scholarly journals Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults

Toxins ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 511
Author(s):  
Mojgan Kavoosi ◽  
Terry E. O’Reilly ◽  
Mehran Kavoosi ◽  
Peng Chai ◽  
Caroline Engel ◽  
...  
Keyword(s):  
Qt Prolongation ◽  
Healthy Adults ◽  
Controlled Study ◽  
Maximum Plasma ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Subcutaneous Injections ◽  
Treatment Groups ◽  
Safety Assessments ◽  
Common Teaes

Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. Randomized, double-blind, placebo-, and positive- (moxifloxacin) controlled study evaluated single ascending doses of 15 µg, 30 µg, and 45 µg TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (Cmax) within 1.5 h. Both extent of exposure (AUC) and Cmax increased in proportion to dose. No QT prolongation was identified by concentration-QTc analysis and the upper bounds of the two-sided 90% confidence interval of predicted maximum baseline and placebo corrected QTcF (ΔΔQTcF) value did not exceed 10 ms for all tetrodotoxin doses, thereby meeting the criteria of a negative QT study. Safety assessments showed no clinically relevant changes with values similar between all groups and no subject withdrawing due to adverse events. Paresthesia, oral-paresthesia, headache, dizziness, nausea, and myalgia were the most common TEAEs (overall occurrence ≥5%) in the TTX treatment groups. TTX doses investigated in this study are safe, well-tolerated, and lack proarrhythmic proclivity.

scholarly journals Phase 1 Randomized, Double-Blind, Placebo-Controlled Study of RG7667, an Anticytomegalovirus Combination Monoclonal Antibody Therapy, in Healthy Adults

2015 ◽  
Vol 59 (8) ◽  
pp. 4919-4929 ◽  
Author(s):  
Julie H. Ishida ◽  
Tracy Burgess ◽  
Michael A. Derby ◽  
Pearline A. Brown ◽  
Mauricio Maia ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Adverse Events ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Healthy Adults ◽  
Host Cells ◽  
Controlled Study ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Double Blind Placebo

ABSTRACTCytomegalovirus can cause debilitating and life-threatening disease in newborns infectedin uteroand immunocompromised individuals, including transplant recipients. RG7667 is a unique combination of two monoclonal antibodies that binds glycoprotein complexes on the surface of cytomegalovirus and inhibits its entry into host cells. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study of RG7667 given intravenously was conducted in 181 healthy adults. The study involved a single ascending dose stage (1, 3, 5, and 10 mg/kg each antibody;n= 21), a multiple ascending dose stage (5 and 10 mg/kg each antibody monthly for 3 doses;n= 10), and a multiple dose expansion stage (10 mg/kg each antibody monthly for 3 doses;n= 150). Subjects were followed for 85 to 141 days to evaluate safety, tolerability, pharmacokinetics, and immunogenicity. Most adverse events were mild, and the incidence of adverse events was similar among the RG7667 and placebo groups. RG7667 had dose-proportional pharmacokinetics in all three dosing stages, a mean terminal half-life of 20 to 30 days, and an overall pharmacokinetic profile consistent with that of a human monoclonal antibody that lacks endogenous host targets. The proportion of subjects developing an antitherapeutic antibody response was not higher in the RG7667 group than in the placebo group. In summary, single and multiple doses of RG7667 were found to be safe and well-tolerated in healthy adults and had a favorable pharmacokinetic and immunogenicity profile. This study supports further development of RG7667 as a therapy for the prevention and treatment of cytomegalovirus infection in susceptible populations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01496755.)

scholarly journals Randomized, controlled trial of lasmiditan over four migraine attacks: Findings from the CENTURION study

Cephalalgia ◽  
2021 ◽  
Vol 41 (3) ◽  
pp. 294-304 ◽  
Author(s):  
Messoud Ashina ◽  
Uwe Reuter ◽  
Timothy Smith ◽  
Judith Krikke-Workel ◽  
Suzanne R Klise ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Study Drug ◽  
Statistical Testing ◽  
Control Group ◽  
Double Blind ◽  
Treatment Groups ◽  
Primary Endpoints ◽  
Registration Number ◽  
Secondary Endpoints ◽  
Common Teaes

Background We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute treatment of migraine across four attacks. Methods Patients were randomized 1:1:1 to one of three treatment groups – lasmiditan 200 mg; lasmiditan 100 mg; or a control group that received placebo for three attacks and lasmiditan 50 mg for either the third or fourth attack. The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in ≥2/3 attacks. Secondary endpoints included pain relief, sustained pain freedom and disability freedom. Statistical testing used a logistic regression model and graphical methodology to control for multiplicity. Results Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg ( p < 0.001). All gated secondary endpoints were met. The incidence of treatment-emergent adverse events (TEAEs) was highest during the first attack. The most common TEAEs with lasmiditan were dizziness, paresthesia, fatigue, and nausea; these were generally mild or moderate in severity. Conclusions These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks. Trial Registration Number: NCT03670810

scholarly journals 902. A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of a Single Immunization of Ad26.RSV.preF against RSV Infection in a Viral Challenge Model in Healthy Adults

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S27-S28 ◽  
Author(s):  
John DeVincenzo ◽  
Efi Gymnopoulou ◽  
Els De Paepe ◽  
Bryan Murray ◽  
Arangassery Rosemary Bastian ◽  
...  
Keyword(s):  
Disease Severity ◽  
Healthy Adults ◽  
Controlled Study ◽  
Clinical Strain ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Qrt Pcr ◽  
Rsv Infection ◽  
First Time ◽  
Over Time

Abstract Background Despite the high disease burden of RSV in older adults and children, there is currently no approved vaccine. Ad26.RSV.preF, an experimental RSV vaccine, has demonstrated immunogenicity and tolerability in first-in-human clinical studies. The aim of this study was to assess the potential of the Ad26.RSV.preF vaccine to protect against RSV infection and disease in an established RSV human challenge model, used for the first time to evaluate a vaccine. Methods We conducted a randomized, double-blind, placebo-controlled, human challenge study (NCT03334695). Healthy adults received 1 × 1011 vp Ad26.RSV.preF vaccine (active) or placebo (pbo) intramuscularly. After 28 days, volunteers were challenged intranasally with a low-passage clinical strain of RSV-A (0.8 mL of Memphis 37b) and then quarantined for 12 days. Nasal washes were collected twice daily throughout quarantine, starting 2 days post-challenge (viral load [VL] by qRT-PCR and quantitative cultures). Disease severity was recorded thrice daily using symptom diary cards. Results Fifty-three volunteers (active, n = 27; pbo, n = 26) were challenged with RSV-A. Quantitative viral assessments were consistently lower in active than pbo. The primary endpoint of the study was met: the area under the curve (AUC) for RSV VL over time (via qRT-PCR) was significantly lower in active pbo (P = 0.012). Median peak VL was lower for active (0 log10 copies/mL) than pbo (5.4 log10 copies/mL). Median AUC for RSV VL over time (quantitative culture) was lower for active than pbo (0 vs. 109, P = 0.002). Disease severity was lower for active than pbo, with a median AUC total symptom score of 35 (active) vs. 167 (pbo) (P = 0.002). Overall, RSV infection (defined by qRT-PCR alone or combined with symptoms) and disease severity over time were lower in active vs. pbo. Conclusion RSV infections, VL, and RSV disease severity were consistently lower in healthy adults receiving Ad26.RSV.preF vs. placebo, demonstrating promising protection from RSV infection and disease. This was the first time that antiviral prevention was observed against RSV after active immunization. Ad26.RSV.preF warrants further evaluation in field trials for efficacy against natural RSV infections in populations considered at risk of severe RSV disease. Disclosures All Authors: No reported Disclosures.

Safety and Efficacy of a Topical Anesthetic for Neonatal Circumcision

PEDIATRICS ◽  
1993 ◽  
Vol 92 (5) ◽  
pp. 710-714 ◽  
Author(s):  
Kathleen B. Weatherstone ◽  
Lynn B. Rasmussen ◽  
Allen Erenberg ◽  
Emily M. Jackson ◽  
Katherine S. Claflin ◽  
...  
Keyword(s):  
Vital Signs ◽  
Behavioral Changes ◽  
Controlled Study ◽  
Topical Anesthetic ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Exact Test ◽  
Treatment Groups ◽  
Topical Lidocaine ◽  
Postoperative Serum

Objective. Circumcision is a common neonatal surgical procedure routinely performed without the use of anesthesia. The purpose of this study was to evaluate the safety and efficacy of topical lidocaine cream as an anesthetic for circumcision. Methods. Thirty newborns were studied in a randomized, double-blind, placebo-controlled study; 15 received a topical 30% lidocaine cream and 15 received the cream base alone. Vital signs were recorded, and preoperative and postoperative serum β-endorphin and lidocaine concentrations were measured. A videotape of the newborn was used to score behavioral changes. Results. Comparisions of the vital signs precircumcision and postcircumcision showed no differences between the placebo and treatment groups, with the exception of mean systolic blood pressure, which significantly increased in the placebo-treated newborns (P &lt; .05). Serum β-endorphin concentrations increased postoperatively in 11 of 15 subjects receiving placebo, but decreased or remained unchanged in 10 of 15 subjects receiving lidocaine (P = .03, Fisher's exact test). When stress-related behaviors in the precircumcision and post-circumcision periods were compared, the mean increase in their occurrence was greater in the placebo than in the treatment group. There was no significant absorption of lidocaine as measured in the serum. Conclusion. Topical application of a 30% lidocaine cream as used in this study may be a safe and efficacious anesthetic for circumcision.

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.

scholarly journals Efficacy and tolerability of the investigational topical cream SD-101 (6% allantoin) in patients with epidermolysis bullosa: a phase 3, randomized, double-blind, vehicle-controlled trial (ESSENCE study)

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Amy S. Paller ◽  
◽  
John Browning ◽  
Milos Nikolic ◽  
Christine Bodemer ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Wound Closure ◽  
Trial Registration ◽  
Controlled Study ◽  
Phase 3 ◽  
Double Blind ◽  
Treatment Groups ◽  
Topical Cream ◽  
Link Type ◽  
Total Body

Abstract Background Epidermolysis bullosa (EB) is a rare genetic disorder that manifests as blistering and/or skin erosion. There is no approved treatment for EB; current standard of care consists of wound and pain management. SD-101 6% is a topical cream containing 6% allantoin that was developed for treating skin lesions in patients with EB. The aim of this phase 3, multicenter, randomized, double-blind, vehicle-controlled study was to assess the efficacy and safety of SD-101 6% cream versus vehicle (0% allantoin) on lesions in patients with EB. Methods Eligible patients were ≥1 month old, had a diagnosis of EB (simplex, recessive dystrophic, or intermediate junctional) and a target wound 10–50 cm2 in size that was present for ≥21 days. Patients were randomly assigned to SD-101 6% cream or vehicle, which was applied topically once a day to the entire body for 3 months. Primary efficacy endpoints were time to complete target wound closure within 3 months and the proportion of patients who experienced complete target wound closure within 3 months. Post hoc subgroup analyses were conducted by patient age and in those with body surface area index of total body wound burden ≥5% at baseline. Results In total, 169 patients were enrolled and randomly assigned to SD-101 6% (n = 82) or vehicle (n = 87). Baseline demographics and disease characteristics were similar between treatment groups. There were no statistically significant differences between treatment groups in time to target wound closure (hazard ratio, 1.004; 95% confidence interval [CI] 0.651, 1.549; P = 0.985) or proportion of patients with complete target wound closure within 3 months (odds ratio [95% CI], 0.733 [0.365, 1.474]; nominal P = 0.390). A positive trend toward faster wound closure with SD-101 6% versus vehicle was observed in patients aged 2 to <12 years and those with total body wound burden ≥5% at baseline. SD-101 6% cream was well tolerated. Conclusions SD-101 6% cream for treatment of EB-associated lesions was not more effective than vehicle in shortening the time to complete target wound closure or achieving complete target wound closure within 3 months. Trial registration ClinicalTrials.gov, NCT02384460; Date of trial registration, February 13, 2015; First participant enrolled, March 11, 2015.

Paroxetine in the Treatment of Panic Disorder a Randomised, Double-Blind, Placebo-Controlled Study

1995 ◽  
Vol 167 (3) ◽  
pp. 374-379 ◽  
Author(s):  
S. Oehrberg ◽  
P. E. Christiansen ◽  
K. Behnke ◽  
A. L. Borup ◽  
B. Severin ◽  
...  
Keyword(s):  
Panic Disorder ◽  
Cognitive Therapy ◽  
Panic Attacks ◽  
Controlled Study ◽  
Positive Trend ◽  
Double Blind ◽  
Treatment Groups ◽  
Efficacy Measures ◽  
The Mean ◽  
Primary Measure

BackgroundThis study compared the efficacy and tolerability of paroxetine with placebo in the treatment of panic disorder.MethodAfter three weeks of placebo, patients received 12 weeks of treatment with paroxetine (20, 40, or 60 mg) or placebo, and finally two weeks of placebo. Dosages were adjusted according to efficacy and tolerability. Standardised cognitive therapy was given to all patients. The primary measure of outcome was reduction in the number of panic attacks.ResultsAnalysis of the results showed statistically significant differences in favour of paroxetine between the two treatment groups in two out of the three primary measures of outcome, i.e. 50% reduction in total number of panic attacks and number of panic attacks reduced to one or zero over the study period. For the third measure of outcome, the mean change in the total number of attacks from baseline, there was a positive trend in favour of paroxetine. The results of the primary measures of outcome were strongly supported by the results of the secondary efficacy measures of outcome. In addition, paroxetine, at all doses, was very well tolerated.ConclusionParoxetine plus cognitive therapy was significantly more effective than placebo plus cognitive therapy in the treatment of panic disorder.

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.

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