scholarly journals Pharmacokinetics and Safety of Icotinib Hydrochloride Cream in Patients with Mild to Moderate Chronic Plaque Psoriasis: A Randomized Double-Blind Vehicle-Controlled Phase 1 Study

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Lunfei Liu ◽  
Honggang Lou ◽  
Jiong Zhou ◽  
Ying Shen ◽  
Min Zheng ◽  
...  
Keyword(s):  
Plaque Psoriasis ◽  
Phase 1 ◽  
Vehicle Group ◽  
Controlled Study ◽  
Application Site ◽  
Dependent Manner ◽  
Local Tolerability ◽  
Phase 1 Study ◽  
Double Blind ◽  
Quality Life

Objective.This phase I study aimed to systematically assess the safety, local tolerability, pharmacokinetics, and preliminary efficacy of topical icotinib hydrochloride cream in patients with mild to moderate plaque psoriasis.Materials and Methods.Eligible Chinese adult patients with mild to moderate psoriasis were assigned to the icotinib cream or vehicle group. Icotinib cream with increasing concentrations (0.5%, 1.0%, 2.0%, and 4.0%) or vehicle were administered by the fingertip unit method to the skin lesions twice a day for 4 weeks. Safety assessments included the incidence and severity of adverse events (AEs), local tolerability at the treatment area, vital signs, and laboratory examinations. Plasma levels of icotinib were also measured for the pharmacokinetics calculation. The efficacy was preliminarily explored by assessing the improvement in the severity level using Target Plaque Severity Score (TPSS) and overall improvement using the Psoriasis Area Severity Index (PASI) and Dermatological Quality Life Index.Results.Forty-one patients were enrolled and qualified for safety analysis. 27 (65.9%) patients experienced at least one AE, of which application-site adverse drug reactions (ADRs) were reported in 6 (14.6%) patients. All ADRs were of grade 1 or 2, most common irritation (4.5%), itching (3.1%), and erythema (2.4%), and resolved during follow-up. The systemic exposure to icotinib was very low; the highest plasma concentration was 0.214 ng/mL, while the area under the curve from 0 to 12 hours was 1.626 h·ng/mL. The TPSS improved for all icotinib groups after treatment in a dose- and time-dependent manner.Conclusion.This phase 1 study demonstrated favorable safety, tolerable toxicity, and preliminary efficacy of icotinib cream in patients with mild to moderate psoriasis. The dose concentration of 2.0% (twice daily based on the fingertip unit method) is recommended for further study.Study Design.This is a single-center, randomized, double-blind, and vehicle-controlled study.

MO258SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE ASCENDING DOSE STUDY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Yusuke Suzuki ◽  
Mohit Mathur ◽  
Jonathan Barratt ◽  
Frank Engler ◽  
Jill Yarbrough ◽  
...  
Keyword(s):  
Phase 1 ◽  
Study Drug ◽  
Dependent Manner ◽  
Double Blind ◽  
Serum Iga ◽  
Dose Study ◽  
Dose Response Effect ◽  
Japanese Descent ◽  
Dose Dependent ◽  
Single Ascending Dose Study

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy (IgAN) is a glomerulonephritis characterized by the presence of circulating and glomerular immune complexes containing galactose-deficient (Gd) IgA1. A proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor superfamily of ligands, is thought to play a key role in the pathogenesis of IgAN by virtue of its role in class-switching to IgA production. VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of APRIL, is in clinical development as a potential treatment for IgAN. The primary objective of this first-in-human study was to evaluate the safety and tolerability of VIS649 in healthy volunteers. Secondary objectives included characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of VIS649. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). The study was conducted in sequential dosing cohorts. The first four cohorts (0.5, 2.0, 6.0, and 12.0 mg/kg, respectively) each enrolled 9 participants (4 of Japanese descent and 5 of non-Japanese descent) who were randomized to VIS649 or placebo in a ratio of 7:2. In addition, a fifth cohort enrolled 15 adults randomized to receive VIS649 6.0 mg/kg or placebo (10:5), followed by tetanus/diphtheria vaccine challenge after 28 days (TENIVAC®, Sanofi Pasteur Limited; the effect of APRIL inhibition on vaccine response is described in a companion abstract). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, and were followed for 16–24 weeks on an outpatient basis. Standard safety assessments and blood sampling for PK and PD were performed at regular intervals. Results 51 participants were randomized and dosed with study drug, of whom 47 (92.2%) completed the study. VIS649 was well tolerated, with no serious adverse events (AEs) or AEs that led to study discontinuation. Most treatment-emergent AEs (TEAEs) were mild; the incidence and severity of TEAEs were not dose dependent. One participant in the 2.0 mg/kg group experienced a severe TEAE of syncope following phlebotomy that the investigator considered unlikely to be related to study drug. There was no clinically relevant effect of treatment on laboratory tests, vital signs, electrocardiogram parameters, or physical examinations. VIS649 had non-linear PK: half-life (t½) increased with dose, while drug exposure (AUC) increased in a greater than dose proportional manner. Serum IgA, Gd-IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner following VIS649 administration. The maximum mean percentage reductions from baseline occurred at Week 12 for the 12.0 mg/kg dose: IgA, -57.2% (Figure); Gd-IgA1, -71.6% (Figure); IgG, -33.6%; and IgM, -67.2%. These reductions were reversible and showed a dose-response effect with respect to time-to-recovery. Mean free (non-VIS649 bound) serum APRIL levels decreased to the lower limit of quantification (50 pg/mL) for all VIS649 doses at Week 1, and also showed a dose-response effect with respect to time-to-recovery. No depletions in circulating lymphocyte populations were observed. There were no significant PK or PD differences between Japanese and non-Japanese participants. Conclusion A single dose of VIS649, up to 12.0 mg/kg, was safe and well tolerated in healthy adults and was able to suppress free serum APRIL to the lower level of quantification. Serum Gd-IgA1 decreased in parallel with total serum IgA and recovered in a dose-dependent manner following reappearance of free APRIL in serum. These data support the further clinical development of VIS649 as a potential treatment for IgAN.

A Double-Blind, Randomized, Placebo-Controlled Phase 1 Study of Ad26.ZIKV.001, an Ad26-Vectored Anti–Zika Virus Vaccine

2021 ◽  
Author(s):  
Nadine C. Salisch ◽  
Kathryn E. Stephenson ◽  
Kristi Williams ◽  
Freek Cox ◽  
Leslie van der Fits ◽  
...  
Keyword(s):  
Virus Vaccine ◽  
Zika Virus ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Double Blind

Abstract 2009: ALX-0081 a Novel Anti-Thrombotic: Results of a Single-Dose Phase 1 Study in Healthy Volunteers and Further Development in Patients with Stable Angina Undergoing PCI

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jozef Bartunek ◽  
Emanuele Barbato ◽  
Josefin-Beate Holz ◽  
Kristof Vercruysse ◽  
Hans Ulrichts ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Dose Escalation ◽  
Stable Angina ◽  
Thrombus Formation ◽  
Phase 1 ◽  
Controlled Study ◽  
Double Blind ◽  
Phase Ib ◽  
Wide Range

Background : ALX-0081 is a bivalent Nanobody ® based on the variable domain of naturally occurring heavy-chain only antibodies. It binds with high affinity to the A1 domain of von Willebrand Factor (vWF) and thereby blocks the interactions between platelets and vascular collagen. It selectively prevents thrombus formation under high shear stress conditions. Aim : Test ALX-0081 single IV infusions (60 minutes) dosed from 0.5mg to 12mg total in 40 male healthy volunteers in double-blind, randomized, placebo controlled study and assess pharmacokinetic (PK), pharmacodynamic (PD), safety and immunogenicity. Results : ALX-0081 displayed non-linear pharmacokinetic properties, following a 2 compartment model. Ristocetin induced platelet aggregation (RIPA) was analyzed as marker for PD effect with full inhibition (defined as measured levels dropping <10%) observed at ALX-0081 concentrations of ~ 400ng/ml. All subjects dosed ≥ 2mg achieved full RIPA inhibition at 1h post-dosing for maximum of 12h. ALX-0081 treatment was well tolerated and safe, no signs of bleeding were reported and no immunogenic response was detected. Target related mild and transient reductions of vWF and FVIII plasma levels were observed and all events were fully reversible. Phase Ib study design : double-blind, randomized, placebo controlled, multiple ascending dose study. ALX-0081 added to standard anti-thrombotic regimen (ASA, clopidogrel, UFH) in patients with stable angina undergoing elective PCI. Single-dose escalation will be followed by multiple dosing (up to 4 doses in 24h). Dose escalation will be guided by safety and efficacy marker. Endpoints: safety, pharmacological profile, biomarker (RIPA, RICO and ACT) and early clinical outcome (MACE, IMR, molecular marker). Conclusion : ALX-0081 can be administered safely over a wide range of dose-regimen. First results of the phase Ib study in stable angina patients will be presented.

scholarly journals A Phase 1 Randomized Placebo-Controlled Study to Assess the Safety, Immunogenicity and Genetic Stability of a New Potential Pandemic H7N9 Live Attenuated Influenza Vaccine in Healthy Adults

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 296
Author(s):  
Irina Kiseleva ◽  
Irina Isakova-Sivak ◽  
Marina Stukova ◽  
Marianna Erofeeva ◽  
Svetlana Donina ◽  
...  
Keyword(s):  
Adverse Events ◽  
Influenza Vaccine ◽  
Phase 1 ◽  
Healthy Adults ◽  
Controlled Study ◽  
Temperature Sensitive ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Human Influenza Virus ◽  
Live Attenuated Influenza Vaccine

This study describes a double-blind randomized placebo-controlled phase I clinical trial in healthy adults of a new potential pandemic H7N9 live attenuated influenza vaccine (LAIV) based on the human influenza virus of Yangtze River Delta hemagglutinin lineage (ClinicalTrials.gov Identifier: NCT03739229). Two doses of H7N9 LAIV or placebo were administered intranasally to 30 and 10 subjects, respectively. The vaccine was well-tolerated and not associated with increased rates of adverse events or with any serious adverse events. Vaccine virus was detected in nasal swabs during the 6 days after vaccination or revaccination. A lower frequency of shedding was observed after the second vaccination. Twenty-five clinical viral isolates obtained after the first and second doses of vaccine retained the temperature-sensitive and cold-adapted phenotypic characteristics of LAIV. There was no confirmed transmission of the vaccine strain from vaccinees to placebo recipients. After the two H7N9 LAIV doses, an immune response was observed in 96.6% of subjects in at least one of the assays conducted.

EFFECTIVENESS AND TOLERABILITY OF CV-3988, A SELECTIVE PAF ANTAGONIST, AFTER INTRAVENOUS ADMINISTRATION TO MAN

1987 ◽  
Author(s):  
J Arnout ◽  
A Van Hecken ◽  
I Delepeleire ◽  
Y Miyamoto ◽  
I Holmes ◽  
...  
Keyword(s):  
Light Transmission ◽  
Platelet Rich Plasma ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Platelet Activating Factor ◽  
Controlled Study ◽  
Dependent Manner ◽  
Double Blind ◽  
Health And Disease

Platelet activating factor (PAF) is a naturally occurring phospholipid with a wide spectrum of biological activities. Although PAF has been ascribed a potential role in various conditions including inflammation, asthma, glomerulonephritis and thrombosis, its precise function in physiologic/pathophysiologic processes remains unclear. The introduction of selective PAF receptor antagonists could represent a useful tool to extend our knowledge of the role of this mediator in health and disease.We have investigated the efficacy and tolerability of (RS)-2-methoxy-3-(octadecylcarbomoyloxy)propy1 2-(3-thiazolio)-ethyIphosphate (CV-3988, Takeda Chem. Ind), a selective PAF antagonist with structural analogies with PAF, after intravenous infusion in man in a double-blind, placebo-controlled study. The compound, in doses from 750 to 2,000 pg/kg, significantly reduced platelet sensitivity to PAF. The threshold aggregating concentration (TAC) of PAF was defined as the minimal concentration causing an irreversible aggregation with a maximal amplitude of at least 50% of the difference in light transmission between platelet rich plasma and platelet poor plasma. It increased in a dose-dependent manner reaching 3.6 times the basal TAC (p<0.0005) at the end and 2.60 times the basal TAC (p<0.0005) 4 hours after infusion of the highest dose. The TAC of PAF returned to the basal value within 24 hours after the end of the infusion.CV-3988 did not cause major side effects nor changes in blood pressure, pulse or respiratory rate. However, small but clinically insignificant changes in plasma haemoglobin and serum haptoglobin were seen at the end and four hours after the end of the infusion, indicating a slight haemolysis probably by high local concentrations at the infusion site.Our results indicate that, when adequate infusion volumes and infusion rates are used, CV-3988 can be safely administered to man and should be useful in elucidating the role of PAF in health and disease.

Are AutoCPAP Devices Reliable? A Double Blind Dummy Controlled Phase 1 Study

2010 ◽  
Author(s):  
Benny Mwenge ◽  
Myriam Dury ◽  
Pierre Delguste ◽  
Daniel Rodenstein
Keyword(s):  
Phase 1 ◽  
Phase 1 Study ◽  
Double Blind
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