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Treatment crossovers in time-to-event non-inferiority randomised trials of radiotherapy in patients with breast cancer.

ABSTRACT: BACKGROUND:In non-inferiority trials of radiotherapy in patients with early stage breast cancer, it is inevitable that some patients will cross over from the experimental arm to the standard arm prior to initiation of any treatment due to complexities in treatment planning or subject preference. Although the intention-to-treat (ITT) analysis is the preferred approach for superiority trials, its role in non-inferiority trials is still under debate. This has led to the use of alternative approaches such as the per-protocol (PP) analysis or the as-treated (AT) analysis, despite the inherent biases of such approaches. METHODS:Using simulations, we investigate the effect of 2%, 5% and 10% random and non-random crossovers prior to radiotherapy initiation on the ITT, PP, AT and the combination of ITT and PP analyses with respect to type I error in trials with time-to-event outcomes. We also evaluate bias and SE of the estimates from the ITT, PP and AT approaches. RESULTS:The AT approach had the best performance in terms of type I error, but was anticonservative as non-random crossover increased. The ITT and PP approaches were anticonservative under all percentages of random and non-random crossover. Similarly, lowest bias was seen with the AT approach; however, bias increased as the percentage of non-random crossover increased. The ITT and PP had poor performance in terms of bias as crossovers increased. CONCLUSIONS:If minimal crossovers were to occur, we have shown that the AT approach has the lowest type I error rates and smallest opportunity for bias. Results of trials with a high number of crossovers should be interpreted with caution, especially when crossover is non-random. Attempts to prevent crossovers should be maximised.

SUBMITTER: Parpia S

PROVIDER: S-EPMC4212183 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Treatment crossovers in time-to-event non-inferiority randomised trials of radiotherapy in patients with breast cancer.

Parpia Sameer S Julian Jim A JA Thabane Lehana L Gu Chushu C Whelan Timothy J TJ Levine Mark N MN

BMJ open 20141024 10

<h4>Background</h4>In non-inferiority trials of radiotherapy in patients with early stage breast cancer, it is inevitable that some patients will cross over from the experimental arm to the standard arm prior to initiation of any treatment due to complexities in treatment planning or subject preference. Although the intention-to-treat (ITT) analysis is the preferred approach for superiority trials, its role in non-inferiority trials is still under debate. This has led to the use of alternative a ...[more]

PMID: 25344487

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Project description:BackgroundNon-inferiority trials are increasingly used to evaluate new treatments that are expected to have secondary advantages over standard of care, but similar efficacy on the primary outcome. When designing a non-inferiority trial with a binary primary outcome, the choice of effect measure for the non-inferiority margin (e.g. risk ratio or risk difference) has an important effect on sample size calculations; furthermore, if the control event risk observed is markedly different from that assumed, the trial can quickly lose power or the results become difficult to interpret.MethodsWe propose a new way of designing non-inferiority trials to overcome the issues raised by unexpected control event risks. Our proposal involves using clinical judgement to specify a 'non-inferiority frontier', i.e. a curve defining the most appropriate non-inferiority margin for each possible value of control event risk. Existing trials implicitly use frontiers defined by a fixed risk ratio or a fixed risk difference. We discuss their limitations and propose a fixed arcsine difference frontier, using the power-stabilising transformation for binary outcomes, which may better represent clinical judgement. We propose and compare three ways of designing a trial using this frontier: testing and reporting on the arcsine scale; testing on the arcsine scale but reporting on the risk difference or risk ratio scale; and modifying the margin on the risk difference or risk ratio scale after observing the control event risk according to the power-stabilising frontier.ResultsTesting and reporting on the arcsine scale leads to results which are challenging to interpret clinically. For small values of control event risk, testing on the arcsine scale and reporting results on the risk difference scale produces confidence intervals at a higher level than the nominal one or non-inferiority margins that are slightly smaller than those back-calculated from the power-stabilising frontier alone. However, working on the arcsine scale generally requires a larger sample size compared to the risk difference scale. Therefore, working on the risk difference scale, modifying the margin after observing the control event risk, might be preferable, as it requires a smaller sample size. However, this approach tends to slightly inflate type I error rate; a solution is to use a slightly lower significance level for testing, although this modestly reduces power. When working on the risk ratio scale instead, the same approach based on the modification of the margin leads to power levels above the nominal one, maintaining type I error under control.ConclusionsOur proposed methods of designing non-inferiority trials using power-stabilising non-inferiority frontiers make trial design more resilient to unexpected values of the control event risk, at the only cost of requiring somewhat larger sample sizes when the goal is to report results on the risk difference scale.

Project description:ObjectiveTo compare the efficacy of oral antibiotic treatment alone with treatment started parenterally and completed orally in children with a first episode of acute pyelonephritis.DesignMulticentre, randomised controlled, open labelled, parallel group, non-inferiority trial.Setting28 paediatric units in north east Italy.Participants502 children aged 1 month to <7 years with clinical pyelonephritis.InterventionOral co-amoxiclav (50 mg/kg/day in three doses for 10 days) or parenteral ceftriaxone (50 mg/kg/day in a single parenteral dose) for three days, followed by oral co-amoxiclav (50 mg/kg/day in three divided doses for seven days). Main outcomes measures Primary outcome was the rate of renal scarring. Secondary measures of efficacy were time to defervescence (<37 degrees C), reduction in inflammatory indices, and percentage with sterile urine after 72 hours. An exploratory subgroup analysis was conducted in the children in whom pyelonephritis was confirmed by dimercaptosuccinic acid (DMSA) scintigraphy within 10 days after study entry.ResultsIntention to treat analysis showed no significant differences between oral (n=244) and parenteral (n=258) treatment, both in the primary outcome (scarring scintigraphy at 12 months 27/197 (13.7%) v 36/203 (17.7%), difference in risk -4%, 95% confidence interval -11.1% to 3.1%) and secondary outcomes (time to defervescence 36.9 hours (SD 19.7) v 34.3 hours (SD 20), mean difference 2.6 (-0.9 to 6.0); white cell count 9.8x10(9)/l (SD 3.5) v 9.5x10(9)/l (SD 3.1), mean difference 0.3 (-0.3 to 0.9); percentage with sterile urine 185/186 v 203/204, risk difference -0.05% (-1.5% to 1.4%)). Similar results were found in the subgroup of 278 children with confirmed acute pyelonephritis on scintigraphy at study entry.ConclusionsTreatment with oral antibiotics is as effective as parenteral then oral treatment in the management of the first episode of clinical pyelonephritis in children.Trial registrationClinical Trials NCT00161330 [ClinicalTrials.gov].

Project description:BackgroundThe reporting of randomised controlled non-inferiority (NI) drug trials is poor with less than 50% of published trials reporting a justification of the NI margin. This is despite the introduction of the Consolidated Standards of Reporting Trials (CONSORT) extension on reporting of NI and equivalence in randomised trials. It is critical to set the appropriate NI margin as this choice dictates the conclusions of the trial. Methods to estimate the margin are heterogeneous but generally based on clinical judgement and statistical reasoning, and hence tailored to each clinical situation. Yet an appraisal of NI in clinical trials has not been undertaken. Therefore the aim of this systematic review is to assess the reporting and methodological quality of defining the NI margin. Surgical NI trials have been chosen as our prototype to assess this.MethodsWe will conduct a systematic review of published randomised controlled trials in abdominal surgery that use an NI design. Key eligibility criteria will be: surgical intervention in at least one trial arm; adult patients and a sample size of 100 or more. Ovid MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials will be searched from inception until the date of the search. Identified studies will be assessed for reporting according to the CONSORT recommendations. The outcomes are the description of the methods for defining the NI margin, and the robustness of the NI margin estimation. The latter will be based on simulations using alternative assumptions for model parameters. The results of the simulation will be compared with the trial authors' conclusions.Anticipated resultsThe review will describe and appraise the design and reporting of surgical NI trials including shortcomings thereof and allow a comparison with pharmaceutical trials. These findings will inform researchers on the appropriate design and pitfalls when conducting surgical randomised controlled trials with an NI design and promote thorough and standardised reporting of study findings.Ethics and disseminationEthical approval is not required and any changes to the protocol will be communicated via the registration platform. The final manuscript will be submitted to a journal for publication and the findings will be disseminated through conference presentations to inform researchers and the public.

Project description:BackgroundBreast cancer is the most common cancer in women. Radiotherapy is an important part of breast cancer treatment after surgery. Breast cancer radiotherapy is usually delivered in 3-5 weeks. This is a long duration for women with breast cancer to stay away from the family and work. We wanted to reduce this duration so that the wages loss and the logistics can be minimised for these patients. Hypofractionation, i.e. high dose per fraction, is delivered in a smaller number of days. In this study, we will compare a 1-week schedule of hypofractionated adjuvant whole breast/chest wall and/or regional nodal radiotherapy against 2 weeks for locoregional disease control, toxicities, quality of life (QoL), survival and second cancers after primary surgery in patients with breast cancer.MethodsEligible patients with breast cancer after mastectomy or breast conserving surgery (BCS) will be treated with a radiotherapy dose of 26 Gy in 5 fractions over 1 week in the study arm and 34 Gy in 10 fractions over 2 weeks in the control arm. The primary endpoint of this noninferiority study will be locoregional tumour control. Secondary endpoints will be early and late radiation toxicities, quality of life, contralateral primary tumours, regional and distant metastases, survival and second cancers. A total of 1018 patients will be randomised (1:1) to receive 1 week or 2 weeks of radiotherapy. An event-driven analysis will be performed after at least 94 patients have documented locoregional recurrences. Acute radiation toxicity will be assessed and scaled according to the RTOG grading system. Late radiation toxicity will be assessed with the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer late radiation morbidity scale. Cosmetic assessment will be done using Harvard/NSABP/RTOG breast cosmesis grading scale at baseline and 3 and 5 years. QoL will be assessed with EORTC QLQ-30 and EORTC QLQ-BR 23 at baseline and 3 and 5 years.DiscussionHypofractionation reduces treatment time to half while maintaining breast cosmesis and gives control rates equal to conventional fractionation. This is possible because breast tissue can tolerate high dose per fraction. In this study, we presume that 1-week radiotherapy will be non-inferior to 2 week radiotherapy, i.e. disease control will be similar with both the schedules without additional side effects, and QoL of these patients will be maintained. If we are able to achieve these outcomes, then patients will be able to complete their radiotherapy in less duration. There is not much data on regional nodal irradiation with hypofraction in breast cancer. We have used hypofraction for regional nodal irradiation in the past and not encountered any safety issue. If we are able to prove that late-term effects are comparable in the two schedules, it will make the radiation oncologist confident about hypofractionation in breast cancer. As breast cancer is a leading cancer in females and radiation therapy is an integral part of its local management, hypofractionation will help radiation centres worldwide to meet the growing need for radiation treatment in breast cancer, particularly in developing countries where resources are limited. It will also reduce the financial burden on the patient and family. Since we will treat these patients with both simple and complex radiotherapy techniques, it will also be possible for the low-income countries to follow this trial without needing a high-end or expensive radiotherapy equipment as the planning and treatment process will be very simple.Trial registrationThe trial is registered with ClinicalTrials.gov ID NCT04472845 and CTRI with REF/2020/09/037050.

Project description:BackgroundNon-inferiority and equivalence trials aim to determine whether a new treatment is good enough (non-inferior) or as good as (equivalent to) another treatment. To inform the decision about non-inferiority or equivalence, a margin is used. We aimed to identify the current methods used to determine non-inferiority or equivalence margins, as well as the main challenges and suggestions from trialists.MethodsWe developed an online questionnaire that included both closed and open-ended questions about methods to elicit non-inferiority or equivalence margins, underlying principles, and challenges and suggestions for improvement. We recruited trialists with experience of determining a margin by contacting corresponding authors for non-inferiority or equivalence trials. We used descriptive statistics and content analysis to identify categories in qualitative data.ResultsWe had forty-one responses, all from non-inferiority trials. More than half of the trials were non-pharmacological (n = 21, 51%), and the most common primary outcome was clinical (n = 29, 71%). The two most used methods to determine the margin were as follows: a review of the evidence base (n = 27, 66%) and opinion seeking methods (n = 24, 59%). From those using reviews, the majority used systematic reviews or reviews of multiple RCTs to determine the margin (n = 17, 63%). From those using opinion seeking methods, the majority involved clinicians with or without other professionals (n = 19, 79%). Respondents reported that patients' opinions on the margin were sought in four trials (16%). Median confidence in overall quality of the margin was 5 out of 7 (maximum confidence); however, around a quarter of the respondents were "completely unconfident" that the margin reflected patient's views. We identified "stakeholder involvement" as the most common category to determine respondent's confidence in the quality of the margins and whether it reflected stakeholder's views. The most common suggestion to improve the definition of margins was "development of methods to involve stakeholders," and the most common challenge identified was "communication of margins."ConclusionsResponders highlighted the need for clearer guidelines on defining a margin, more and better stakeholder involvement in its selection, and better communication tools that enable discussions about non-inferiority trials with stakeholders. Future research should focus on developing best practice recommendations.

Project description:ObjectiveTo compare the effectiveness and acceptability of outpatient polypectomy with inpatient polypectomy.DesignPragmatic multicentre randomised controlled non-inferiority study.SettingOutpatient hysteroscopy clinics in 31 UK National Health Service hospitals.Participants507 women who attended as outpatients for diagnostic hysteroscopy because of abnormal uterine bleeding and were found to have uterine polyps.InterventionsParticipants were randomly assigned to either outpatient uterine polypectomy under local anaesthetic or inpatient uterine polypectomy under general anaesthesia. Data were collected on women's self reported bleeding symptoms at baseline and at 6, 12, and 24 months. Data were also collected on pain and acceptability of the procedure at the time of polypectomy.Main outcome measuresThe primary outcome was successful treatment, determined by the women's assessment of bleeding at six months, with a prespecified non-inferiority margin of 25%. Secondary outcomes included generic (EQ-5D) and disease specific (menorrhagia multi-attribute scale) quality of life, and feasibility and acceptability of the procedure.Results73% (166/228) of women in the outpatient group and 80% (168/211) in the inpatient group reported successful treatment at six months (intention to treat relative risk 0.91, 95% confidence interval 0.82 to 1.02; per protocol relative risk 0.92, 0.82 to 1.02). Failure to remove polyps was higher (19% v 7%; relative risk 2.5, 1.5 to 4.1) and acceptability of the procedure was lower (83% v 92%; 0.90, 0.84 to 0.97) in the outpatient group Quality of life did not differ significantly between the groups. Four uterine perforations, one of which necessitated bowel resection, all occurred in the inpatient group.ConclusionsOutpatient polypectomy was non-inferior to inpatient polypectomy. Failure to remove a uterine polyp was, however, more likely with outpatient polypectomy and acceptability of the procedure was slightly lower.Trial registrationInternational Clinical Trials Registry 65868569.

Project description:BackgroundThe effectiveness of intermittent preventive treatment of malaria in pregnancy (IPTp) may be compromised by the spread of resistance to sulphadoxine/pyrimethamine (SP) across Africa. But little information exists on alternative drugs for IPTp or alternative strategies for the prevention of malaria in pregnancy. Therefore, we have investigated whether screening with a rapid diagnostic test and treatment of those who are positive (IST) at routine antenatal clinic attendances is as effective and as safe as SP-IPTp in pregnant women.Methods and findingsDuring antenatal clinic sessions in six health facilities in Ghana held between March 2007 and September 2007, 3333 pregnant women who satisfied inclusion criteria were randomised into three intervention arms (1) standard SP-IPTp, (2) IST and treatment with SP or (3) IST and treatment with amodiaquine+artesunate (AQ+AS). All women received a long-lasting insecticide treated net. Study women had a maximum of three scheduled follow-up visits following enrollment. Haemoglobin concentration and peripheral parasitaemia were assessed between 36 and 40 weeks of gestation. Birth weight was measured at delivery or within 72 hours for babies delivered at home. Parasite prevalence at enrollment in primigravidae and in multigravidae was 29.6% and 10.2% respectively. At 36-40 weeks of gestation the prevalence of asymptomatic parasitaemia was 12.1% in study women overall and was very similar in all treatment groups. The risk of third trimester severe anaemia or low birth weight did not differ significantly between the three treatment groups regardless of gravidity. IST with AQ+AS or SP was not inferior to SP-IPTp in reducing the risk of low birth weight (RD = -1.17[95%CI; -4.39-1.02] for IST-SP vs. SP-IPTp and RD = 0.78[95%CI; -2.11-3.68] for IST-AQAS vs. SP-IPTp); third trimester severe anaemia (RD = 0.29[95%CI; -0.69-1.30] for IST-SP vs. SP-IPTp and RD = -0.36[95%CI;-1.12-0.44] for IST-AQAS vs. SP-IPTp).ConclusionThe results of this study suggest that in an area of moderately high malaria transmission, IST with SP or AS+AQ may be a safe and effective strategy for the control of malaria in pregnancy. However, it is important that these encouraging findings are confirmed in other geographical areas and that the impact of IST on placental malaria is investigated.Trial registrationClinicalTrials.gov NCT00432367 [NCT00432367].

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Treatment crossovers in time-to-event non-inferiority randomised trials of radiotherapy in patients with breast cancer.

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Treatment crossovers in time-to-event non-inferiority randomised trials of radiotherapy in patients with breast cancer.

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