scholarly journals Efficacy, Safety, and Tolerability of Gepotidacin (GSK2140944) in the Treatment of Patients with Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
William O'Riordan ◽  
Courtney Tiffany ◽  
Nicole Scangarella-Oman ◽  
Caroline Perry ◽  
Mohammad Hossain ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Utility ◽  
The United States ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Open Label ◽  
Gram Positive ◽  
Double Blind ◽  
Skin Structure

ABSTRACT Gepotidacin is a novel, first-in-class, triazaacenaphthylene antibacterial agent which has in vitro activity against causative pathogens of acute bacterial skin and skin structure infections (ABSSSIs). This phase 2, randomized, 2-part, multicenter, dose-ranging, response-adaptive study with optional intravenous-oral switch evaluated the efficacy and safety of gepotidacin for the treatment of Gram-positive ABSSSIs in 122 adult patients in the United States. The study had a double-blind phase (part 1; intravenous [750 mg or 1,000 mg every 12 h {q12h}]) and an open-label phase (part 2; intravenous [750 mg q12h, 1,000 mg q12h, or 1,000 q8h]). The primary endpoint was a composite of efficacy and safety which consisted of the early cure rate and the withdrawal rate due to drug-related adverse events and utilized a clinical utility index for dose selection. At the early efficacy visit (48 to 72 h after the first dose), the 750-mg q12h and 1,000-mg q8h groups met prespecified success criteria for clinical utility in terms of efficacy and safety; however, the 1,000-mg q12h group did not meet these criteria due to observed lower efficacy rates. The most frequently reported adverse events were nausea (20%) and diarrhea (13%). These encouraging phase 2 results demonstrate the potential for gepotidacin to meet the medical need for novel antibacterial agents to treat ABSSSIs due to drug-resistant pathogens through a unique mechanism of action. (This study has been registered at ClinicalTrials.gov under registration no. NCT02045797.)

scholarly journals In VitroActivity and Microbiological Efficacy of Tedizolid (TR-700) against Gram-Positive Clinical Isolates from a Phase 2 Study of Oral Tedizolid Phosphate (TR-701) in Patients with Complicated Skin and Skin Structure Infections

2012 ◽  
Vol 56 (9) ◽  
pp. 4608-4613 ◽  
Author(s):  
Philippe Prokocimer ◽  
Paul Bien ◽  
Carisa DeAnda ◽  
Chris M. Pillar ◽  
Ken Bartizal
Keyword(s):  
Clinical Efficacy ◽  
Phase 2 ◽  
Coagulase Negative Staphylococci ◽  
Gram Positive ◽  
Double Blind ◽  
Content Type ◽  
Skin Structure ◽  
Phase 2 Trial ◽  
Complicated Skin

ABSTRACTTedizolid (TR-700, formerly torezolid) is the active moiety of the prodrug tedizolid phosphate (TR-701), a next-generation oxazolidinone, with high potency against Gram-positive species, including methicillin-resistantStaphylococcus aureus(MRSA). A recently completed randomized, double-blind phase 2 trial evaluated 200, 300, or 400 mg of oral tedizolid phosphate once daily for 5 to 7 days in patients with complicated skin and skin structure infections. This report examines thein vitroactivity of tedizolid and Zyvox (linezolid) against Gram-positive pathogens isolated at baseline and describes the microbiological and clinical efficacy of tedizolid. Of 196 isolates tested, 81.6% wereS. aureus, and of these, 76% were MRSA. The MIC50and MIC90of tedizolid against both methicillin-susceptibleS. aureus(MSSA) and MRSA were 0.25 μg/ml, compared with a MIC50of 1 μg/ml and MIC90of 2 μg/ml for linezolid. For coagulase-negative staphylococci (n= 7), viridans group streptococci (n= 15), and beta-hemolytic streptococci (n= 3), the MICs ranged from 0.03 to 0.25 μg/ml for tedizolid and from 0.12 to 1 μg/ml for linezolid. The microbiological eradication rates at the test-of-cure visit (7 to 14 days posttreatment) in the microbiologically evaluable population (n= 133) were similar in all treatment groups, with overall eradication rates of 97.7% for all pathogens, 97.9% for MRSA, and 95.7% for MSSA. The clinical cure rates for MRSA and MSSA infections were 96.9% and 95.7%, respectively, across all dose groups. This study confirms the potentin vitroactivity of tedizolid against pathogenic Gram-positive cocci, including MRSA, and its 4-fold-greater potency in comparison with linezolid. All dosages of tedizolid phosphate showed excellent microbiological and clinical efficacy against MRSA and MSSA.

Review on the Clinical Pharmacology of Hydroxychloroquine Sulfate for the Treatment of COVID-19

2020 ◽  
Vol 21 (6) ◽  
pp. 427-435 ◽  
Author(s):  
Cheng Cui ◽  
Siqi Tu ◽  
Valerie Sia Jie En ◽  
Xiaobei Li ◽  
Xueting Yao ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Clinical Efficacy ◽  
Relevant Literature ◽  
The United States ◽  
Efficacy And Safety ◽  
Open Label ◽  
Infected People ◽  
Treatment Regimens ◽  
Therapeutic Drugs

Background: As the number of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infected people is greatly increasing worldwide, the international medical situation becomes very serious. Potential therapeutic drugs, vaccine and stem cell replacement methods are emerging, so it is urgent to find specific therapeutic drugs and the best treatment regimens. After the publications on hydroxychloroquine (HCQ) with anti- SARS-COV-2 activity in vitro, a small, non-randomized, open-label clinical trial showed that HCQ treatment was significantly associated with reduced viral load in patients with coronavirus disease-19 (COVID-19). Meanwhile, a large prophylaxis study of HCQ sulfate for COVID-19 has been initiated in the United States. HCQ offered a promising efficacy in the treatment of COVID-19, but the optimal administration is still being explored. Methods: We used the keyword "hydroxychloroquine" to conduct a literature search in PubMed to collect relevant literature on the mechanism of action of HCQ, its clinical efficacy and safety, pharmacokinetic characteristics, precautions for clinical use and drug interactions to extract and organize information. Results: This paper reviews the mechanism, clinical efficacy and safety, pharmacokinetic characteristics, exposureresponse relationship and precautions and drug interactions of HCQ, and summarizes dosage recommendations for HCQ sulfate. Conclusion: It has been proved that HCQ, which has an established safety profile, is effective against SARS-CoV-2 with sufficient pre-clinical rationale and evidence. Data from high-quality clinical trials are urgently needed worldwide.

scholarly journals Phase 2, Randomized, Double-Blind Study of the Efficacy and Safety of Two Dose Regimens of Eravacycline versus Ertapenem for Adult Community-Acquired Complicated Intra-Abdominal Infections

2013 ◽  
Vol 58 (4) ◽  
pp. 1847-1854 ◽  
Author(s):  
Joseph S. Solomkin ◽  
Mayakonda Krishnamurthy Ramesh ◽  
Gintaras Cesnauskas ◽  
Nikolajs Novikovs ◽  
Penka Stefanova ◽  
...  
Keyword(s):  
Clinical Success ◽  
Clinical Success Rate ◽  
Blind Study ◽  
Double Blind Study ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Gram Negative ◽  
Abdominal Infections

ABSTRACTEravacycline is a novel fluorocycline, highly active against Gram-positive and Gram-negative pathogensin vitro, including those with tetracycline and multidrug resistance. This phase 2, randomized, double-blind study was conducted to evaluate the efficacy and safety of two dose regimens of eravacycline compared with ertapenem in adult hospitalized patients with complicated intra-abdominal infections (cIAIs). Patients with confirmed cIAI requiring surgical or percutaneous intervention and antibacterial therapy were randomized (2:2:1) to receive eravacycline at 1.5 mg/kg of body weight every 24 h (q24h), eravacycline at 1.0 mg/kg every 12 h (q12h), or ertapenem at 1 g (q24h) for a minimum of 4 days and a maximum of 14 days. The primary efficacy endpoint was the clinical response in microbiologically evaluable (ME) patients at the test-of-cure (TOC) visit 10 to 14 days after the last dose of study drug therapy. Overall, 53 patients received eravacycline at 1.5 mg/kg q24h, 56 received eravacycline at 1.0 mg/kg q12h, and 30 received ertapenem. For the ME population, the clinical success rate at the TOC visit was 92.9% (39/42) in the group receiving eravacycline at 1.5 mg/kg q24h, 100% (41/41) in the group receiving eravacycline at 1.0 mg/kg q12h, and 92.3% (24/26) in the ertapenem group. The incidences of treatment-emergent adverse events were 35.8%, 28.6%, and 26.7%, respectively. Incidence rates of nausea and vomiting were low in both eravacycline groups. Both dose regimens of eravacycline were as efficacious as the comparator, ertapenem, in patients with cIAI and were well tolerated. These results support the continued development of eravacycline for the treatment of serious infections, including those caused by drug-resistant Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01265784.)

scholarly journals Controlled Trial of a 5-Day Course of Telithromycin versus Doxycycline for Treatment of Mild to Moderate Scrub Typhus

2007 ◽  
Vol 51 (6) ◽  
pp. 2011-2015 ◽  
Author(s):  
Dong-Min Kim ◽  
Ki Dong Yu ◽  
Ji Hyun Lee ◽  
Hyun Kuk Kim ◽  
Seung-Hyun Lee
Keyword(s):  
Adverse Events ◽  
Scrub Typhus ◽  
Controlled Trial ◽  
Sensitivity Study ◽  
University Hospital ◽  
Efficacy And Safety ◽  
Open Label ◽  
Serious Adverse Events ◽  
New Antibiotics

ABSTRACT New antibiotics are required to have the antibacterial activity against doxycycline-resistant Orientia tsutsugamushi. An in vitro sensitivity study showed that telithromycin was more effective than erythromycin for Rickettsia, Bartonella, and Coxiella burnetii. In this prospective, open-label, randomized trial, we enrolled patients with mild-to-moderate scrub typhus. We compared the efficacy and safety of a 5-day telithromycin therapy with those of a 5-day doxycycline therapy at Chosun University Hospital or one of its two community-based affiliated hospitals (Jangheung Hospital and Cheomdan Hospital), which are all located in southwestern Korea, between September and December 2005. A total of 92 patients were randomly assigned to either the telithromycin group (n = 47) or the doxycycline group (n = 45). After the treatment, fever control time was 20.45 ± 12.9 h in the telithromycin group and 22.60 ± 21.44 h in the doxycycline group (P > 0.05). After the treatment, the cure rate was 100% in the telithromycin group and 97.8% in the doxycycline group (P > 0.05). Furthermore, there were no significant differences in time elapsed until such symptoms as headache, myalgia, and rash disappeared. No serious adverse events or death were noted following the treatment in both groups. There were no significant differences in adverse events. In conclusion, the efficacy and safety of a 5-day once-a-day regimen of 800 mg telithromycin were equivalent to those of a 5-day twice-a-day regimen of 100 mg doxycycline in patients with mild-to-moderate scrub typhus. Telithromycin could be considered a promising new antibacterial agent for patients with scrub typhus.

scholarly journals MERIDIAN: A phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of pegcetacoplan in patients with amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Frederico Mennucci de Haidar Jorge ◽  
Angela Genge ◽  
Ammar Al- Chalabi ◽  
Orla Hardiman ◽  
Alice Shen ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Rating Scale ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Open Label ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Sporadic Als ◽  
The Difference ◽  
Lateral Sclerosis

Introduction: Inflammation underlies the pathogenesis of numerous neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In ALS, the complement system has been implicated in the neuropathology of disease and disease progression. Pegcetacoplan, a subcutaneously administered C3 complement inhibitor, is being investigated in hematology, nephrology, and neurology. The current clinical study (NCT04579666) is investigating whether pegcetacoplan can improve survival and function in people diagnosed with apparent sporadic ALS. Objectives and Methodology: Evaluate the efficacy and safety of pegcetacoplan compared to placebo among people diagnosed with ALS in a global, multicenter, randomized, double-blind, placebo-controlled, phase 2 study. Approximately 228 patients diagnosed with apparent sporadic ALS, ≥18 years of age and with an ALS Functional Rating Scale-Revised (ALSFRS-R) score ≥30, slow vital capacity (SVC) ≥60% of the predicted value at screening, and with symptom onset within 72 weeks before screening, are eligible for enrollment. After screening, patients will be randomized 2:1 to treatment groups receiving either subcutaneous pegcetacoplan (1080 mg) or placebo twice weekly for a duration of 52 weeks. The primary efficacy endpoint is the difference in the Combined Assessment of Function and Survival (CAFS) ranked score at 52 weeks after treatment initiation. Additional, secondary functional efficacy (ALSFRS-R, percent SVC, muscle strength, quality of life, and caregiver burden) and safety endpoints will be analyzed at 52 weeks. After the placebo-controlled period, all patients will have the option to receive pegcetacoplan in an open-label period for an additional 52 weeks. Results: This ongoing study is currently enrolling participants. Conclusions: Results of this study will determine the role of complement and C3 inhibition in patients with ALS.

scholarly journals JNJ-Q2, a New Fluoroquinolone with PotentIn VitroActivity against Staphylococcus aureus, Including Methicillin- and Fluoroquinolone-Resistant Strains

2011 ◽  
Vol 55 (7) ◽  
pp. 3631-3634 ◽  
Author(s):  
David J. Farrell ◽  
Lisa C. Liverman ◽  
Douglas J. Biedenbach ◽  
Ronald N. Jones
Keyword(s):  
United States ◽  
Staphylococcus Aureus ◽  
Broad Spectrum ◽  
The United States ◽  
Gram Positive ◽  
Content Type ◽  
Skin Structure ◽  
Resistant Strains

ABSTRACTJNJ-Q2 is a broad-spectrum bactericidal fluoroquinolone with potent activity against Gram-positive and -negative pathogens. In this study, thein vitroactivity of JNJ-Q2 was evaluated against 511 selectedStaphylococcus aureussamples isolated in 2008-2009 from patients with acute bacterial skin and skin structure infections in the United States by using reference methodology. JNJ-Q2 was the most potent fluoroquinolone tested overall (MIC50and MIC90, 0.12 and 0.5 μg/ml, respectively) and against methicillin- and fluoroquinolone-resistant subgroups in direct comparisons to moxifloxacin, levofloxacin, and ciprofloxacin (each being ≥16-fold less potent than JNJ-Q2).

scholarly journals In Vitro Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Nicole E. Scangarella-Oman ◽  
Karen A. Ingraham ◽  
Courtney A. Tiffany ◽  
Lynn Tomsho ◽  
Stephanie F. Van Horn ◽  
...  
Keyword(s):  
Susceptibility Testing ◽  
Phase 2 ◽  
Topoisomerase Inhibitors ◽  
Gram Positive ◽  
Content Type ◽  
Skin Structure ◽  
Phase 2 Study ◽  
Secondary Endpoints ◽  
Dose Ranging

ABSTRACT A phase 2 study of gepotidacin demonstrated the safety and efficacy of 3 gepotidacin doses (750 mg every 12 h [q12h], 1,000 mg q12h, and 1,000 mg every 8 h [q8h]) in hospitalized patients with suspected/confirmed Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). Evaluating microbiology outcomes and responses were secondary endpoints. Pretreatment isolates recovered from infected lesions underwent susceptibility testing per Clinical and Laboratory Standards Institute guidelines. Staphylococcus aureus accounted for 78/102 (76%) of Gram-positive isolates; 54/78 (69%) were methicillin-resistant S. aureus (MRSA), and 24/78 (31%) were methicillin-susceptible S. aureus (MSSA). Posttherapy microbiological success (culture-confirmed eradication of the pretreatment pathogen or presumed eradication based on a clinical outcome of success) for S. aureus was 90% for the gepotidacin 750-mg q12h group, 89% for the 1,000-mg q12h, and 73% in the 1000-mg q8h group. For 78 S. aureus isolates obtained from pretreatment lesions, gepotidacin MIC50/MIC90 values were 0.25/0.5 μg/ml against both MRSA and MSSA. Isolates recovered from the few patients with posttreatment cultures showed no significant reduction in gepotidacin susceptibility (≥4-fold MIC increase) between pretreatment and posttreatment isolates. Two of the 78 S. aureus isolates from pretreatment lesions had elevated gepotidacin MICs and had mutations known to occur in quinolone-resistant S. aureus (GyrA S84L, ParC S80Y, and ParE D422E) or to confer elevated MICs to novel bacterial topoisomerase inhibitors (GyrA D83N, both isolates; ParC V67A, one isolate). This first report of microbiological outcomes and responses of gepotidacin in patients with ABSSSIs supports further evaluation of gepotidacin as a novel first-in-class antibacterial agent. (This study has been registered at ClinicalTrials.gov under identifier NCT02045797.)

MOUNTAINEER-02: Phase II/III study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2+ gastric or gastroesophageal junction adenocarcinoma—Trial in Progress.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS252-TPS252
Author(s):  
John H. Strickler ◽  
Yoshiaki Nakamura ◽  
Takayuki Yoshino ◽  
Daniel V.T. Catenacci ◽  
Yelena Y. Janjigian ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind ◽  
Gastroesophageal Junction Adenocarcinoma

TPS252 Background: Tucatinib (TUC), a highly selective HER2-directed TKI recently approved for HER2+ metastatic breast cancer (MBC), is being developed as a novel therapy for patients (pts) with metastatic colorectal cancer (mCRC) and other GI tumors. While trastuzumab (Tras) with chemotherapy is standard in the 1st-line setting for metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC), no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy in 2nd-line, possibly due to loss of HER2 expression following Tras-based therapy. In GEC xenograft models, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras in HER2+ mCRC. The MOUNTAINEER-02 study is evaluating the efficacy and safety of TUC in combination with Tras, ramucirumab (Ram), and paclitaxel (Pac) in pts with HER2+ GEC. Methods: MOUNTAINEER-02 (NCT04499924) is a phase 2/3 study evaluating TUC and Tras with the 2nd-line standard of care, Ram and Pac. Pts receive TUC 300 mg or placebo PO BID, Tras (6 then 4 mg/kg) or placebo (IV on Days 1 and 15 of each 28-day cycle), Pac (IV on Days 1, 8, 15), and Ram (IV on Days 1 and 15). Eligible pts have locally-advanced unresectable or metastatic HER2+ GEC, have received a HER2-directed antibody, and 1 prior line of therapy for advanced disease. Pts must be ≥18 years of age, with an ECOG ≤1, and have had no prior exposure to Ram, anti-HER2 or anti-EGFR TKI, HER2-directed antibody-drug conjugates, or taxanes ≤12 months before enrollment. Due to the potential impact of TUC on Pac metabolism, the study will include an initial Pac dose finding stage. The open-label phase 2 part will determine the recommended dose of Pac (60 or 80 mg/m²) combined with TUC, Tras, and Ram in 6-12 patients, and evaluate the safety and activity of the regimen in Cohorts 2A and 2B (30 patients each). The randomized, double-blind, phase 3 part will compare the efficacy and safety of TUC and Tras (Arm 3A; ~235 patients) vs. placebo (Arm 3B; ~235 patients), both in combination with Ram and Pac, and also evaluate activity of TUC with Ram and Pac (Arm 3C; ~30 patients). The dual primary phase 3 endpoints are OS and PFS per investigator, with confirmed ORR as a key secondary endpoint. HER2 status is determined at baseline using a blood-based NGS assay, and IHC/ISH of fresh or archival tumor biopsies, if available. Pts must be HER2+ by blood-based NGS in Cohort 2A and phase 3; in Cohort 2B, pts must be HER2+ in a biopsy taken post-progression during/after 1st-line therapy, but HER2-negative by blood-based NGS. Disease assessments per RECISTv1.1 will occur q6 weeks for 36 weeks, then q9 weeks. The pharmacokinetics of TUC, Pac, and their metabolites will be evaluated in a subset of pts, including a cohort with gastrectomies. Enrollment is ongoing in the U.S. Clinical trial information: NCT04499924.

scholarly journals Review of Efficacy and Safety of Duloxetine 40 to 60 mg Once Daily in Patients with Diabetic Peripheral Neuropathic Pain

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Vladimir Skljarevski ◽  
Elijah P. Frakes ◽  
Doron Sagman ◽  
Sarah Lipsius ◽  
Alexandra N. Heinloth ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Adverse Events ◽  
Brief Pain Inventory ◽  
Primary Outcome Measure ◽  
Pain Severity ◽  
Efficacy And Safety ◽  
Open Label ◽  
Double Blind ◽  
Peripheral Neuropathic Pain ◽  
Once Daily

We summarize efficacy and safety findings from 4 double-blind, placebo-controlled, 12-week studies and 1 open-label, uncontrolled, 34-week maintenance-of-effect (MOE) study that examine duloxetine 40 and 60 mg once daily (QD) in patients with diabetic peripheral neuropathic pain (DPNP). In all placebo-controlled studies, duloxetine showed significantly (P≤.01) greater reduction in pain severity (weekly mean of 24-hour average pain severity ratings, primary outcome measure) compared with placebo. In all placebo-controlled studies, duloxetine showed significantly (P≤.05) greater improvement on brief pain inventory-Interference ratings. Patient global impression of improvement ratings were superior to placebo (P≤.01) for duloxetine patients in all placebo-controlled studies. Response rates (based on 30% pain reduction) ranged from 57% to 68% for duloxetine and from 35% to 47% for placebo and were statistically significantly different (P≤.01) between treatment groups in 3 out of 4 studies. The open-label study showed maintenance of analgesic effect of duloxetine in DPNP. In the duloxetine groups, 4.3% to 14.9% of patients discontinued because of adverse events (placebo groups: 2.6% to 7.4%). Most commonly reported treatment-emergent adverse events were nausea, somnolence, and headache. Duloxetine 40 and 60 mg QD was efficacious and well tolerated in the management of DPNP.

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