within 6 months of receiving a platinum-based chemotherapy) were enrolled in this 1:1 randomized, double blind, placebo controlled trial of gemcitabine with or without P. Gemcitabine was administered IV on day 1 and 8 at 800 mg/m2 of a 21 day cycle. Blinded placebo or 420 mg P was administered IV on day 1. Gemcitabine was dose reduced for neutropenia or thrombocytopenia. P was not dose reduced. Results: 40 pts have been enrolled and treated with at least 1 cycle of gemcitabine in combination with blinded study drug. The median age was 58.5 (range 18–82); 26 had PS ECOG 0, 13 ECOG 1, 1 ECOG 2. The most common grade 3/4 events were neutropenia in 7 pts (17.5%), thrombocytopenia in 6 pts (15%), small bowel obstruction in 4 pts (10%), constipation in 3 pts (7.5%) and elevated ALT in 3 pts (7.4%). There was one grade 3 diarrhea, but no grade 3 or 4 rash. There were 4 serious adverse events (SAEs) attributed to study drug. These were a pleural effusion, thrombocytopenia, febrile neutropenia, and a deep vein thrombosis. Nine pts required one or two dose reductions of gemcitabine for hematological toxicity. Of 29 pts with post-baseline echo or MUGA values obtained, no pt had LVEF drop to <50%. The adverse events evaluated after 40 pts did not meet the prespecified criteria to call for an independent safety monitoring board evaluation of unblinded data. Conclusions: Preliminary safety data indicate that pertuzumab or placebo combined with gemcitabine is well tolerated with no unexpected additive toxicity. The nature and frequency of the adverse events are similar to what has been observed with either single agent gemcitabine or P. Updated data will be presented at ASCO. [Table: see text]

scholarly journals Fostamatinib for the treatment of hospitalized adults with COVD-19 A randomized trial

2021 ◽  
Author(s):  
Jeffrey R Strich ◽  
Xin Tian ◽  
Mohamed Samour ◽  
Christopher S King ◽  
Oksana Shlobin ◽  
...  
Keyword(s):  
Immune Response ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Controlled Trial ◽  
Standard Of Care ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Reactive Protein ◽  
To Receive ◽  
Confirmatory Trials

Abstract Background Coronavirus Disease 2019 (Covid-19) requiring hospitalization is characterized by robust antibody production, dysregulated immune response and immunothrombosis. Fostamatinib, is a novel spleen tyrosine kinase inhibitor we hypothesize will ameliorate Fc activation and attenuate harmful effects of the anti-COVID-19 immune response. Methods We conducted a double-blind, randomized, placebo-controlled trial in hospitalized adults requiring oxygen with Covid-19 where patients receiving standard of care were randomized to receive fostamatinib or placebo. The primary outcome was serious adverse events by day 29. Results A total of 59 patients underwent randomization (30 to fostamatinib and 29 to placebo). Serious adverse events occurred in 10.5% of patients in the fostamatinib group compared to 22% in placebo (P = .2). Three deaths occurred by day 29, all receiving placebo. The mean change in ordinal score at day 15 was greater in the fostamatinib group (-3.6 ± 0.3 vs. -2.6 ± 0.4, P = .035) and the median length in the ICU was 3 days in the fostamatinib group vs. 7 days in placebo (P = .07). Differences in clinical improvement were most evident in patients with severe or critical disease (median days on oxygen, 10 vs. 28, P = .027). There were trends towards more rapid reductions in C-reactive protein, D-dimer, fibrinogen and ferritin levels in the fostamatinib group. Conclusion For COVID-19 requiring hospitalization, the addition of fostamatinib to standard of care was safe and patients were observed to have improved clinical outcomes compared to placebo. These results warrant further validation in larger confirmatory trials.

Open-label, phase IIIb, multicenter, expanded access study of everolimus in patients with advanced neuroendocrine tumors (NET).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4138-4138
Author(s):  
Oliver Edgar Bechter ◽  
Nicole Unger ◽  
Ivan Borbath ◽  
Sergio Ricci ◽  
Tsann-Long Hwang ◽  
...  
Keyword(s):  
Performance Status ◽  
Safety Data ◽  
Primary Objective ◽  
Phase Iii ◽  
Open Label ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Expanded Access ◽  
Open Label Phase ◽  
Grade 3

4138 Background: Everolimus (EVE) antitumor efficacy in patients (pts) with advanced NET was demonstrated in 2 double-blind, placebo (P)–controlled, phase III trials (RADIANT-2 and RADIANT-3). Median PFS in pancreatic (pNET) pts was 11.0 months (EVE) vs. 4.6 months (P) (HR 0.35, 95% CI 0.27-0.45, P <0.001) in RADIANT-3. Median EVE exposure in RADIANT-3 was 38 wks. EVE was approved for advanced pNET in the US and Europe in 2011. An expanded access protocol was launched to gather additional safety data and provide access to EVE for pts with advanced NET while awaiting regulatory approval. Methods: Pts aged ≥18 years with biopsy-proven NET; WHO performance status 0-2; and adequate bone, hepatic, and renal function were enrolled. Main exclusion criteria were poorly differentiated NET and cytotoxic therapy within 4 wks of enrollment. EVE (10 mg/d) was administered until disease progression, unacceptable toxicity, discontinuation, death, commercial availability of EVE, or until May 30, 2012. Pts were enrolled from April 21, 2011 to April 20, 2012. Primary objective was grade 3/4 and serious adverse events (AEs). Secondary objectives included investigator-assessed best overall response rate and PFS. Results: The full analysis set included 246 pts (pNET, n=126; non-pNET, n=120); the safety set included 240 pts (pNET, n=123; non-pNET, n=117). Median age was 61 and 66 years; 54% and 49% were male. Main primary tumor sites in non-pNET pts included small intestine (40%) and lung (22%). Median duration of EVE exposure was 12.1 wks and 24 wks in pNET and non-pNET. At data cutoff, there were 21 and 32 PFS events; 105 and 88 pts were censored. Grade 3/4 AEs were reported in 42.3% and 69.2% of pNET and non-pNET; those reported in ≥10% of pts in pNET and non-pNET included hyperglycemia (12.2% and 5.1%), diarrhea (10.6% and 31.6%), stomatitis (9.8% and 11.1%), nausea (8.1% and 10.3%), and anemia (5.7% and 11.1%). Median investigator-assessed PFS was 7.6 (95% CI 5.52-7.62) months and 10.8 (8.77-Not Estimable) months in pNET and non-pNET. Conclusions: EVE was well tolerated in pts with advanced NET. AEs were similar to those previously reported. Protocol-specified early termination of pts limits the interpretation of PFS medians. Clinical trial information: EudraCT Number: 2010-023032-17.

scholarly journals 1288. Phase 1 First-in-Human Single- and Multiple-Ascending Dose Trial Demonstrates Pharmacokinetics (PK) and Tolerability of SPR720, an Oral DNA GyrB Inhibitor for Mycobacterial Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S659-S659
Author(s):  
Angela Talley ◽  
Archie Thurston ◽  
Grayson Moore ◽  
Myriah M Satterfield ◽  
Erika L Manyak ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Volunteers ◽  
Controlled Trial ◽  
Phase 1 ◽  
Safety Data ◽  
Elderly Subjects ◽  
Independent Contractor ◽  
Serious Adverse Events ◽  
Healthy Elderly ◽  
Dose Proportional

Abstract Background SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. SPR719 has broad-spectrum activity versus clinically relevant mycobacteria in vitro and in murine and hollow fiber (HF) infection models. In this first-in-human single ascending dose (SAD) /multiple ascending dose (MAD) study, the safety, tolerability and pharmacokinetics (PK) of SPR720/SPR719 were evaluated in healthy volunteers. Methods This was a Phase 1 randomized, double-blind, placebo-controlled trial with 7 SAD cohorts (including a food effect cohort) and 5 MAD cohorts. Healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 or placebo in single oral doses of ranging from 100 mg to 2000 mg or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. Safety monitoring and PK sampling occurred throughout the trial. Plasma and urine concentrations of SPR720/SPR719 were measured by validated LC-MS/MS methods. PK parameters were calculated using non-compartmental analysis. Results A total of 96 subjects (including 8 healthy elderly subjects, age ≥ 65 years) were randomized and received study drug. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. Across SAD cohorts, a dose proportional and greater-than-dose proportional increase in SPR719 plasma Cmax and AUC0-24, respectively were observed. SPR720 was rapidly absorbed with a mean SPR719 t1/2 of 2.9-4.5 h. Dosing with food decreased SPR719 plasma AUC by ~20%. No clinically meaningful effect of age on plasma AUC was observed. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Day 1 and Day 7, suggesting induction of an elimination pathway. However, plasma AUC0-24 was similar at Days 7 and 14. Conclusion Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned. Disclosures Angela Talley, MD, Spero Therapeutics (Employee, Shareholder) Archie Thurston, Jr., PhD, Spero Therapeutics (Consultant) Grayson Moore, BA, RN, Spero Therapeutics, Inc. (Shareholder, Independent Contractor) Vipul Kumar, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder) Aaron Dane, MSc, Spero theraputics (Consultant) David Melnick, MD, Spero Therapeutics (Employee)Spero Therapeutics (Employee)

scholarly journals Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial

2021 ◽  
Author(s):  
Kathryn E. Stephenson ◽  
Boris Julg ◽  
C. Sabrina Tan ◽  
Rebecca Zash ◽  
Stephen R. Walsh ◽  
...  
Keyword(s):  
Viral Load ◽  
T Cell ◽  
Adverse Events ◽  
Antiviral Activity ◽  
Controlled Trial ◽  
Phase 1 ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Cell Counts ◽  
Hiv 1

AbstractHuman immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg–1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg–1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.

A Controlled Trial of Extended-Release Guanfacine and Psychostimulants on Executive Function and ADHD

2018 ◽  
Vol 24 (2) ◽  
pp. 318-325 ◽  
Author(s):  
Judy P. M. van Stralen
Keyword(s):  
Executive Function ◽  
Adverse Events ◽  
Extended Release ◽  
Rating Scale ◽  
Controlled Trial ◽  
Severity Of Illness ◽  
P Value ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Stimulant Therapy

Objective: To evaluate the effectiveness of guanfacine extended-release (GXR) versus placebo as adjunct therapy to usual care stimulant therapy in improving executive function in children aged 6 to 12 years diagnosed with ADHD. Method: In this single center, double-blind placebo-controlled crossover trial, subjects continued to take their psychostimulant and were randomly assigned at baseline to receive active treatment or placebo first. Efficacy measures included Behavioural Rating Inventory of Executive Function (BRIEF-P), ADHD Rating Scale IV (ADHD-RS IV), and Clinical Global Impressions of Severity of Illness (CGI-S) and Improvement (CGI-I) scales. Safety measures included adverse events and vital signs. Results: Significant benefits of GXR plus psychostimulant were observed on BRIEF-P ( p value = .0392), ADHD-RS-IV ( p < .0001), CGI-S ( p = .0007), and CGI-I ( p = .003). There were no serious adverse events and no new safety signals. Conclusion: Use of GXR as adjunctive therapy to stimulant therapy significantly improves executive function in children with ADHD.

scholarly journals Safety and Tolerability of Adjunctive Eslicarbazepine Acetate in Pediatric Patients (Aged 4-17 Years) With Focal Seizures

2019 ◽  
Vol 35 (4) ◽  
pp. 265-273 ◽  
Author(s):  
Mark Mintz ◽  
Jesus E. Pina-Garza ◽  
Steven M. Wolf ◽  
Patricia E. McGoldrick ◽  
Sergiusz Józwiak ◽  
...  
Keyword(s):  
Adverse Events ◽  
Pediatric Patients ◽  
Safety Data ◽  
Adjunctive Treatment ◽  
Eslicarbazepine Acetate ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Focal Seizures ◽  
Clear Dose Response ◽  
Cluster Seizures

Objective: To evaluate the safety and tolerability of adjunctive eslicarbazepine acetate (ESL) in pediatric patients (aged 4-17 years) with refractory focal seizures. Methods: Pooled safety data from patients aged 4-17 years in Study 208 (NCT01527513) and Study 305 (NCT00988156) were analyzed. Both were randomized, double-blind, placebo-controlled studies of ESL as adjunctive treatment in pediatric patients with refractory focal seizures receiving 1 or 2 antiepileptic drugs. Incidences of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to discontinuation, and TEAEs of special interest were evaluated. Results: The safety population comprised 362 patients (placebo, n = 160; ESL, n = 202). The overall incidence of TEAEs was similar between the ESL (67.8%) and placebo groups (65.6%), with no clear dose-response relationship. The most frequently reported TEAEs with ESL were headache, somnolence, vomiting, and diplopia. Overall incidences of SAEs and TEAEs leading to discontinuation were higher with ESL versus placebo (9.9% vs 5.0% and 5.9% vs 2.5%, respectively). The majority of SAEs with ESL occurred in Study 305. Two deaths were reported, 1 with ESL (0.5%) due to cluster seizures (resulting in herniation of the cerebellar tonsils) and 1 with placebo (0.6%) due to asphyxia. TEAEs related to allergic reaction, hyponatremia, hypothyroidism, cytopenia, seizure exacerbation, cognitive dysfunction, psychiatric disorders, or suicide occurred infrequently (<9%). Conclusion: Adjunctive ESL was generally well tolerated in children aged 4-17 years with focal seizures. The safety profile of ESL in children was comparable to that observed in adults.

scholarly journals Two vs. three weeks of treatment with amoxicillin-clavulanate for stabilized community-acquired complicated parapneumonic effusions. A preliminary non-inferiority, double-blind, randomized, controlled trial

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
José M. Porcel ◽  
Lucia Ferreiro ◽  
Laura Rumi ◽  
Esther Espino-Paisán ◽  
Carmen Civit ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Success ◽  
Controlled Trial ◽  
Statistical Significance ◽  
Primary Objective ◽  
Double Blind ◽  
Pleural Thickening ◽  
Small Series ◽  
Amoxicillin Clavulanate ◽  
Clinical Stability

AbstractBackgroundThe optimal duration of antibiotic treatment for complicated parapneumonic effusions (CPPEs) has not been properly defined. Our aim was to compare the efficacy of amoxicillin-clavulanate for 2 vs. 3 weeks in patients with CPPE (i.e. those which required chest tube drainage).MethodsIn this non-inferiority, randomized, double-blind, controlled trial, patients with community-acquired CPPE were recruited from two centers in Spain and, after having obtained clinical stability following 2 weeks of amoxicillin-clavulanate, they were randomly assigned to placebo or antibiotic for an additional week. The primary objective was clinical success, tested for a non-inferiority margin of<10%. Secondary outcomes were the proportion of residual pleural thickening of>10 mm at 3 months, and adverse events. The study was registered with EudraCT, number 2014-003137-25. We originally planned to randomly assign 284 patients.ResultsAfter recruiting 55 patients, the study was terminated early owing to slow enrolment. A total of 25 patients were assigned to 2 weeks and 30 patients to 3 weeks of amoxicillin-clavulanate. Clinical success occurred in the 25 (100%) patients treated for 2 weeks and 29 (97%) treated for 3 weeks (difference 3%, 95% CI −3 to 9.7%). Respective between-group differences in the rate of residual pleural thickening (−12%, 95%CI −39 to 14%) and adverse events (−7%, 95%CI −16 to 2%) did not reach statistical significance.ConclusionsIn this small series of selected adult patients with community-acquired CPPE, amoxicillin-clavulanate treatment could be safely discontinued by day 14 if clinical stability was obtained.

scholarly journals First-in-Human Phase 1 Study To Assess Safety, Tolerability, and Pharmacokinetics of a Novel Antifungal Drug, VL-2397, in Healthy Adults

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Mammen P. Mammen ◽  
Danielle Armas ◽  
Frank H. Hughes ◽  
Andrew M. Hopkins ◽  
Cindy L. Fisher ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Safety Data ◽  
Healthy Adults ◽  
Antifungal Drug ◽  
Renal Elimination ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Time Curve

ABSTRACT VL-2397 is an antifungal drug with a novel mechanism of action, rapid fungicidal in vitro activity, and potent in vivo activity against Aspergillus fumigatus, including azole-resistant strains. VL2397-101, a phase 1 first-in-human, randomized, double-blind, placebo-controlled dose-escalation study, was conducted in healthy adults to determine the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous (i.v.) doses of VL-2397. All dosing cohorts were fully enrolled; all subjects completed the safety follow-up. A safety committee reviewed the safety data for each dosing cohort prior to recommending the initiation of each subsequent cohort. No serious adverse events (SAEs) occurred; the majority of treatment-emergent adverse events (TEAEs) were mild and self-limited. The most common drug-related TEAEs were infusion site reactions. No clinically concerning trends were noted in vital signs, electrocardiograms, physical examinations, or safety laboratory results. Following single infusions of VL-2397, the overall and maximum exposures rose less than proportionally with increasing doses from 3 mg to 1,200 mg as indicated by area under the concentration-time curve over 24 h (AUC24) and maximum concentration (Cmax). No signs of VL-2397 accumulation were observed following i.v. infusions of 300, 600, and 1,200 mg every 24 h (q24h) for 7 days. Renal elimination played a major role in total body clearance, with up to 47% of unmetabolized drug in urine 24 h after administration at single doses of >30 mg. Overall, VL-2397 dosing in the study appeared to be safe and well tolerated in the healthy subjects. The safety profile, consistent PK, and lack of drug accumulation support further development of VL-2397 in patients with invasive aspergillosis.

scholarly journals 2724. Safety and Immunogenicity of a Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) Administered in Healthy Meningococcal Vaccine-Naïve Children (2–9 Years)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S958-S959
Author(s):  
Michael W Simon ◽  
Donald Brandon ◽  
Shane Christensen ◽  
Carmen Baccarini ◽  
Emilia Jordanov ◽  
...  
Keyword(s):  
Adverse Events ◽  
Injection Site ◽  
Conjugate Vaccine ◽  
Safety Data ◽  
Phase Iii ◽  
Meningococcal Vaccine ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Post Vaccination ◽  
Quadrivalent Meningococcal Conjugate Vaccine

Abstract Background MenACYW-TT is an investigational quadrivalent meningococcal conjugate vaccine that contains tetanus toxoid as carrier protein. The vaccine is intended for global use in individuals 6 weeks of age and older. We evaluated the safety and immunogenicity of MenACYW-TT compared with a licensed quadrivalent conjugate meningococcal vaccine (MenACWY-CRM [Menveo®]) in US children 2–9 years of age. Methods In a modified double-blind Phase III study (NCT03077438), 1000 children were randomized to receive one dose of either MenACYW-TT vaccine or MenACWY-CRM vaccine. Serum bactericidal assays with human (hSBA) and baby rabbit (rSBA) complement were used to measure antibodies against representative meningococcal serogroup strains at baseline and 30 days after vaccination. Safety data were collected up to 6 months post-vaccination. Results Non-inferiority of immune responses for all four serogroups, based on percentages of participants achieving hSBA vaccine seroresponse, was demonstrated for MenACYW-TT compared with MenACWY-CRM at Day 30 compared with baseline. The proportions of individuals with hSBA titers ≥ 1:8 following MenACYW-TT administration were higher than those after MenACWY-CRM administration for all four serogroups (A: 86.4% vs 79.3%; C: 97.8% vs 67.1%; W: 94.8% vs 86.3%; Y: 98.5% vs 90.8%). Similar results were observed in two age substrata (2 to 5 years and 6 to 9 years). Percentages of participants with post-vaccination rSBA titers ≥ 1:128 were comparable between both groups. The safety profiles of MenACYW-TT and MenACWY-CRM were comparable. Reactogenicity at the MenACYW-TT injection site was lower than at the MenACWY-CRM injection site. There were no immediate adverse events (AEs), no AEs leading to study discontinuation, and no vaccine-related serious adverse events reported in the study. Conclusion MenACYW-TT vaccine was well tolerated and demonstrated a non-inferior immune response compared with that for the licensed MenACWY-CRM vaccine when administered as a single dose to meningococcal vaccine-naïve children. Disclosures All authors: No reported disclosures.

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