Tiotropium Respimat® in cystic fibrosis: Phase 3 and Pooled phase 2/3 randomized trials

Background: Tiotropium Respimat® improved lung function in a phase 2 trial in patients with cystic fibrosis (CF). We investigated its efficacy and safety in a phase 3 trial, including a pre-specified pooled analysis of the phase 2 and 3 trials. 

Methods: 12-week, randomized, double-blind, placebo-controlled trial of tiotropium Respimat® 5. μg once daily in patients with CF (N = 463). 

Results: Co-primary efficacy endpoints showed no statistical difference between tiotropium and placebo: percent-predicted forced expiratory volume in 1s (FEV₁) area under the curve from 0-4h (AUC_0-4h) (95% CI): 1.64% (0.27,3.55; p=0.092); percent-predicted trough FEV₁ (95% CI) 1.40% (0.50,3.30; p=0.15). Adverse events were similar between groups. Pooled phase 2/3 trial results showed a treatment difference in favor of tiotropium: percent-predicted FEV₁ AUC_0-4h (95% CI): 2.62% (1.34,3.90). 

Conclusion: Tiotropium was well tolerated in patients with CF; lung function improvements compared with placebo were not statistically significant in the phase 3 trial. Clinical trials: These studies are registered with clinical trial identifier numbers NCT00737100 and NCT01179347NCT00737100NCT01179347. These studies are also registered with the EudraCT number: 2008-001156-43 and 2010-019802-17.

Dose-response relationship in phase 1 clinical trials: a European Drug Development Network (EDDN) Collaboration Study

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.

Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.

Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).

Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD)

Patient-reported outcomes in randomised controlled trials on age-related macular degeneration

BACKGROUND/AIMS: The purpose of this systematic review was to identify the frequency and type of patient-reported outcome measures (PROMs) used in recent randomised controlled trials (RCTs) for age-related macular degeneration (AMD).

METHODS: The authors conducted a systematic search between January 2010 and November 2013 in MEDLINE, EMBASE, Scopus, Cochrane Library (Central) and the clinical trials registries (http://www.controlled-trials.com and http://www.ClinicalTrials.gov) according to defined inclusion criteria (RCTs on AMD in English). Two independent reviewers evaluated studies for inclusion. One reviewer extracted data of included studies, and a second masked reviewer assessed 10% to confirm accuracy in data collection. Reference lists of included papers and appendices of relevant Cochrane systematic reviews were scanned to identify other relevant RCTs. Information collected on extracted outcomes was analysed using descriptive statistics.

RESULTS: Literature and registry search yielded 3816 abstracts of journal articles and 493 records from trial registries. A total of 177 RCTs were deemed to have met inclusion criteria. Of the 858 outcomes reported, 38 outcomes were identified as PROMs (4.4%). Of the 177 RCTs examined, PROMs were used in 25 trials (14.1%). The National Eye Institute Visual Function Questionnaire-25 was the most frequently used PROM instrument (64% of RCTs with PROMs included).

CONCLUSIONS: This review highlights that a small proportion of AMD RCTs included PROMs as outcome measures and that there was a variety in the instruments used.

Core Outcomes in Ventilation Trials (COVenT): protocol for a core outcome set using a Delphi survey with a nested randomised trial and observational cohort study

Background
Among clinical trials of interventions that aim to modify time spent on mechanical ventilation for critically ill patients there is considerable inconsistency in chosen outcomes and how they are measured. The Core Outcomes in Ventilation Trials (COVenT) study aims to develop a set of core outcomes for use in future ventilation trials in mechanically ventilated adults and children.

Methods/design
We will use a mixed methods approach that incorporates a randomised trial nested within a Delphi study and a consensus meeting. Additionally, we will conduct an observational cohort study to evaluate uptake of the core outcome set in published studies at 5 and 10 years following core outcome set publication. The three-round online Delphi study will use a list of outcomes that have been reported previously in a review of ventilation trials. The Delphi panel will include a range of stakeholder groups including patient support groups. The panel will be randomised to one of three feedback methods to assess the impact of the feedback mechanism on subsequent ranking of outcomes. A final consensus meeting will be held with stakeholder representatives to review outcomes.

Discussion
The COVenT study aims to develop a core outcome set for ventilation trials in critical care, explore the best Delphi feedback mechanism for achieving consensus and determine if participation increases use of the core outcome set in the long term.

Consensus on Outcome Measures for Glaucoma Effectiveness Trials: Results From a Delphi and Nominal Group Technique Approaches

PURPOSE: Comparing the relative effectiveness of interventions across glaucoma trials can be problematic due to differences in definitions of outcomes. We sought to identify a key set of clinical outcomes and reach consensus on how best to measure them from the perspective of glaucoma experts.

METHODS: A 2-round electronic Delphi survey was conducted. Round 1 involved 25 items identified from a systematic review. Round 2 was developed based on information gathered in round 1. A 10-point Likert scale was used to quantify importance and consensus of outcomes (7 outcomes) and ways of measuring them (44 measures). Experts were identified through 2 glaucoma societies membership-the UK and Eire Glaucoma Society and the European Glaucoma Society. A Nominal Group Technique (NGT) followed the Delphi process. Results were analyzed using descriptive statistics.

RESULTS: A total of 65 participants completed round 1 out of 320; of whom 56 completed round 2 (86%). Agreement on the importance of outcomes was reached on 48/51 items (94%). Intraocular pressure (IOP), visual field (VF), safety, and anatomic outcomes were classified as highly important. Regarding methods of measurement of IOP, "mean follow-up IOP" using Goldmann applanation tonometry achieved the highest importance, whereas for evaluating VFs "global index mean deviation/defect (MD)" and "rate of VF progression" were the most important. Retinal nerve fiber layer (RNFL) thickness measured by optical coherence tomography (OCT) was identified as highly important. The NGT results reached consensus on "change of IOP (mean of 3 consecutive measurements taken at fixed time of day) from baseline," change of VF-MD values (3 reliable VFs at baseline and follow-up visit) from baseline, and change of RNFL thickness (2 good quality OCT images) from baseline.

CONCLUSIONS: Consensus was reached among glaucoma experts on how best to measure IOP, VF, and anatomic outcomes in glaucoma randomized controlled trials.

Making randomised trials more efficient: report of the first meeting to discuss the Trial Forge platform

Randomised trials are at the heart of evidence-based healthcare, but the methods and infrastructure for conducting these sometimes complex studies are largely evidence free. Trial Forge (www.trialforge.org) is an initiative that aims to increase the evidence base for trial decision making and, in doing so, to improve trial efficiency.

This paper summarises a one-day workshop held in Edinburgh on 10 July 2014 to discuss Trial Forge and how to advance this initiative. We first outline the problem of inefficiency in randomised trials and go on to describe Trial Forge. We present participants' views on the processes in the life of a randomised trial that should be covered by Trial Forge.

General support existed at the workshop for the Trial Forge approach to increase the evidence base for making randomised trial decisions and for improving trial efficiency. Agreed upon key processes included choosing the right research question; logistical planning for delivery, training of staff, recruitment, and retention; data management and dissemination; and close down. The process of linking to existing initiatives where possible was considered crucial. Trial Forge will not be a guideline or a checklist but a 'go to' website for research on randomised trials methods, with a linked programme of applied methodology research, coupled to an effective evidence-dissemination process. Moreover, it will support an informal network of interested trialists who meet virtually (online) and occasionally in person to build capacity and knowledge in the design and conduct of efficient randomised trials.

Some of the resources invested in randomised trials are wasted because of limited evidence upon which to base many aspects of design, conduct, analysis, and reporting of clinical trials. Trial Forge will help to address this lack of evidence.

Challenges to undertaking randomised trials with looked after children in social care settings

Background: Randomised controlled trials (RCTs) are widely viewed as the gold standard for assessing effectiveness in health research; however many researchers and practitioners believe that RCTs are inappropriate and un-doable in social care settings, particularly in relation to looked after children. The aim of this article is to describe the challenges faced in conducting a pilot study and phase II RCT of a peer mentoring intervention to reduce teenage pregnancy in looked after children in a social care setting.

Methods: Interviews were undertaken with social care professionals and looked after children, and a survey conducted with looked after children, to establish the feasibility and acceptability of the intervention and research design.

Results: Barriers to recruitment and in managing the intervention were identified, including social workers acting as informal gatekeepers; social workers concerns and misconceptions about the recruitment criteria and the need for and purpose of randomisation; resource limitations, which made it difficult to prioritise research over other demands on their time and difficulties in engaging and retaining looked after children in the study.

Conclusions: The relative absence of a research infrastructure and culture in social care and the lack of research support funding available for social care agencies, compared to health organisations, has implications for increasing evidence-based practice in social care settings, particularly in this very vulnerable group of young people.

Design characteristic of randomised controlled trials for geographic atrophy in age-related macular degeneration: selection of outcomes and sample size calculation

PurposeThe selection of suitable outcomes and sample size calculation are critical factors in the design of a randomised controlled trial (RCT). The goal of this study was to identify the range of outcomes and information on sample size calculation in RCTs on geographic atrophy (GA).MethodsWe carried out a systematic review of age-related macular degeneration (AMD) RCTs. We searched MEDLINE, EMBASE, Scopus, Cochrane Library, www.controlled-trials.com, and www.ClinicalTrials.gov. Two independent reviewers screened records. One reviewer collected data and the second reviewer appraised 10% of collected data. We scanned references lists of selected papers to include other relevant RCTs.ResultsLiterature and registry search identified 3816 abstracts of journal articles and 493 records from trial registries. From a total of 177 RCTs on all types of AMD, 23 RCTs on GA were included. Eighty-one clinical outcomes were identified. Visual acuity (VA) was the most frequently used outcome, presented in 18 out of 23 RCTs and followed by the measures of lesion area. For sample size analysis, 8 GA RCTs were included. None of them provided sufficient Information on sample size calculations.ConclusionsThis systematic review illustrates a lack of standardisation in terms of outcome reporting in GA trials and issues regarding sample size calculation. These limitations significantly hamper attempts to compare outcomes across studies and also perform meta-analyses.

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

BACKGROUND: Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer.

METHODS: We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs).

FINDINGS: We received data on 18 766 women (18 206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02).

INTERPRETATION: Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.

FUNDING: Cancer Research UK, Medical Research Council.

Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials

BACKGROUND: The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain.

METHODS: We undertook meta-analyses of individual data on 31 920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5; and of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs).

FINDINGS: In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·64, 95% CI 0·52-0·78) and 2-4 (RR 0·80, 0·68-0·93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12·1% vs 14·2%; RR 0·85, 0·75-0·96; 2p=0·009). In the comparison of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·74, 0·62-0·89) but not while both groups received aromatase inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0·90, 0·81-0·99; 2p=0·045), though the breast cancer mortality reduction was not significant (RR 0·89, 0·78-1·03; 2p=0·11). In the comparison of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2-4 (RR 0·56, 0·46-0·67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8·7% vs 10·1%; 2p=0·015). Aggregating all three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0·70, 0·64-0·77), but not significantly thereafter (RR 0·93, 0·86-1·01; 2p=0·08). Breast cancer mortality was reduced both while treatments differed (RR 0·79, 0·67-0·92), and subsequently (RR 0·89, 0·81-0·99), and for all periods combined (RR 0·86, 0·80-0·94; 2p=0·0005). All-cause mortality was also reduced (RR 0·88, 0·82-0·94; 2p=0·0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0·4% vs 1·2%; RR 0·33, 0·21-0·51) but more bone fractures (5-year risk 8·2% vs 5·5%; RR 1·42, 1·28-1·57); non-breast-cancer mortality was similar.

INTERPRETATION: Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment.

FUNDING: Cancer Research UK, Medical Research Council.

Individual Participant Data (IPD) Meta-analyses of Randomised Controlled Trials: Guidance on Their Use

Jayne Tierney and colleagues offer guidance on how to spot a well-designed and well-conducted individual participant data meta-analysis.

Summary Points 

• Systematic reviews are most commonly based on aggregate data extracted from publications or obtained from trial investigators. 

• Systematic reviews involving the central collection and analysis of individual participant data (IPD) usually are larger-scale, international, collaborative projects that can bring about substantial improvements to the quantity and quality of data, give greater scope in the analyses, and provide more detailed and robust results. 

• The process of collecting, checking, and analysing IPD is more complex than for aggregate data, and not all IPD meta-analyses are done to the same standard, making it difficult for researchers, clinicians, patients, policy makers, funders, and publishers to judge their quality. 

• Following our step-by-step guide will help reviewers and users of IPD meta-analyses to understand them better and recognise those that are well designed and conducted and so help ensure that policy, practice, and research are informed by robust evidence about the effects of interventions.

UK publicly funded Clinical Trials Units supported a controlled access approach to share individual participant data but highlighted concerns

OBJECTIVES: Evaluate current data sharing activities of UK publicly funded Clinical Trial Units (CTUs) and identify good practices and barriers.

STUDY DESIGN AND SETTING: Web-based survey of Directors of 45 UK Clinical Research Collaboration (UKCRC)-registered CTUs.

RESULTS: Twenty-three (51%) CTUs responded: Five (22%) of these had an established data sharing policy and eight (35%) specifically requested consent to use patient data beyond the scope of the original trial. Fifteen (65%) CTUs had received requests for data, and seven (30%) had made external requests for data in the previous 12 months. CTUs supported the need for increased data sharing activities although concerns were raised about patient identification, misuse of data, and financial burden. Custodianship of clinical trial data and requirements for a CTU to align its policy to their parent institutes were also raised. No CTUs supported the use of an open access model for data sharing.

CONCLUSION: There is support within the publicly funded UKCRC-registered CTUs for data sharing, but many perceived barriers remain. CTUs are currently using a variety of approaches and procedures for sharing data. This survey has informed further work, including development of guidance for publicly funded CTUs, to promote good practice and facilitate data sharing.