Non-adherence in non-inferiority trials: pitfalls and recommendations

Mo, Yin; Lim, Cherry; Watson, James A; White, Nicholas J.; Cooper, Ben

doi:10.1136/bmj.m2215

Cited by 42 publications

(38 citation statements)

References 34 publications

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“…Excluding these patients with less painful ankles from the NWB group could induce bias favoring the EWB group. 25,27 We conducted an ITT analysis including these patients and also performed a PP analysis in patients who completed the allocated protocol. Loss to follow-up is well known to be a difficult and common problem when studying patients treated for an injury.…”

Section: Discussionmentioning

confidence: 99%

Early Weightbearing Versus Nonweightbearing After Operative Treatment of an Ankle Fracture: A Multicenter, Noninferiority, Randomized Controlled Trial

Park

Kim

et al. 2021

Am J Sports Med

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Background: Acute ankle fractures can occur during sports activities, and unstable ankle fractures are commonly treated operatively. However, controversy exists about the optimal time to allow weightbearing. Hypothesis: Early weightbearing after the stable fixation of an ankle fracture is not inferior to nonweightbearing in terms of ankle function assessed at 12 months after injury. Study design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 258 patients were assessed for eligibility. Of these patients, 194 were randomly allocated to either the early weightbearing group (95 patients who were allowed weightbearing at 2 weeks postoperatively) or the nonweightbearing group (99 patients who were not allowed weightbearing until 6 weeks postoperatively). The primary outcome measure was the mean difference in the Olerud-Molander ankle score (OMAS) between the groups, assessed at the 12-month follow-up examination. The secondary outcome measures were the time to return to preinjury activities and patients’ subjective satisfaction. Complications such as hardware loosening or failure, fracture displacement, and nonunion were evaluated. Results: The mean difference in the OMAS for the early weightbearing group compared with the nonweightbearing group was 1.6 (95% CI, –1.9 to 5.0) in the intention-to-treat analysis. The lower limit of the 95% CI (–1.9) exceeded the noninferiority margin of –8, indicating that early weightbearing was not inferior to nonweightbearing. The difference in the proportion of patients who were satisfied or very satisfied with their treatment was not statistically significant (84.3% vs 76.2%; P = .19); however, the time taken to return to preinjury activities was shorter with early weightbearing than with nonweightbearing (9.1 ± 3.0 vs 11.0 ± 3.0 weeks; P < .001). No cases of nonunion were observed in either group. Conclusion: Early weightbearing after the operative treatment of an unstable ankle fracture was not inferior to nonweightbearing in terms of OMAS assessed at 12 months after injury. The patients’ subjective satisfaction was similar between the groups, although the time taken to return to preinjury activities was shorter in the early weightbearing group. Registration: NCT02029170 (ClinicalTrials.gov identifier).

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Section: Discussionmentioning

confidence: 99%

Early Weightbearing Versus Nonweightbearing After Operative Treatment of an Ankle Fracture: A Multicenter, Noninferiority, Randomized Controlled Trial

Park

Kim

et al. 2021

Am J Sports Med

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“…Crossovers, if they occur, will be analysed using appropriate statistical methods. 27 In order to maximise the ability of additional centres to join, minimise the study infrastructure required in each centre, and to contain study costs for this, as yet unfunded international trial, we have chosen to use an open label design. For the primary endpoint of mortality, which is objective, we do not anticipate risk of detection bias.…”

Section: Interventionmentioning

confidence: 99%

Piperacillin–tazobactam versus meropenem for treatment of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacteriaceae: a study protocol for a non-inferiority open-label randomised controlled trial (PeterPen)

et al. 2021

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IntroductionThe optimal treatment for extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae bloodstream infections has yet to be defined. Retrospective studies have shown conflicting results, with most data suggesting the non-inferiority of beta-lactam–beta-lactamase inhibitor combinations compared with carbapenems. However, the recently published MERINO trial failed to demonstrate the non-inferiority of piperacillin–tazobactam to meropenem. The potential implications of the MERINO trial are profound, as widespread adoption of carbapenem treatment will have detrimental effects on antimicrobial stewardship in areas endemic for ESBL and carbapenem-resistant bacteria. Therefore, we believe that it is justified to re-examine the comparison in a second randomised controlled trial prior to changing clinical practice.Methods and analysisPeterPen is a multicentre, investigator-initiated, open-label, randomised controlled non-inferiority trial, comparing piperacillin–tazobactam with meropenem for third-generation cephalosporin-resistant Escherichia coli and Klebsiella bloodstream infections. The study is currently being conducted in six centres in Israel and one in Canada with other centres from Israel, Italy and Canada expected to join. The two primary outcomes are all-cause mortality at day 30 from enrolment and treatment failure at day seven (death, fever above 38°C in the last 48 hours, continuous symptoms, increasing Sequential Organ Failure Assessment Score or persistent blood cultures with the index pathogen). A sample size of 1084 patients was calculated for the mortality endpoint assuming a 12.5% mortality rate in the control group with a 5% non-inferiority margin and assuming 100% follow-up for this outcome.Ethics and disseminationThe study is approved by local and national ethics committees as required. Results will be published, and trial data will be made available.Trial registration numbersClinicalTrials.gov Registry (NCT03671967); Israeli Ministry of Health Trials Registry (MOH_2018-12-25_004857).

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“…Admittedly, non-inferiority drug trials are complex. 37,50 Limitations of this study There were several limitations other than those imposed by the COVID-19 pandemic. The health-care workers led a very busy and stressful schedule, and must have found it difficult to adhere to the requirements of the study.…”

Section: Other Studiesmentioning

confidence: 96%

A safer option to hydroxychloroquine in the chemoprophylaxis of COVID-19 in high-risk health- care workers: A randomized controlled, non-inferiority trial

Chopra¹,

Rao²,

Reddy³

et al. 2021

Preprint

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Objectives: Comparative study of Ashwagandha (Withania somnifera; WS) and hydroxychloroquine (HCQ) for chemoprophylaxis against COVID-19 in actively engaged high-risk health-care workers. Design: Randomized, multicentric, open label, active control, two arm parallel efficacy study of 16 weeks. Sample size was based on pre-set 15% non-inferiority margin to HCQ for prophylaxis against COVID-19 with 80% power and alpha < 0.05. Participants: 400 health-care workers from three sites who were asymptomatic and tested negative for a quantitative Reverse Transcription Polymerase Chain Reaction test (RT-PCR) for COVID-19 and SARS-CoV-2 antibodies (IgG) were randomized in a 1:1 ratio. Participants observed physical protection measures as per the national policy. All incident confirmed COVID-19 were withdrawn.Interventions: Two tablets of 250 mg standardized aqueous extract of WS, twice daily after meal or HCQ 800 mg loading followed by 400 mg weekly for 16 weeks as per the national guidelines. Main outcome measures: The primary efficacy measure was “failure of prophylaxis” as confirmed by RT-PCR at any time during the study. Both intention-to-treat (ITT) and per-protocol (PP) efficacy analyses were performed.Results: 95 participants in the Ashwagandha (WS) arm and 101 participants in the HCQ arm completed the study. Both groups were well matched at the baseline. 91 participants from the Ashwagandha arm and 84 from the HCQ arm were withdrawn because they received the COVID-19 vaccination. Four participants (2%; 95% CI 2.8 to 3.9%) in the Ashwagandha and 5 (2.5%; 95% CI 5.4 to 8%) in the HCQ arm developed confirmed COVID-19. This was within the prefixed non-inferiority margin and the 95% CI of the absolute risk reduction (ARR) was -2.9 to 3.8% intention to treat (ITT) and -5.9 to 7.5% per protocol (PP). The 95% CI of ARR for the total COVID-19 cases was -2.8 to 11.9% ITT and -5.7 to 20.3% PP. Several health measures, particularly anxiety and stress, improved significantly in the Ashwagandha arm. Seven out of 117 in the Ashwagandha and 59 out of 178 in the HCQ groups were reported to be possible drug-related adverse events (AE); there were significantly less gut-related AE in the Ashwagandha group. AE were mostly mild and did not cause withdrawal. All incident COVID-19 cases recovered without complications. Conclusions: Ashwagandha was non-inferior to HCQ in the chemoprophylaxis against COVID-19 in high risk health-care workers. It was significantly safer, well tolerated and improved quality of life measures. Ashwagandha as COVID-19 prophylaxis seems appropriate in high-risk populations. Trial registration: The Clinical Trials Registry India Number CTRI/2020/08/027163 dated August 14, 2020.

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Non-adherence in non-inferiority trials: pitfalls and recommendations

Cited by 42 publications

References 34 publications

Early Weightbearing Versus Nonweightbearing After Operative Treatment of an Ankle Fracture: A Multicenter, Noninferiority, Randomized Controlled Trial

Early Weightbearing Versus Nonweightbearing After Operative Treatment of an Ankle Fracture: A Multicenter, Noninferiority, Randomized Controlled Trial

Piperacillin–tazobactam versus meropenem for treatment of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacteriaceae: a study protocol for a non-inferiority open-label randomised controlled trial (PeterPen)

A safer option to hydroxychloroquine in the chemoprophylaxis of COVID-19 in high-risk health- care workers: A randomized controlled, non-inferiority trial

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