SAFETY AND TOLERABILITY OF LEFAMULIN VS MOXIFLOXACIN IN ADULTS WITH COMMUNITY-ACQUIRED BACTERIAL PNEUMONIA: RESULTS OF THE LEFAMULIN EVALUATION AGAINST PNEUMONIA (LEAP) 1 AND LEAP 2 DOUBLE-BLIND NONINFERIORITY PHASE-3 CLINICAL TRIALS

Abstract Background Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are associated with high mortality rates. We evaluated the efficacy and safety of tedizolid (administered as tedizolid phosphate) for treatment of gram-positive ventilated HABP/VABP. Methods In this randomized, noninferiority, double-blind, double-dummy, global phase 3 trial, patients were randomized 1:1 to receive intravenous tedizolid phosphate 200 mg once daily for 7 days or intravenous linezolid 600 mg every 12 hours for 10 days. Treatment was 14 days in patients with concurrent gram-positive bacteremia. The primary efficacy end points were day 28 all-cause mortality (ACM; noninferiority margin, 10%) and investigator-assessed clinical response at test of cure (TOC; noninferiority margin, 12.5%) in the intention-to-treat population. Results Overall, 726 patients were randomized (tedizolid, n = 366; linezolid, n = 360). Baseline characteristics, including incidence of methicillin-resistant Staphylococcus aureus (31.3% overall), were well balanced. Tedizolid was noninferior to linezolid for day 28 ACM rate: 28.1% and 26.4%, respectively (difference, –1.8%; 95% confidence interval [CI]: –8.2 to 4.7). Noninferiority of tedizolid was not demonstrated for investigator-assessed clinical cure at TOC (tedizolid, 56.3% vs linezolid, 63.9%; difference, –7.6%; 97.5% CI: –15.7 to 0.5). In post hoc analyses, no single factor accounted for the difference in clinical response between treatment groups. Drug-related adverse events occurred in 8.1% and 11.9% of patients who received tedizolid and linezolid, respectively. Conclusions Tedizolid was noninferior to linezolid for day 28 ACM in the treatment of gram-positive ventilated HABP/VABP. Noninferiority of tedizolid for investigator-assessed clinical response at TOC was not demonstrated. Both drugs were well tolerated. Clinical Trials Registration NCT02019420.

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Efficacy and Safety of Oritavancin Relative to Vancomycin for Patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in the Outpatient Setting: Results From the SOLO Clinical Trials

Open Forum Infectious Diseases ◽

10.1093/ofid/ofw274 ◽

2017 ◽

Vol 4 (1) ◽

Cited By ~ 7

Author(s):

Thomas P. Lodise ◽

Mark Redell ◽

Shannon O. Armstrong ◽

Katherine A. Sulham ◽

G. Ralph Corey

Keyword(s):

Clinical Trials ◽

Composite Endpoint ◽

Outpatient Setting ◽

Efficacy And Safety ◽

Phase 3 ◽

Double Blind ◽

Skin Structure ◽

Efficacy Outcome ◽

End Of Treatment ◽

Secondary Endpoints

Abstract Background The objective of this analysis was to evaluate the efficacy and safety of oritavancin compared with vancomycin for patients with acute bacterial skin and skin structure infections (ABSSSIs) who received treatment in the outpatient setting in the Phase 3 SOLO clinical trials. Methods SOLO I and SOLO II were 2 identically designed comparative, multicenter, double-blind, randomized studies to evaluate the efficacy and safety of a single 1200-mg dose of intravenous (IV) oritavancin versus 7–10 days of twice-daily IV vancomycin for the treatment of ABSSSI. Protocols were amended to allow enrolled patients to complete their entire course of antimicrobial therapy in an outpatient setting. The primary efficacy outcome was a composite endpoint (cessation of spread or reduction in size of the baseline lesion, absence of fever, and no rescue antibiotic at early clinical evaluation [ECE]) (48 to 72 hours). Key secondary endpoints included investigator-assessed clinical cure 7 to 14 days after end of treatment (posttherapy evaluation [PTE]) and 20% or greater reduction in lesion area at ECE. Safety was assessed until day 60. Results Seven hundred ninety-two patients (oritavancin, 392; vancomycin, 400) received entire course of treatment in the outpatient setting. Efficacy response rates at ECE and PTE were similar (primary composite endpoint at ECE: 80.4% vs 77.5% for oritavancin and vancomycin, respectively) as was incidence of adverse events. Five patients (1.3%) who received oritavancin and 9 (2.3%) vancomycin patients were subsequently admitted to a hospital. Conclusions Oritavancin provides a single-dose alternative to multidose vancomycin for treatment of ABSSSI in the outpatient setting.

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Baseline endometriosis-associated pain burden: Data from 1600+ women enrolled in elagolix clinical trials

Journal of Endometriosis and Pelvic Pain Disorders ◽

10.1177/2284026519864232 ◽

2019 ◽

Vol 11 (3) ◽

pp. 117-125 ◽

Cited By ~ 1

Author(s):

Nicholas Leyland ◽

Stephanie J Estes ◽

Samantha Eichner ◽

Ahmed M Soliman ◽

Yabing Mai ◽

...

Keyword(s):

Clinical Trials ◽

Pelvic Pain ◽

Rating Scale ◽

Numeric Rating Scale ◽

Phase 3 ◽

Double Blind ◽

Scale Range ◽

Study Participants ◽

Numeric Rating Scale Score ◽

Numeric Rating

Background: The daily pain burden experienced by women with endometriosis has not been well studied. Objective: To characterize baseline pain among women with moderate-to-severe endometriosis-associated pain enrolled in phase 3 studies of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist. Study design: Data were pooled from the screening phase of two randomized, double-blind, placebo-controlled clinical trials. After cessation of endometriosis medications, patients entered the screening phase during which symptoms (dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia) and rescue medication use were recorded daily in electronic diaries. Endometriosis-associated pain was also scored using the Numeric Rating Scale (range 0–10). Baseline was defined as the last 35 days during the screening period. Results: Endometriosis-associated pain was reported by the 1686 study participants on most days during the baseline interval. Pain was often moderate or severe, with a mean Numeric Rating Scale score of 5.6 ± 1.7. Women reported dysmenorrhea an average of 8.1 ± 3.0 days (97.9% ± 7.0% of menstruating days), nonmenstrual pelvic pain on 20.5 ± 5.4 days (90.3% ± 15.8% of nonmenstruating days), and dyspareunia on 8.7 ± 8.0 days (81.7% ± 29.7% of sexually active days). When they occurred, dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia were frequently moderate or severe in intensity. Women were free of pelvic pain for an average of 2.4 ± 3.9 days during the 35-day evaluation interval. Conclusion: Among women with untreated moderate-to-severe endometriosis pain, the daily burden of pain was extensive, both during menstruation and on nonmenstruating days.

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153P Ramucirumab safety in East Asian (EA) compared to non-EA patients: A meta-analysis of adverse events (AEs) in 6 global, randomized, double-blind, phase 3 clinical trials

Annals of Oncology ◽

10.1093/annonc/mdw579.005 ◽

2016 ◽

Vol 27 (suppl_9) ◽

Author(s):

H.C. Chung ◽

Y. Chao ◽

K-W. Lee ◽

M. Kudo ◽

C-J. Yen ◽

...

Keyword(s):

Clinical Trials ◽

Adverse Events ◽

Meta Analysis ◽

East Asian ◽

Phase 3 ◽

Double Blind

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Phase 3, Randomized, Double-blind Noninferiority (NI) Study of Ceftazidime–Avibactam (CAZ-AVI) vs. Meropenem (MER) in the Treatment of Patients with Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP): Analyses of the REPROVE Study per US FDA Endpoints

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.1394 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S535-S535 ◽

Cited By ~ 2

Author(s):

Antoni Torres ◽

Doug Rank ◽

Ludmyla Rekeda ◽

Xiang Chen ◽

Todd Riccobene ◽

...

Keyword(s):

Bacterial Pneumonia ◽

Phase 3 ◽

Double Blind ◽

Us Fda ◽

Hospital Acquired

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Carbapenem-Resistant Enterobacteriaceae Infections: Results From a Retrospective Series and Implications for the Design of Prospective Clinical Trials

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx063 ◽

2017 ◽

Vol 4 (2) ◽

Cited By ~ 24

Author(s):

Elizabeth L. Alexander ◽

Jeffery Loutit ◽

Mario Tumbarello ◽

Richard Wunderink ◽

Tim Felton ◽

...

Keyword(s):

Clinical Trials ◽

Patient Population ◽

Bacterial Pneumonia ◽

Complicated Urinary Tract Infection ◽

Clinical Trial Design ◽

New Drugs ◽

External Control ◽

Phase 3 ◽

Carbapenem Resistant ◽

Carbapenem Resistant Enterobacteriaceae

Abstract Background The increasing incidence of multidrug-resistant Gram negatives, such as carbapenem-resistant Enterobacteriaceae (CRE), has resulted in a critical need for new antimicrobials. Most studies of new antimicrobials have been performed in patients with nondrug-resistant pathogens. We performed a retrospective analysis of patients with CRE infections to inform the design of phase 3 clinical trials. Methods This was a retrospective study at 22 centers in 4 countries. Baseline data, treatment, and outcomes were collected in patients with complicated urinary tract infection (cUTI)/acute pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and bacteremia due to CRE. Results Two hundred fifty-six cases of CRE infection were identified: 75 cUTI/AP, 21 HABP, 20 VABP, and 140 bacteremia. The patient population had significant comorbidities: 32.8% had chronic renal insufficiency, and 26.2% were immunocompromised. Illness severity at presentation was high: 29.3% presented with septic shock. Treatment regimens varied widely; however, a majority of patients received combination therapy. Outcomes were universally poor (28-day mortality was 28.1%) across all sites of infection, particularly in dialysis patients and those with sepsis. Conclusions The CRE infections occured in patients with substantial comorbidities and were associated with high mortality and low rates of clinical cure with available antibiotics. Patients with these comorbidities are often excluded from enrollment in clinical trials for registration of new drugs. These results led to changes in the inclusion/exclusion criteria of a phase 3 trial to better represent the patient population with CRE infections and enable enrollment. Observational studies may become increasingly important to guide clinical trial design, inform on the existing standard of care, and provide an external control for subsequent trials.

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Psychometric properties of FACIT-Fatigue in systemic lupus erythematosus: a pooled analysis of three phase 3 randomised, double-blind, parallel-group controlled studies (BLISS-SC, BLISS-52, BLISS-76)

Journal of Patient-Reported Outcomes ◽

10.1186/s41687-021-00298-x ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Regina Rendas-Baum ◽

Nishtha Baranwal ◽

Ashish V. Joshi ◽

Josephine Park ◽

Mark Kosinski

Keyword(s):

Systemic Lupus Erythematosus ◽

Clinical Trials ◽

Lupus Erythematosus ◽

Convergent Validity ◽

Pooled Analysis ◽

Systemic Lupus ◽

Phase 3 ◽

Double Blind ◽

Parallel Group ◽

Test Retest Reliability

Abstract Background Fatigue is a key symptom in patients with systemic lupus erythematosus (SLE), and regulatory bodies recommend its assessment in clinical trials of SLE therapies. Methods This post hoc pooled analysis of the three BeLimumab In Subjects with Systemic lupus erythematosus (BLISS) Phase 3 randomised, double-blind, parallel-group controlled trials evaluated the measurement properties of the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Patients (N = 2520) completed the FACIT-Fatigue every 4 weeks from baseline until the end of each study period. Internal consistency, test–retest reliability, convergent validity, and ability to detect changes in SLE were evaluated for the FACIT-Fatigue. Results The FACIT-Fatigue showed good internal consistency reliability (Cronbach’s alpha > 0.90), very good test–retest reliability (0.76 ≤ intraclass correlation coefficient ≤ 0.92), and moderate-strong convergent validity (0.49 ≤ |r| ≤ 0.86) against scale and summary measure scores from the Short Form 36 Health Survey Version 2. Correlations between FACIT-Fatigue and British Isles Lupus Assessment Group (BILAG) General/Musculoskeletal scores (0.24 ≤ |r| ≤ 0.43) supported convergent validity. Correlations between FACIT-Fatigue and the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores and SLE annualised flare rate were weak but in the expected direction (ranging from − 0.02 to − 0.25). Known-groups validity testing showed that the FACIT-Fatigue can significantly discriminate between patient groups with differing scores for SELENA-SLEDAI, BILAG (General and Musculoskeletal) ratings, and Physician’s Global Assessment (PGA). Patients showing improvement in PGA and meeting the BILAG responder criteria had significantly higher mean improvement in FACIT-Fatigue scores than those without improvements in either measure (Week 52 mean score difference [95% confidence interval]: − 4.0 [− 5.0, − 3.0] and −2.2 [−3.1, −1.2], respectively; both p < 0.0001). The range of important (i.e. meaningful) change in FACIT-Fatigue, based on multiple anchors, was 3–6 points. Conclusions The FACIT-Fatigue demonstrated adequate psychometric properties in patients with SLE. The body of evidence from the three BLISS trials (both pooled and individually) supports the FACIT-Fatigue as a reliable and valid measure of SLE-related fatigue in clinical trials. Clinical trial identifiers BLISS-SC (NCT01484496), BLISS-52 (NCT00424476), and BLISS-76 (NCT00410384).

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