scholarly journals Comparative Susceptibilities to Fidaxomicin (OPT-80) of Isolates Collected at Baseline, Recurrence, and Failure from Patients in Two Phase III Trials of Fidaxomicin against Clostridium difficile Infection

2011 ◽  
Vol 55 (11) ◽  
pp. 5194-5199 ◽  
Author(s):  
Ellie J. C. Goldstein ◽  
Diane M. Citron ◽  
Pamela Sears ◽  
Farah Babakhani ◽  
Susan P. Sambol ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Restriction Endonuclease Analysis ◽  
Phase Iii ◽  
Two Phase ◽  
Double Blind ◽  
Single Strain ◽  
Content Type ◽  
Treatment Groups ◽  
Phase Iii Trials ◽  
Intent To Treat

ABSTRACTA 10-day course of oral fidaxomicin (200 mg twice a day [b.i.d.]), a potent new macrocyclic drug, was compared to vancomycin (125 mg four times a day [q.i.d.]) in 1,164 adults (1,105 in the modified intent-to-treat [mITT] population) withClostridium difficileinfection in two phase III randomized, double-blind trials at sites in North America and 7 European countries. Of 1,105 mITT patients, 792 (71.7%), including 719/999 (72.0%) in the per-protocol (PP) population, provided aC. difficilestrain at baseline, of whom 356 received fidaxomicin with 330 cures (92.7%) and 363 received vancomycin with 329 cures (90.6%). The susceptibilities (MIC90) of baseline isolates did not predict clinical cure, failure, or recurrence for fidaxomicin (MIC90, 0.25 μg/ml for both; range, ≤0.007 to 1 μg/ml), but there was a one-dilution difference in the MIC90(but not the MIC50) for vancomycin (MIC90, 2 μg/ml [range, 0.25 to 8 μg/ml] for cure and 4.0 μg/ml [range, 0.5 to 4 μg/ml] for failures). A total of 65 (7.9%) “rifaximin-resistant” (MIC > 256 μg/ml) strains were isolated in both treatment groups on enrollment, which increased to 25% for failures at the end of therapy. No resistance to either fidaxomicin or vancomycin developed during treatment in either of the phase III studies, although a single strain isolated from a cured patient had an elevated fidaxomicin MIC of 16 μg/ml at the time of recurrence. All isolates were susceptible to ≤4 μg/ml of metronidazole. When analyzed by restriction endonuclease analysis (REA) type, 247/719 (34.4%) isolates were BI group isolates, and the MICs were generally higher for all four drugs tested (MIC90s: fidaxomicin, 0.5; vancomycin, 2.0; metronidazole, 2.0; and rifaximin, >256 μg/ml) than for the other REA types. There was no correlation between the MIC of a baseline clinical isolate and clinical outcome. MIC90s were generally low for fidaxomicin and vancomycin, but BI isolates had higher MICs than other REA group isolates.

Eravacycline: a new treatment option for complicated intra-abdominal infections in the age of multidrug resistance

2019 ◽  
Vol 14 (15) ◽  
pp. 1293-1308
Author(s):  
Joseph S Solomkin ◽  
Angie Sway ◽  
Kenneth Lawrence ◽  
Melanie Olesky ◽  
Sergey Izmailyan ◽  
...  
Keyword(s):  
Pooled Analysis ◽  
Phase Iii ◽  
Two Phase ◽  
Carbapenem Resistant ◽  
Phase Iii Trials ◽  
New Treatment ◽  
Intent To Treat ◽  
Intra Abdominal Infection ◽  
Abdominal Infections ◽  
Cure Rates

Aim: Recently approved for use in complicated intra-abdominal infection, eravacycline is a novel fluorocycline with broad spectrum of activity against resistant Gram-negative pathogens. This manuscript is a pooled analysis of two Phase III trials. Clinical efficacy: Clinical cure rates were 86.8% for eravacycline versus 87.6% for ertapenem, and 90.8% for eravacycline versus 91.2% for meropenem in the Intent to Treat (micro-ITT) populations, and 87.0% for eravacycline versus 88.8% ertapenem, and 92.4 versus 91.6% for meropenem in the Modified Intent to Treat (MITT) populations. Safety: Eravacycline is well tolerated, with lower rates of nausea, vomiting and diarrhea than other tetracyclines. Conclusion: Eravacycline is an effective new option for use in complicated intra-abdominal infections, and in particular, for the treatment of extended-spectrum β-lactamase- and carbapenem-resistant Enterobacteriaceae-expressing organisms.

Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials

2000 ◽  
Vol 6 (2) ◽  
pp. 99-104 ◽  
Author(s):  
I L Tan ◽  
G J Lycklmaà Nijeholt ◽  
C H Polman ◽  
H J Adér ◽  
F Barkhof ◽  
...  
Keyword(s):  
Rebound Effect ◽  
Phase Iii ◽  
Outcome Parameter ◽  
Two Phase ◽  
Treatment Groups ◽  
Secondary Progressive ◽  
Significant Difference ◽  
Relapsing Remitting ◽  
Phase Iii Trials ◽  
Modest Effect

Due to an unexpected increase in serious cardiovascular event in MS patient treated with Linomide, a synthetic immunomodulator, two phase-III multinational relapsing remitting (RR) and secondary progressive (SP) MS trials had to be discontinued. MRI result of 413 patient who participated for at least 3 months were analysed. Patient received placebo, 2.5 or 5 mg Linomide. Scans were performed at pre-enrolment, month 3 and termination. The number and volume of enhancing lesions (ELV), and the number of active scans were evaluated At month 3, the decrease in the number of enhancing lesions in the placebo group was I I1%, compared with 15% in the 2.5 mg group (P=0.027) and 23% in the 5 mg group (P=0.057). Using the percentage of active scans as outcome parameter, the odds ratio for improvement between placebo and 2.5 mg group was 1.62 (P=0.14); between placebo and 5 mg Linomide group 3.58 (P=0.003). At termination, a rebound effect was noted in the 2.5 mg group (P=0.0 1). Analysis of the ELV showed no significant difference between placebo and treatment groups. Although Linomide has unacceptable side effect, it seems to have a modest effect on MS disease activity, as measured by MRI.

Failure of the competitive N-methyl-d-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two Phase III clinical trials

1999 ◽  
Vol 91 (5) ◽  
pp. 737-743 ◽  
Author(s):  
Gabrielle F. Morris ◽  
Ross Bullock ◽  
Sharon Bowers Marshall ◽  
Anthony Marmarou ◽  
Andrew Maas ◽  
...  
Keyword(s):  
Head Injury ◽  
Demographic Data ◽  
Phase Iii ◽  
Double Blind ◽  
Content Type ◽  
Treatment Groups ◽  
Severity Of Injury ◽  
Significant Difference ◽  
Cgs 19755 ◽  
Fine Print

Object. Excessive activity of excitatory amino acids released after head trauma has been demonstrated to contribute to progressive injury in animal models and human studies. Several pharmacological agents that act as antagonists to the glutamate receptor have shown promise in limiting this progression. The efficacy of the N-methyl-d-aspartate receptor antagonist Selfotel (CGS 19755) was evaluated in two parallel studies of severely head injured patients, defined as patients with postresuscitation Glasgow Coma Scale scores of 4 to 8.Methods. A total of 693 patients were prospectively enrolled in two multicenter double-blind studies. Comparison between the treatment groups showed no significant difference with regard to demographic data, previous incidence of hypotension, and severity of injury. As the study progressed, the Safety and Monitoring Committee became concerned about possible increased deaths and serious brain-related adverse events in the treatment arm of the two head injury trials, as well as deaths in the two stroke trials being monitored concurrently. The Selfotel trials were stopped prematurely because of this concern and because an interim efficacy analysis indicated that the likelihood of demonstrating success with the agent if the studies had been completed was almost nil.Conclusions. Subsequently, more complete data analysis revealed no statistically significant difference in mortality rates in all cases between the two treatment groups in the head injury trials. In this report the authors examine the studies in detail and discuss the potential application of the data to future trial designs.

scholarly journals Afabicin, a First-in-Class Antistaphylococcal Antibiotic, in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Clinical Noninferiority to Vancomycin/Linezolid

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Frederick Wittke ◽  
Catherine Vincent ◽  
James Chen ◽  
Barry Heller ◽  
Heidi Kabler ◽  
...  
Keyword(s):  
Acyl Carrier Protein ◽  
Acid Synthesis ◽  
High Dose ◽  
Double Blind ◽  
Content Type ◽  
Skin Structure ◽  
Treatment Groups ◽  
Mitt Population ◽  
Parallel Group ◽  
Intent To Treat

ABSTRACT Afabicin (formerly Debio 1450, AFN-1720) is a prodrug of afabicin desphosphono, an enoyl-acyl carrier protein reductase (FabI) inhibitor, and is a first-in-class antibiotic with a novel mode of action to specifically target fatty acid synthesis in Staphylococcus spp. The efficacy, safety, and tolerability of afabicin were compared with those of vancomycin/linezolid in the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to staphylococci in this multicenter, parallel-group, double-blind, and double-dummy phase 2 study. Randomized patients (1:1:1) received either low-dose (LD) afabicin (intravenous [i.v.] 80 mg, followed by oral 120 mg, twice a day [BID]), high-dose (HD) afabicin (i.v. 160 mg, followed by oral 240 mg, BID), or vancomycin/linezolid (i.v. vancomycin 1 g or 15 mg/kg, followed by oral linezolid 600 mg, BID). The most frequent baseline pathogen was Staphylococcus aureus (97.5% of microbiological intent-to-treat [mITT] population), and 50.4% of patients had methicillin-resistant S. aureus. Clinical response rates at 48 to 72 h postrandomization in the mITT population were comparable among treatment groups (94.6%, 90.1%, and 91.1%, respectively). Both LD and HD afabicin were noninferior to vancomycin/linezolid (differences, −3.5% [95% confidence interval {CI}, −10.8%, 3.9%] and 1.0% [95% CI, −7.3%, 9.2%], respectively). Most common treatment-emergent adverse events were mild and were headache (9.1% and 16.8%) and nausea (6.4% and 8.4%) with LD and HD afabicin, respectively. Afabicin was efficacious and well tolerated in the treatment of ABSSSI due to staphylococci, and these data support further development of afabicin for the treatment of ABSSSI and potentially other types of staphylococcal infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02426918.)

Baseline characteristics from two ongoing phase III trials for the prevention and treatment of muscle wasting in NSCLC.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19100-e19100
Author(s):  
Mitchell S. Steiner ◽  
Richard J. Gralla ◽  
Carla M. M. Prado ◽  
Michael L. Hancock ◽  
James T. Dalton ◽  
...  
Keyword(s):  
Weight Loss ◽  
Muscle Wasting ◽  
Functional Decline ◽  
Phase Iii ◽  
First Line ◽  
Two Phase ◽  
Double Blind ◽  
Prevention And Treatment ◽  
Phase Iii Trials ◽  
Baseline Characteristics

e19100 Background: Although muscle wasting and cancer cachexia occur in > 80% of patients with advanced cancer, few well-powered scientifically-based trials have been conducted. Using enobosarm, a novel SARM, we have now enlisted 650 patients (pts) with advanced NSCLC in two phase III trials. Recent studies indicate major advantages for supportive care in NSCLC at chemotherapy initiation (Temel, NEJM 2010).This presentation examines the feasibility of pt enlistment at chemo initiation, the major characteristics of these pts and trial design for the prevention and treatment of muscle wasting. Methods: Both double-blind, placebo-controlled, international trials evaluate the effect of enobosarm in NSCLC. ˜300 pts with stage III or IV NSCLC were randomized in each trial at initiation of first-line chemo to receive additionally enobosarm or placebo for 5 months. Pts were males and postmenopausal females ≥30 years, ECOG ≤1. First line chemo: a platinum + taxane (Power 1) or platinum + non-taxane (Power 2). Co-primary endpoints at Day 84 are physical function assessed by stair climb power (SCP) and lean body mass (LBM) by DXA. Baseline characteristics are available on 634 pts (98%), as in the Table. Results: See Table. Conclusions: These results indicate that it is feasible to enlist pts receiving first-line chemo in trials designed to prevent or treat muscle wasting and cachexia; their presenting characteristics are typical for NSCLC. Median weight loss at baseline was 5% even though weight loss was not required for study inclusion. LBM and SCP were lower than typically observed in healthy individuals indicating significant functional decline before starting chemo for NSCLC. These phase III trials will determine the effect of enobosarm on preventing and treating muscle wasting in NSCLC. Clinical trial information: NCT01355484 and NCT01355497. [Table: see text]

Bezlotoxumab: Could This be the Answer for Clostridium difficile Recurrence?

2017 ◽  
Vol 51 (9) ◽  
pp. 804-810 ◽  
Author(s):  
Ryan W. Chapin ◽  
Tiffany Lee ◽  
Christopher McCoy ◽  
Carolyn D. Alonso ◽  
Monica V. Mahoney
Keyword(s):  
Monoclonal Antibody ◽  
Clostridium Difficile ◽  
English Language ◽  
Adverse Drug Events ◽  
Data Extraction ◽  
Standard Of Care ◽  
Phase Iii ◽  
Relative Reduction ◽  
Two Phase ◽  
Mesh Terms

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of bezlotoxumab (BEZ), a novel monoclonal antibody against Clostridium difficile toxin B. Data Sources: A PubMed search was conducted for data between 1946 and April 2017 using MeSH terms bezlotoxumab, MK-6072, or MDX-1388 alone and the terms Clostridium difficile combined with monoclonal antibody or antitoxin. Study Selection and Data Extraction: The literature search was limited to English-language studies that described clinical efficacy, safety, and pharmacokinetics in humans and animals. Abstracts featuring prepublished data were also evaluated for inclusion. Data Synthesis: BEZ is indicated for adult patients receiving standard-of-care (SoC) antibiotics for C difficile infection (CDI) to prevent future recurrence. Two phase III trials—MODIFY I (n = 1452) and MODIFY II (n = 1203)—demonstrated a 40% relative reduction in recurrent CDI (rCDI) with BEZ compared with placebo (16.5% vs 26.6%, P < 0.0001). The most common adverse drug events associated with BEZ were mild to moderate infusion-related reactions (10.3%). Conclusions: In patients treated with SoC antibiotics, BEZ is effective in decreasing rCDI. BEZ has no apparent effect on treatment of an initial CDI episode. In light of increasing rates of CDI, BEZ is a promising option for preventing recurrent episodes. The greatest benefit has been demonstrated in high-risk patients, though the targeted patient population is yet to be defined.

scholarly journals POS0928 NETAKIMAB EFFICACY IN ANTI-TNF-NAIVE AND ANTI-TNF-EXPERIENCED PATIENTS WITH ACTIVE ANKYLOSING SPONDYLITIS: RESULTS OF SUBANALYSIS OF PHASE 3 ASTERA TRIAL

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 726.2-727
Author(s):  
S. Erdes ◽  
V. Mazurov ◽  
T. Dubinina ◽  
I. Gaydukova ◽  
A. Kundzer ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
Phase Iii ◽  
P Value ◽  
Interleukin 17 ◽  
Inadequate Response ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Two Phase ◽  
Double Blind ◽  
Asas Criteria

Background:According to previous studies, the effectiveness of interleukin-17 (IL-17) inhibitors was higher in anti-TNF-naïve patients with ankylosing spondylitis (AS) [1,2]. Netakimab (NTK) is a humanized anti-IL-17A antibody approved for the treatment of AS, psoriatic arthritis, moderate-to-severe plaque psoriasis in Russia and Belarus.Objectives:To compare the efficacy of NTK in anti-TNF-naïve patients with anti-TNF-experienced patients with active AS at week 16 of therapy.Methods:ASTERA (NCT03447704) is an ongoing phase 3 placebo (PBO)-controlled clinical study, aimed at evaluating NTK efficacy in AS [3]. 228 adult patients with active AS (BASDAI ≥ 4) were randomly assigned (1:1) to receive 120 mg NTK or PBO subcutaneously at week 0,1,2 and then q2w. This analysis includes 112 patients in NTK group. Efficacy endpoints included ASAS20/40, ASAS5/6 and ASAS partial remission (PR) at week 16 of therapy.Results:28 (25.0%) of 112 patients in NTK group had previous inadequate response/intolerance to anti-TNF (anti-TNF-IR): 24 (21.4%) – one anti-TNF, and 4 (3.6%) – two anti-TNF. 84 (75.0%) patients were TNF-naive. Achievement of ASAS criteria response at week 16 was similar in both groups (Table 1).Table 1.Efficacy of NTK at week 16ParameterTNF-naïve (n = 84)anti-TNF-IR (n = 28)p-value*ASAS20, n (%)52 (61.9%)17 (60.7%)0.91ASAS40, n (%)35 (41.7%)11 (39.3%)0.82ASAS5/6, n (%)39 (46.4%)11 (39.3%)0.51ASAS(PR), n (%)15 (17.9%) 4 (14.3%)0.78*- Fisher’s exact testConclusion:NTK 120 mg provided sustained improvements in signs and symptoms of AS in anti-TNF-naive and anti-TNF-IR patients at 16 weeks of therapy.References:[1]Blair HA, Dhillon S. Secukinumab: A Review in Ankylosing Spondylitis. Drugs. 2016;76(10):1023-30.[2]Dougados M, et al. Efficacy and safety of ixekizumab through 52 weeks in two phase 3, randomised, controlled clinical trials in patients with active radiographic axial spondyloarthritis (COAST-V and COAST-W). Ann Rheum Dis. 2020;79(2):176-185.[3]Mazurov VI, et al. Efficacy and safety of Netakimab, anti-IL-17A monoclonal antibody, in patients with ankylosing spondylitis. Results of phase III international, multicenter, randomized double-blind clinical trial BCD-085-5/ASTERA. Nauchno-Practicheskaya Revmatologia=Rheumatology Science and Practice. 2020;58 (4):376–386 (In Russ).Acknowledgements:This study was sponsored by JSC BIOCAD.Disclosure of Interests:Shandor Erdes: None declared, V Mazurov: None declared, Tatiana Dubinina: None declared, Inna Gaydukova Speakers bureau: Abbvie, Biocad, Eli Lilly, MSD, Novartis, Pfizer, Sandoz, Alena Kundzer: None declared, Nikolaj Soroka: None declared, Anna Eremeeva Employee of: Biocad

Abstract 5063: Cardiovascular Effects of Transdermal Testosterone in Postmenopausal Women

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
C Vitale ◽  
P Collins ◽  
G Marazzi ◽  
G Caminiti ◽  
I Lodhi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Trials ◽  
Hormone Replacement ◽  
Cardiovascular Effects ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Double Blind ◽  
Treatment Groups ◽  
Clinical Program ◽  
Large Phase

Testosterone Transdermal Patch (TTP) has been developed for the treatment of postmeno-pausal women (PMW) with hypoactive sexual desire disorder (HSDD). Since the cardiovascular (CV) effects of testosterone in women are still unclear we conducted a pooled analysis of the large phase III clinical program to evaluate the efficacy and safety of 300 μg/day TTP, alone or in association with hormone replacement therapy (HRT), versus placebo in surgical or natural PMW. Design & Methods: A total of 2795 women aged between 26 –70 years (mean age 52(SD=6.8) years) were included in 5 phase III randomized, double-blind, placebo-controlled clinical trials (treatment duration range 24 – 52 weeks) as part of the TTP Clinical program. 4 studies included PMW (natural and surgical, two each respectively) receiving HRT while 1 study was conducted without HRT, in either surgical or natural PMW. Women with known CV disorders were excluded from the studies. Changes from baseline in standard metabolic and CV risk factors were compared. The incidence of stroke, myocardial infarction (MI) and venous thromboembolism (VTE) alone or as a composite CV endpoint was assessed. Results: The 2795 PMW were randomized to receive either placebo (n=1297) or TTP (n=1498). Baseline mean BMI was 27 kg/m2 (SD=5.3 kg/m2) and 56% were naturally menopausal. The demographic and baseline parameters were similar among the treatment groups. No significant changes in CV risk factors (Total Cholesterol, Triglycerides, Insulin, Glucose, Systolic and Diastolic Blood Pressure) were detected during the study period, apart from a blunting of the increases in HDL-C by TTP at 24 and 52 weeks (Placebo 52-week mean change 2.59 mg/dl vs. TTP 52-week mean change 1.20 mg/dl, p<0.005) and of the decrease in LDL-C by TTP at 24 (p<0.05), but not at 52 weeks. During the double-blind (24 weeks), placebo-controlled period of the combined studies, 4 major CV events (2 MIs and 2 strokes) were reported in placebo patients and 3 (2 MIs and 1 stroke) in those receiving TTP. One VTE occurred in a patient receiving TTP and HRT. Conclusion: TTP therapy in these clinical trials did not adversely affect CV risk profile and did not change the risk of major CV events in these surgical and naturally PMW with or without concomitant HRT.

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