A Neutral Trial With an Improper Noninferiority Margin

2022 ◽  
Vol 79 (1) ◽  
pp. 31-34
Author(s):  
Lauren E. Mamer ◽  
William J. Meurer
Author(s):  
Richard G Wunderink ◽  
Antoine Roquilly ◽  
Martin Croce ◽  
Daniel Rodriguez Gonzalez ◽  
Satoshi Fujimi ◽  
...  

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.


2021 ◽  
Vol 10 (6) ◽  
pp. 443-455
Author(s):  
Mahmoud Hashim ◽  
Talitha Vincken ◽  
Florint Kroi ◽  
Samron Gebregergish ◽  
Mike Spencer ◽  
...  

Aim: A systematic literature review was conducted to identify and characterize noninferiority margins for relevant end points in oncology clinical trials. Materials & methods: Randomized, controlled, noninferiority trials of patients with cancer were identified in PubMed and Embase. Results: Of 2284 publications identified, 285 oncology noninferiority clinical trials were analyzed. The median noninferiority margin was a hazard ratio of 1.29 (mean: 1.32; range: 1.05–2.05) for studies that reported time-to-event end points (n = 192). The median noninferiority margin was 13.0% (mean: 12.7%; range: 5.0–20.0%) for studies that reported response end points as absolute rate differences (n = 31). Conclusion: Although there was consistency in the noninferiority margins’ scale, variability was evident in noninferiority margins across trials. Increased transparency may improve consistency in noninferiority margin application in oncology clinical trials.


2021 ◽  
Vol 16 (1) ◽  
pp. 59-63
Author(s):  
Hee Jong Ki ◽  
Bum-soo Kim ◽  
Jun-Ki Kim ◽  
Jai Ho Choi ◽  
Yong Sam Shin ◽  
...  

Purpose: Three-dimensional (3D) measurement of intracranial aneurysms is important in planning endovascular treatment, and 3D rotational angiography (RA) is effective in accurate measurement. The purpose of this study was to evaluate the feasibility of low dose 3D RA (5 seconds 0.10 μGy/frame) in measuring an intracranial aneurysm using an in vitro phantom.Materials and Methods: We investigated an <I>in vitro</i> 3D phantom of an intracranial aneurysm with 10 acquisitions of 3D RA with a conventional dose (5 seconds 0.36 μGy/frame) and 10 acquisitions with a low-dose (5 seconds 0.10 μGy/frame). 3D size and neck diameters of the aneurysm were measured and compared between the 2 groups (conventional and low-dose) using noninferiority statistics.Results: The aneurysm measurements were well-correlated between the 2 readers, and noninferiority in the measurement of aneurysmal size of low-dose 3D RA was demonstrated, as the upper margin of the 1-sided 97.5% confidence interval did not cross the pre-defined noninferiority margin of 0.2 mm by the 2 readers.Conclusion: Low-dose (5 seconds 0.10 μGy/frame) cerebral 3D RA is technically feasible and not inferior in in vitro 3D measurement of an intracranial aneurysm. Thus, low-dose 3D RA is promising and needs further evaluation for its clinical utility in the planning of endovascular treatment of an intracranial aneurysm.


2020 ◽  
Vol 7 ◽  
Author(s):  
Lingke Chen ◽  
Liu Yang ◽  
Weitian Tian ◽  
Xiao Zhang ◽  
Yanhua Zhao ◽  
...  

Background: Transnasal humidified rapid insufflation ventilatory exchange (THRIVE) was used to extend the safe apnea time. However, THRIVE is only effective in patients with airway opening. Nasopharyngeal airway (NPA) is a simple device that can help to keep airway opening. This study aimed to investigate the noninferiority of NPA to jaw thrust for airway opening during anesthesia-induced apnea.Methods: This was a prospective randomized single-blinded noninferiority clinical trial on the use of THRIVE in patients with anesthesia-induced apnea. The participants were randomly allocated to receive NPA or jaw thrust. The primary outcomes were PaO2 and PaCO2 at 20 min after apnea, with noninferiority margin criteria of −6.67 and 0.67 kPa, respectively.Results: A total of 123 patients completed the trial: 61 in the NPA group and 62 in the jaw thrust group. PaO2 at 20 min after apnea was 42.9 ± 14.0 kPa in the NPA group and 42.7 ± 13.6 kPa in the jaw thrust group. The difference between these two means was 0.25 kPa (95% CI, −3.87 to 4.37 kPa). Since the lower boundary of the 95% CI was &gt; −6.67 kPa, noninferiority was established because higher PO2 is better. PaCO2 at 20 min after apnea was 10.74 ± 1.09 kPa in the NPA group and 10.54 ± 1.18 kPa in the jaw thrust group. The difference between the two means was 0.19 kPa (95% CI, −0.14 to 0.53 kPa). Since the upper boundary of the 95% CI was &lt;0.67 kPa, noninferiority was established because lower PCO2 is better. No patient had a SpO2 &lt; 90% during apnea.Conclusion: When THRIVE was applied during anesthesia-induced apnea, NPA placement kept airway opening and was noninferior to jaw thrust in terms of its effects on PaO2 and PaCO2 at 20 min after apnea.Clinical Trial Registration:ClinicalTrials.gov (NCT03741998).


Author(s):  
Anthony D Bai ◽  
Adam S Komorowski ◽  
Carson K L Lo ◽  
Pranav Tandon ◽  
Xena X Li ◽  
...  

Abstract Background Antibiotic noninferiority randomized controlled trials (RCTs) are used for approval of new antibiotics and making changes to antibiotic prescribing in clinical practice. We conducted a systematic review to assess the methodological and reporting quality of antibiotic noninferiority RCTs. Methods We searched MEDLINE, Embase, the Cochrane Database of Systematic Reviews, and the Food and Drug Administration drug database from inception until November 22, 2019, for noninferiority RCTs comparing different systemic antibiotic therapies. Comparisons between antibiotic types, doses, administration routes, or durations were included. Methodological and reporting quality indicators were based on the Consolidated Standards of Reporting Trials reporting guidelines. Two independent reviewers extracted the data. Results The systematic review included 227 studies. Of these, 135 (59.5%) studies were supported by pharmaceutical industry. Only 83 (36.6%) studies provided a justification for the noninferiority margin. Reporting of both intention-to-treat (ITT) and per-protocol (PP) analyses were done in 165 (72.7%) studies. The conclusion was misleading in 34 (15.0%) studies. The studies funded by pharmaceutical industry were less likely to be stopped early because of logistical reasons (3.0% vs 19.1%; odds ratio [OR] = 0.13; 95% confidence interval [CI], .04–.37) and to show inconclusive results (11.1% vs 42.9%; OR = 0.17; 95% CI, .08–.33). The quality of studies decreased over time with respect to blinding, early stopping, reporting of ITT with PP analysis, and having misleading conclusions. Conclusions There is room for improvement in the methodology and reporting of antibiotic noninferiority trials. Quality can be improved across the entire spectrum from investigators, funding agencies, as well as during the peer-review process. There is room for improvement in the methodology and reporting of antibiotic noninferiority trials including justification of noninferiority margin, reporting of intention-to-treat analysis with per-protocol analysis, and having conclusions that are concordant with study results. PROSPERO registration number CRD42020165040.


2020 ◽  
Vol 48 (6) ◽  
pp. 1305-1315 ◽  
Author(s):  
Martha M. Murray ◽  
Braden C. Fleming ◽  
Gary J. Badger ◽  
Christina Freiberger ◽  
Rachael Henderson ◽  
...  

Background: Preclinical studies suggest that for complete midsubstance anterior cruciate ligament (ACL) injuries, a suture repair of the ACL augmented with a protein implant placed in the gap between the torn ends (bridge-enhanced ACL repair [BEAR]) may be a viable alternative to ACL reconstruction (ACLR). Hypothesis: We hypothesized that patients treated with BEAR would have a noninferior patient-reported outcomes (International Knee Documentation Committee [IKDC] Subjective Score; prespecified noninferiority margin, –11.5 points) and instrumented anteroposterior (AP) knee laxity (prespecified noninferiority margin, +2-mm side-to-side difference) and superior muscle strength at 2 years after surgery when compared with patients who underwent ACLR with autograft. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: One hundred patients (median age, 17 years; median preoperative Marx activity score, 16) with complete midsubstance ACL injuries were enrolled and underwent surgery within 45 days of injury. Patients were randomly assigned to receive either BEAR (n = 65) or autograft ACLR (n = 35 [33 with quadrupled semitendinosus-gracilis and 2 with bone–patellar tendon–bone]). Outcomes—including the IKDC Subjective Score, the side-to-side difference in instrumented AP knee laxity, and muscle strength—were assessed at 2 years by an independent examiner blinded to the procedure. Patients were unblinded after their 2-year visit. Results: In total, 96% of the patients returned for 2-year follow-up. Noninferiority criteria were met for both the IKDC Subjective Score (BEAR, 88.9 points; ACLR, 84.8 points; mean difference, 4.1 points [95% CI, –1.5 to 9.7]) and the side-to-side difference in AP knee laxity (BEAR, 1.61 mm; ACLR, 1.77 mm; mean difference, –0.15 mm [95% CI, –1.48 to 1.17]). The BEAR group had a significantly higher mean hamstring muscle strength index than the ACLR group at 2 years (98.2% vs 63.2%; P < .001). In addition, 14% of the BEAR group and 6% of the ACLR group had a reinjury that required a second ipsilateral ACL surgical procedure ( P = .32). Furthermore, the 8 patients who converted from BEAR to ACLR in the study period and returned for the 2-year postoperative visit had similar primary outcomes to patients who had a single ipsilateral ACL procedure. Conclusion: BEAR resulted in noninferior patient-reported outcomes and AP knee laxity and superior hamstring muscle strength when compared with autograft ACLR at 2-year follow-up in a young and active cohort. These promising results suggest that longer-term studies of this technique are justified. Registration: NCT02664545 (ClinicalTrials.gov identifier)


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