•Omadacycline is non-inferior to moxifloxacin for investigator-assessed response at post-treatment evaluation.•High rates of clinical success were reported in patients with Pneumonia Patient Outcomes ...Research Team risk class III and IV.•Clinical success rates were similar between groups against identified pathogens.•Clinical success rates were similar between groups across key patient subgroups.
Community-acquired bacterial pneumonia (CABP) is a major clinical burden worldwide. In the phase III OPTIC study (NCT02531438) in CABP, omadacycline was found to be non-inferior to moxifloxacin for investigator-assessed clinical response (IACR) at post-treatment evaluation (PTE, 5–10 days after last dose). This article reports the efficacy findings, as specified in the European Medicines Agency (EMA) guidance.
Patients were randomized 1:1 to omadacycline 100 mg intravenously (every 12 h for two doses, then every 24 h) with optional transition to 300 mg orally after 3 days, or moxifloxacin 400 mg intravenously (every 24 h) with optional transition to 400 mg orally after 3 days. The total treatment duration was 7−14 days. The primary endpoint for EMA efficacy analysis was IACR at PTE in patients with Pneumonia Patient Outcomes Research Team (PORT) risk class III and IV.
In total, 660 patients were randomized as PORT risk class III and IV. Omadacycline was non-inferior to moxifloxacin at PTE. The clinical success rates were 88.4% and 85.2%, respectively intent-to-treat population; difference 3.3; 97.5% confidence interval (CI) −2.7 to 9.3, and 92.5% and 90.5%, respectively (clinically evaluable population; difference 2.0; 97.5% CI 3.2–7.4). Clinical success rates with omadacycline and moxifloxacin were similar against identified pathogens and across key subgroups.
Omadacycline was non-inferior to moxifloxacin for IACR at PTE, with high clinical success across pathogen types and patient subgroups.
Hydroxychloroquine (HCQ) was initially promoted as an oral therapy for early treatment of coronavirus disease 2019 (COVID‐19). Conventional meta‐analyses cannot fully address the heterogeneity of ...different designs and outcomes of randomized controlled trials (RCTs) assessing the efficacy of HCQ in outpatients with mild COVID‐19. We conducted a pooled analysis of individual participant data from RCTs that evaluated the effect of HCQ on hospitalization and viral load reduction in outpatients with confirmed COVID‐19. We evaluated the overall treatment group effect by log‐likelihood ratio test (−2LL) from a generalized linear mixed model to accommodate correlated longitudinal binary data. The analysis included data from 11 RCTs. The outcome of virological effect, assessed in 1560 participants (N = 795 HCQ, N = 765 control), did not differ significantly between the two treatment groups (−2LL = 7.66; p = 0.18) when adjusting for cohort, duration of symptoms, and comorbidities. The decline in polymerase chain reaction positive tests from day 1 to 7 was 42.0 and 41.6 percentage points in the HCQ and control groups, respectively. Among the 2037 participants evaluable for hospitalization (N = 1058 HCQ, N = 979 control), we found no significant differences in hospitalization rate between participants receiving HCQ and controls (odds ratio 0.995; 95% confidence interval 0.614–1.610; −2LL = 0.0; p = 0.98) when adjusting for cohort, duration of symptoms, and comorbidities. This individual participant data meta‐analysis of 11 HCQ trials that evaluated severe acute respiratory syndrome‐coronavirus 2 viral clearance and COVID‐19 hospitalization did not show a clinical benefit of HCQ. Our meta‐analysis provides evidence to support the interruption in the use of HCQ in mild COVID‐19 outpatients to reduce progression to severe disease.
The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector ...dose.
In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 10
vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 10
vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII.
The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean ±SD factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval CI, -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year range, 0 to 43.0 before vector administration vs. 0.3 events per year range, 0 to 6.5 after vector administration).
Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).
Abstract
Background
Early clinical response (ECR) is a new endpoint to determine whether a drug should be approved for community-acquired bacterial pneumonia in the United States. The Omadacycline ...for Pneumonia Treatment In the Community (OPTIC) phase III study demonstrated noninferiority of omadacycline to moxifloxacin using this endpoint. This study describes the performance of the ECR endpoint and clinical stability relative to a posttreatment evaluation (PTE) of clinical success.
Methods
ECR was defined as symptom improvement 72–120 hours after the first dose of study drug (ECR window), no use of rescue antibiotics, and patient survival. Clinical success at PTE was an investigator assessment of success. Clinical stability was defined based on vital sign stabilization, described in the American Thoracic Society and Infectious Diseases Society of America community-acquired pneumonia treatment guidelines.
Results
During the ECR window, ECR was achieved in 81.1% and 82.7% of omadacycline and moxifloxacin patients, respectively. Similar numbers of patients achieved clinical stability in each treatment group (omadacycline 74.6%, moxifloxacin 77.6%). The proportion of patients with improved symptoms who were considered clinically stable increased across the ECR window (69.2–77.6% for omadacycline; 68.0–79.7% for moxifloxacin). There was high concordance (>70%) and high positive predictive value (>90%) of ECR and clinical stability with overall clinical success at PTE.
Conclusions
Omadacycline was noninferior to moxifloxacin, based on a new ECR endpoint. Clinical stability was similarly high when measured in the same time frame as ECR. Both ECR and clinical stability showed high concordance and high positive predictive value with clinical success at PTE.
Clinical Trials Registration
NCT02531438.
Although most research professionals believe that protocol designs contain a growing number of unnecessary and redundant procedures generating unused data, incurring high cost, and jeopardizing study ...success, there are no published studies systematically examining this issue. Between November 2011 and May 2012, Tufts Center for the Study of Drug Development conducted a study among a working group of 15 pharmaceutical companies in which a total of 25,103 individual protocol procedures were evaluated and classified using clinical study reports and analysis plans. The results show that the typical later-stage protocol had an average of 7 objectives and 13 end points of which 53.8% are supplementary. One (24.7%) of every 4 procedures performed per phase-III protocol and 17.7% of all phase-II procedures per protocol were classified as "Noncore" in that they supported supplemental secondary, tertiary, and exploratory end points. For phase-III protocols, 23.6% of all procedures supported regulatory compliance requirements and 15.9% supported those for phase-II protocols. The study also found that on average, $1.7 million (18.5% of the total) is spent in direct costs to administer Noncore procedures per phase-III protocol and $0.3 million (13.1% of the total) in direct costs are spent on Noncore procedures for each phase-II protocol. Based on the results of this study, the total direct cost to perform Noncore procedures for all active annual phase-II and phase-III protocols is conservatively estimated at $3.7 billion annually, not including the indirect costs associated with collecting and managing Noncore procedure data and the ethical costs of exposing study volunteers to unnecessary risks associated with conducting extraneous procedures.
Abstract
Background
The risk of serious infections and poor treatment outcomes is reported to be higher in patients with diabetes compared with the general population. Omadacycline (OMC) is an ...intravenous (IV) and oral aminomethylcycline antibiotic approved in the US to treat acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults. Here we assessed safety and efficacy results from OMC Phase 3 studies (ABSSSI: Omadacycline in Acute Skin and skin structure Infections Study OASIS-1 and OASIS-2; CABP: Omadacycline for Pneumonia Treatment In the Community study OPTIC), by diabetes history.
Methods
In OASIS-1 (IV to optional oral medication) and OASIS-2 (oral only), patients were randomized to OMC or linezolid (LZD) for 7–14 days. In OPTIC, patients were randomized to IV OMC or moxifloxacin (MOX) for 7–14 days, with optional transition to oral medication. Data from OASIS-1 and OASIS-2 were pooled, and patient subgroups were defined by any medical history of diabetes (type 1, type 2, or unspecified), or no medical history of diabetes. Efficacy outcomes were early clinical response (ECR) and investigator’s assessment of clinical response at post-treatment evaluation (PTE), as defined for each indication. Safety was assessed by treatment-emergent adverse events (TEAEs) and laboratory measures, and data were pooled across the three studies.
Results
A total of 2,150 patients were included, of whom 238 (11.1%) had any history of diabetes (n = 105 for ABSSSI, n = 133 for CABP). In the pooled ABSSSI studies and the CABP study, clinical success at ECR and PTE was similar between patients with or without diabetes, and between OMC and the respective comparator (figure). TEAEs and serious TEAEs, respectively, were reported in similar numbers of OMC-, LZD-, and MOX-treated patients with diabetes (41.8–49.3%, 4.5–7.0%) and without (41.2–48.3%, 1.6–6.9%). Rates of nausea and vomiting, respectively, in patients with diabetes were similar across treatment arms: OMC (5.0%, 5.0%), LZD (7.5%, 6.0%), MOX (7.0%, 2.8%).
Conclusion
Omadacycline efficacy and safety were similar and consistent in patients with or without diabetes.
Disclosures
All authors: No reported disclosures.
Abstract
Background
Severity/mortality risk scores and disease characteristics may assist in deciding whether patients with community-acquired bacterial pneumonia (CABP) require outpatient treatment ...or hospitalization. The phase 3 OPTIC (Omadacycline for Pneumonia Treatment In the Community) study enrolled patients with Pneumonia Outcomes Research Team (PORT) risk class II–IV. Omadacycline demonstrated noninferiority to moxifloxacin in adults with CABP, at early clinical response (ECR) and posttreatment evaluation (PTE). We assessed efficacy of omadacycline versus moxifloxacin in these patients based on disease severity.
Methods
Patients were randomized 1:1 to receive intravenous (IV) omadacycline (100 mg every 12 hours for 2 doses followed by 100 mg daily q24h, with optional transition to omadacycline 300 mg orally q24h after 3 days of IV treatment) or moxifloxacin IV 400 mg q24h (with optional transition to 400 mg orally q24h after 3 days of IV treatment). Total treatment duration was 7–14 days. We compared rates of early clinical success (72–120 hours after first dose) and investigator-assessed clinical success at PTE (5–10 days after last dose) in subgroups based (1) on severity/mortality risk scores (PORT, CURB-65, systemic inflammatory response syndrome, quick Sequential Sepsis-related Organ Failure Assessment, modified ATS, SMART-COP) and (2) on presence of baseline radiographic characteristics, chronic obstructive pulmonary disease (COPD)/asthma, or bacteremia.
Results
Altogether, 774 patients (omadacycline, n = 386; moxifloxacin, n = 388) were randomized. Clinical success rates (ECR/PTE) were similar between treatment groups (across all subgroups). Efficacy across treatment groups was similar in patients with baseline radiographic characteristics or COPD/asthma, but moxifloxacin had higher clinical success rates in patients with bacteremia.
Conclusions
Efficacy of omadacycline was similar to that of moxifloxacin, regardless of disease severity/mortality risk and disease characteristics.
In the phase 3 OPTIC study in non-ICU patients hospitalized for community-acquired bacterial pneumonia, the efficacy of omadacycline was comparable to that of moxifloxacin, including in patients with heightened disease severity and/or mortality risk.
Abstract
Background
The appearance of multidrug-resistant Gram-positive bacteria is a major challenge in clinical care. Omadacycline is the first aminomethylcycline antibiotic (semisynthetic ...compounds related to tetracyclines) in late-stage clinical development for acute bacterial skin and skin structure infections (ABSSSI), and demonstrates potent in vitro activity against many pathogens.
Methods
Seven hundred thirty-five patients were enrolled in the OASIS-2 randomized controlled trial comparing omadacycline and linezolid for the treatment of adult subjects with ABSSSI known or suspected to be due to a Gram-positive pathogen, with 368 and 367 enrolled in each group, respectively. Subjects completed the 36-Item Short Form Health Survey Version 2 (SF-36v2), a validated questionnaire on physical and mental health, at both screening and post-treatment evaluation. Results of the SF-36v2 were analyzed in accordance with established norm-based standards for the survey (Ware 2000) for the intention-to-treat population.
Results
Subjects who received omadacycline experienced a 3.25 point mean improvement in overall physical health (P < 0.001, Figure 1) and reported significant improvements across all but one component parameter of overall physical and mental health, including physical functioning, bodily pain, role physical, vitality, role emotional, mental health, and social functioning (Figure 2). In contrast, while overall physical health improved for subjects who received linezolid, the improvement in vitality, role emotional, mental health, and general health was not significant (Figure 2). Although omadacycline achieved greater increase from baseline than linezolid across all domains analyzed, the difference in scores was not statistically significant at the P < 0.05 level (Figure 1).
Conclusion
Omadacycline provides significant improvement in the physical component of quality of life over baseline for adult subjects with ABSSSI known or suspected to be due to a Gram-positive pathogen. Although the OASIS-2 trial was neither designed nor powered to measure differences in quality of life following treatment, trends identified in this analysis merit further investigation.
References
1. Ware JE. SF-36 Health Survey Update. SPINE 2000; 25(24); 3130–3139.
Disclosures
E. Tzanis, Paratek Pharmaceuticals: Employee, Salary. M. Curran, Paratek Pharmaceuticals: Employee, Salary. P. McGovern, Paratek Pharmaceuticals: Employee, Salary. J. Hinahara, Paratek Pharmaceuticals: Consultant, Consulting fee. T. Goss, Paratek Pharmaceuticals: Consultant, Consulting fee.
Abstract
Background
Omadacycline (OMC) is an intravenous (IV) and oral aminomethylcycline antibiotic in the tetracycline class approved in the United States to treat acute bacterial skin and skin ...structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults. The approved dosing regimens of OMC include a loading dose designed to achieve steady-state exposures early in the course of therapy. We assessed the impact on OMC exposure and subsequent pharmacodynamics (PD) on Day 2 and at steady state (Day 5) in the situation where a loading dose may not be given.
Methods
Phase 1 pharmacokinetic (PK) data were used to determine OMC exposure on Day 2 and at steady state (Day 5) for the following: IV regimens 100 mg IV q12h on Day 1 then 100 mg IV QD (load), 100 mg IV QD (no load); and oral regimens 450 mg oral QD on Days 1 and 2 then 300 mg QD (load) and 300 mg oral QD (no load). AUCs on Day 2 and Day 5 for no-load regimens were compared with the regimens with loading doses. Additionally, AUC:MIC ratios were calculated using OMC MIC90 for two main pathogens of interest in ABSSSI and CABP, respectively, Staphylococcus aureus (0.25 mg/L) and Streptococcus pneumoniae (0.12 mg/L). In vivo AUC:MIC targets for stasis and 1-log kill used were 21.9 and 57.7 (S. aureus) and 31.2 and 65.8 (S. pneumoniae).
Results
Day 2 and 5 AUCs are shown in the Figure. AUCs on Day 2 were lower for the two regimens without loading doses and were 72% (IV) and 73% (oral) of those with a loading dose. However, at steady state on Day 5, no-load regimen AUCs were essentially the same at 98% for both the IV and oral regimens. Despite lower AUCs on Day 2 for the no-load regimens, the AUC:MIC ratio would still be expected to exceed the stasis threshold for both pathogens and the 1-log kill threshold for S. pneumoniae (figure). This same pattern was also noted on Day 5.
Conclusion
Exposure as assessed using AUC was lower early on in therapy on Day 2 for both IV and oral regimens. However, exposures were not different on Day 5 at steady state. Despite lower exposure on Day 2, OMC would still be expected to meet or exceed PK/PD thresholds associated with stasis for S. aureus and S. pneumoniae. The 1-log kill threshold was exceeded for S. pneumoniae. Further studies are needed to confirm any clinical impact of the omission of OMC loading doses.
Disclosures
All authors: No reported disclosures.
PDF
