Variation of clinical outcomes used in glaucoma randomised controlled trials:a systematic review

Purpose: In randomised clinical trials (RCTs) the selection of appropriate outcomes is crucial to the assessment of whether one intervention is better than another. The purpose of this review is to identify different clinical outcomes reported in glaucoma trials.

Methods We conducted a systematic review of glaucoma RCTs. A sample or selection of glaucoma trials were included bounded by a time frame (between 2006 and March 2012). Only studies in English language were considered. All clinical measured and reported outcomes were included. The possible variations of clinical outcomes were defined prior to data analysis. Information on reported clinical outcomes was tabulated and analysed using descriptive statistics. Other data recorded included type of intervention and glaucoma, duration of the study, defined primary outcomes, and outcomes used for sample size calculation, if nominated.

Results The search strategy identified 4323 potentially relevant abstracts. There were 315 publications retrieved, of which 233 RCTs were included. A total of 967 clinical measures were reported. There were large variations in the definitions used to describe different outcomes and their measures. Intraocular pressure was the most commonly reported outcome (used in 201 RCTs, 86%) with a total of 422 measures (44%). Safety outcomes were commonly reported in 145 RCTs (62%) whereas visual field outcomes were used in 38 RCTs (16%).

Conclusions There is a large variation in the reporting of clinical outcomes in glaucoma RCTs. This lack of standardisation may impair the ability to evaluate the evidence of glaucoma interventions.

Homologous size-extension of hybrid vanadate capsules – solid state structures, solution stability and surface deposition

The dimensions and cavity sizes of the molecular capsules with the general formula [V₁₀O₁₈L₄]¹⁰⁻ can be controlled modularly through the nature of the bifunctional, rigid organophosphonate ligands L¹ and L² (L¹ = bis(4-phosphonatophenyl)ethyne and L² = bis(4-phosphonatophenyl)butadiyne); the solution stability of the molecular entities as demonstrated by ESI-MS studies permits their assembly on the Au(111) surface on a sub-monolayer scale giving rise to a 2D supramolecular structure that is comparable to the packing arrangements of the capsules in the crystal structures.

Overview of clinical outcome measures used in glaucoma randomised controlled trials (RCTs)

Background: In clinical trials the selection of appropriate outcomes is crucial to the assessment of whether one intervention is better than another. Glaucoma is a chronic eye disease and the leading cause of irreversible blindness in the world. A variety of outcomes has been used and reported in glaucoma RCTs.

Objectives: The purpose of this review is to identify different clinical outcome measures used in glaucoma RCTs between January 2006 and March 2012.

Methods: A systematic review was conducted using standard methodology. We searched for RCTs in glaucoma published in English with no restrictions on the population type or size, or applied interventions. All clinical outcomes were included. Patient-reported, pharmacokinetic and economic outcomes were excluded.

Results: The search strategy identified 4288 potentially relevant abstracts. There were 315 publications retrieved, of which 233 RCTs were included. A total of 967 clinical measures were reported. There were large variations in the definitions used to describe different outcomes and their measures. Intraocular pressure (IOP) was the most commonly reported outcome (used in 201 RCTs, 86%) with a total of 422 measures (44%). Amongst the IOPrelated measures, the most commonly used was mean IOP (n=143, 15% of all measures). Safety outcomes were commonly reported, in 145 RCTs (62%) whereas visual field outcomes were utilized in 38 RCTs (16%).

Conclusions: There is a large variability in clinical outcomes used for glaucoma RCTs and in the way each outcome is reported. This lack of standardisation may impair the ability to evaluate the evidence of glaucoma interventions.

A New Stereocontrolled Total Synthesis of the Mast Cell inhibitory Alkaloid, (+)-Monanchorin, via the Wittig Reaction of a Stabilized Ylide with a Cyclic Guanidine Hemiaminal

Abstract Image

An asymmetric total synthesis of the mast cell inhibitor (+)-monanchorin is reported in which a Sharpless AD on 11 and a cyclic sulfate ring opening with an azide feature as key steps. After further manipulation, a novel guanidine-controlled ester reduction provided the guanidine-hemiaminal 25 which underwent Wittig olefination to give 27. Hydrogenation and a second guanidine-controlled reduction of the ester in 28, to obtain aldehyde 29, then set up a trifluoroacetic acid mediated cyclization to give (+)-monanchorin TFA salt.

A randomised controlled trial of increasing fruit and vegetable intake and how this influences the carotenoid concentration and activities of PON-1 and LCAT in HDL from subjects with type 2 diabetes

Background

High density lipoproteins (HDL) have many cardioprotective roles; however, in subjects with type 2 diabetes (T2D) these cardioprotective properties are diminished. Conversely, increased fruit and vegetable (F&V) intake may reduce cardiovascular disease risk, although direct trial evidence of a mechanism by which this occurs in subjects with T2D is lacking. Therefore, the aim of this study was to examine if increased F&V consumption influenced the carotenoid content and enzymes associated with the antioxidant properties of HDL in subjects with T2D.

Eighty obese subjects with T2D were randomised to a 1- or ≥6-portion/day F&V diet for 8-weeks. Fasting serum was collected pre- and post-intervention. HDL was subfractionated into HDL₂ and HDL₃ by rapid ultracentrifugation. Carotenoids were measured in serum, HDL₂ and HDL₃ by high performance liquid chromatography. The activity of paraoxonase-1 (PON-1) was measured in serum, HDL₂ and HDL₃ by a spectrophotometric assay, while the activity of lecithin cholesterol acyltransferase (LCAT) was measured in serum, HDL₂ and HDL₃ by a fluorometric assay.

In the ≥6- vs. 1-portion post-intervention comparisons, carotenoids increased in serum, HDL₂ and particularly HDL₃, (α-carotene, p = 0.008; β-cryptoxanthin, p = 0.042; lutein, p = 0.012; lycopene, p = 0.016), as did the activities of PON-1 and LCAT in HDL₃ (p = 0.006 and 0.044, respectively).

To our knowledge, this is the first study in subjects with T2D to demonstrate that increased F&V intake augmented the carotenoid content and influenced enzymes associated with the antioxidant properties of HDL. We suggest that these changes would enhance the cardioprotective properties of this lipoprotein.

The statistical significance of randomized controlled trial results is frequently fragile: A case for a Fragility Index

Objectives

A P-value <0.05 is one metric used to evaluate the results of a randomized controlled trial (RCT). We wondered how often statistically significant results in RCTs may be lost with small changes in the numbers of outcomes.

Study Design and Setting

A review of RCTs in high-impact medical journals that reported a statistically significant result for at least one dichotomous or time-to-event outcome in the abstract. In the group with the smallest number of events, we changed the status of patients without an event to an event until the P-value exceeded 0.05. We labeled this number the Fragility Index; smaller numbers indicated a more fragile result.

Results

The 399 eligible trials had a median sample size of 682 patients (range: 15-112,604) and a median of 112 events (range: 8-5,142); 53% reported a P-value <0.01. The median Fragility Index was 8 (range: 0-109); 25% had a Fragility Index of 3 or less. In 53% of trials, the Fragility Index was less than the number of patients lost to follow-up.

Conclusion

The statistically significant results of many RCTs hinge on small numbers of events. The Fragility Index complements the P-value and helps identify less robust results. 

Meta-analysis of the influence of experimental design on effect size in peer tutoring outcomes in elementary, middle and high school settings.

A meta-analysis was undertaken on a form of cooperative learning, peer tutoring. The effects of experimental design on outcomes were explored, as measured by Effect Size (ES). 185 studies were included in the meta-analysis. Highest ES were reported for quasi-experimental studies. ES reduced as experimental design moved from single pre-test factor matched, to multiple-factor matched randomized controlled trials. ES reduced when designs used standardised, rather than self-designed measures, The implications for future meta-analyses and research in cooperative learning are explored.

Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial

Background: Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis in 10% of patients. This trial was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis. 

Methods: This randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged ≥6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s [FEV₁] ≥40% and ≤90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV₁. The primary endpoint was relative change in percent-predicted FEV₁ from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205. 

Findings: Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV₁ did not differ significantly between ataluren and placebo at week 48 (-2·5% vs -5·5%; difference 3·0% [95% CI -0·8 to 6·3]; p=0·12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0·77 [95% CI 0·57-1·05]; p=0·0992). However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5·7% difference (95% CI 1·5-10·1) in relative change from baseline in percent-predicted FEV₁ between the ataluren and placebo groups at week 48 (-0·7% [-4·0 to 2·1] vs -6·4% [-9·8 to -3·7]; nominal p=0·0082), and fewer pulmonary exacerbations in the ataluern group (1·42 events [0·9-1·9] vs 2·18 events [1·6-2·7]; rate ratio 0·60 [0·42-0·86]; nominal p=0·0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group. I

nterpretation: Although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, it might be beneficial for patients not taking chronic inhaled tobramycin. 

Funding: PTC Therapeutics, Cystic Fibrosis Foundation, US Food and Drug Administration's Office of Orphan Products Development, and the National Institutes of Health. 

A facile method for the synthesis of Au/PEDOT:PSS nanocomposite

In this work, we have successfully synthesized Au nanoparticles (NPs) in situ in PEDOT:PSS deploying a room temperature atmospheric pressure microplasma. The size of the AuNPs is a function of the gold salt precursor concentration and the plasma processing time. The Au/polymer colloids after processing remain well dispersed over a prolonged period of time. Both gold salt concentration and the plasma processing time have influence on the electrical conductivity of the dried Au/PEDOT:PSS nanocomposite films. An enhanced electrical conductivity of the Au/PEDOT:PSS nanocomposite films has been attributed to (i) the interfacial ligand formation between the S atoms in PEDOT:PSS molecules and the Au surface and (ii) charge transfer from the AuNPs to the holes of PEDOT:PSS molecules.

Effectiveness of a Multifaceted Intervention for Potentially Inappropriate Prescribing in Older Patients in Primary Care: A Cluster-Randomized Controlled Trial (OPTI-SCRIPT Study)

PURPOSE Potentially inappropriate prescribing (PIP) is common in older people and can result in increased morbidity, adverse drug events, and hospitalizations. The OPTI-SCRIPT study (Optimizing Prescribing for Older People in Primary Care, a cluster-randomized controlled trial) tested the effectiveness of a multifaceted intervention for reducing PIP in primary care.

METHODS We conducted a cluster-randomized controlled trial among 21 general practitioner practices and 196 patients with PIP. Intervention participants received a complex, multifaceted intervention incorporating academic detailing; review of medicines with web-based pharmaceutical treatment algorithms that provide recommended alternative-treatment options; and tailored patient information leaflets. Control practices delivered usual care and received simple, patient-level PIP feedback. Primary outcomes were the proportion of patients with PIP and the mean number of potentially inappropriate prescriptions. We performed intention-to-treat analysis using random-effects regression.

RESULTS All 21 practices and 190 patients were followed. At intervention completion, patients in the intervention group had significantly lower odds of having PIP than patients in the control group (adjusted odds ratio = 0.32; 95% CI, 0.15–0.70; P = .02). The mean number of PIP drugs in the intervention group was 0.70, compared with 1.18 in the control group (P = .02). The intervention group was almost one-third less likely than the control group to have PIP drugs at intervention completion, but this difference was not significant (incidence rate ratio = 0.71; 95% CI, 0.50–1.02; P = .49). The intervention was effective in reducing proton pump inhibitor prescribing (adjusted odds ratio = 0.30; 95% CI, 0.14–0.68; P = .04).

CONCLUSIONS The OPTI-SCRIPT intervention incorporating academic detailing with a pharmacist, and a review of medicines with web-based pharmaceutical treatment algorithms, was effective in reducing PIP, particularly in modifying prescribing of proton pump inhibitors, the most commonly occurring PIP drugs nationally.

Effectiveness of a biomarker-based exclusion of ventilator-acquired pneumonia to reduce antibiotic use: protocol for a randomised controlled trial (VAPrapid-2):Study protocol for a randomised controlled trial

Background Ventilator-acquired pneumonia (VAP) is a common reason for antimicrobial therapy in the intensive care unit (ICU). Biomarker-based diagnostics could improve antimicrobial stewardship through rapid exclusion of VAP. Bronchoalveloar lavage (BAL) fluid biomarkers have previously been shown to allow the exclusion of VAP with high confidence. Methods/Design This is a prospective, multi-centre, randomised, controlled trial to determine whether a rapid biomarker-based exclusion of VAP results in fewer antibiotics and improved antimicrobial management. Patients with clinically suspected VAP undergo BAL, and VAP is confirmed by growth of a potential pathogen at > 104 colony-forming units per millilitre (CFU/ml). Patients are randomised 1:1, to either a ‘biomarker-guided recommendation on antibiotics’ in which BAL fluid is tested for IL-1β and IL-8 in addition to routine microbiology testing, or to ‘routine use of antibiotics’ in which BAL undergoes routine microbiology testing only. Clinical teams are blinded to intervention until 6 hours after randomisation, when biomarker results are reported to the clinician. The primary outcome is a change in the frequency distribution of antibiotic-free days (AFD) in the 7 days following BAL. Secondary outcome measures include antibiotic use at 14 and 28 days; ventilator-free days; 28-day mortality and ICU mortality; sequential organ failure assessment (SOFA) at days 3, 7 and 14; duration of stay in critical care and the hospital; antibiotic-associated infections; and antibiotic-resistant pathogen cultures up to hospital discharge, death or 56 days. A healthcare-resource-utilisation analysis will be calculated from the duration of critical care and hospital stay. In addition, safety data will be collected with respect to performing BAL. A sample size of 210 will be required to detect a clinically significant shift in the distribution of AFD towards more patients having fewer antibiotics and therefore more AFD. Discussion This trial will test whether a rapid biomarker-based exclusion of VAP results in rapid discontinuation of antibiotics and therefore improves antibiotic management in patients with suspected VAP.

Development of polymeric–cationic peptide composite nanoparticles, a nanoparticle-in-nanoparticle system for controlled gene delivery

We report the formulation of novel composite nanoparticles that combine the high transfection efficiency of cationic peptide-DNA nanoparticles with the biocompatibility and prolonged delivery of polylactic acid–polyethylene glycol (PLA-PEG). The cationic cell-penetrating peptide RALA was used to condense DNA into nanoparticles that were encapsulated within a range of PLA-PEG copolymers. The composite nanoparticles produced exhibited excellent physicochemical properties including size <200 nm and encapsulation efficiency >80%. Images of the composite nanoparticles obtained with a new transmission electron microscopy staining method revealed the peptide-DNA nanoparticles within the PLA-PEG matrix. Varying the copolymers modulated the DNA release rate >6 weeks in vitro. The best formulation was selected and was able to transfect cells while maintaining viability. The effect of transferrin-appended composite nanoparticles was also studied. Thus, we have demonstrated the manufacture of composite nanoparticles for the controlled delivery of DNA.

Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial

BACKGROUND: Acute promyelocytic leukaemia is a chemotherapy-sensitive subgroup of acute myeloid leukaemia characterised by the presence of the PML-RARA fusion transcript. The present standard of care, chemotherapy and all-trans retinoic acid (ATRA), results in a high proportion of patients being cured. In this study, we compare a chemotherapy-free ATRA and arsenic trioxide treatment regimen with the standard chemotherapy-based regimen (ATRA and idarubicin) in both high-risk and low-risk patients with acute promyelocytic leukaemia.

METHODS: In the randomised, controlled, multicentre, AML17 trial, eligible patients (aged ≥16 years) with acute promyelocytic leukaemia, confirmed by the presence of the PML-RARA transcript and without significant cardiac or pulmonary comorbidities or active malignancy, and who were not pregnant or breastfeeding, were enrolled from 81 UK hospitals and randomised 1:1 to receive treatment with ATRA and arsenic trioxide or ATRA and idarubicin. ATRA was given to participants in both groups in a daily divided oral dose of 45 mg/m(2) until remission, or until day 60, and then in a 2 weeks on-2 weeks off schedule. In the ATRA and idarubicin group, idarubicin was given intravenously at 12 mg/m(2) on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m(2) on days 1-4 of course 2; mitoxantrone at 10 mg/m(2) on days 1-4 of course 3, and idarubicin at 12 mg/m(2) on day 1 of the final (fourth) course. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0·3 mg/kg on days 1-5 of each course, and at 0·25 mg/kg twice weekly in weeks 2-8 of course 1 and weeks 2-4 of courses 2-5. High-risk patients (those presenting with a white blood cell count >10 × 10(9) cells per L) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m(2) intravenously). Neither maintenance treatment nor CNS prophylaxis was given to patients in either group. All patients were monitored by real-time quantitative PCR. Allocation was by central computer minimisation, stratified by age, performance status, and de-novo versus secondary disease. The primary endpoint was quality of life on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 global health status. All analyses are by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN55675535.

FINDINGS: Between May 8, 2009, and Oct 3, 2013, 235 patients were enrolled and randomly assigned to ATRA and idarubicin (n=119) or ATRA and arsenic trioxide (n=116). Participants had a median age of 47 years (range 16-77; IQR 33-58) and included 57 high-risk patients. Quality of life did not differ significantly between the treatment groups (EORTC QLQ-C30 global functioning effect size 2·17 [95% CI -2·79 to 7·12; p=0·39]). Overall, 57 patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3-4 toxicities. After course 1 of treatment, grade 3-4 alopecia was reported in 23 (23%) of 98 patients in the ATRA and idarubicin group versus 5 (5%) of 95 in the ATRA and arsenic trioxide group, raised liver alanine transaminase in 11 (10%) of 108 versus 27 (25%) of 109, oral toxicity in 22 (19%) of 115 versus one (1%) of 109. After course 2 of treatment, grade 3-4 alopecia was reported in 25 (28%) of 89 patients in the ATRA and idarubicin group versus 2 (3%) of 77 in the ATRA and arsenic trioxide group; no other toxicities reached the 10% level. Patients in the ATRA and arsenic trioxide group had significantly less requirement for most aspects of supportive care than did those in the ATRA and idarubicin group.

INTERPRETATION: ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with acute promyelocytic leukaemia, with a high cure rate and less relapse than, and survival not different to, ATRA and idarubicin, with a low incidence of liver toxicity. However, no improvement in quality of life was seen.

Improved Efficiency for Partial Oxidation of Methane by Controlled Copper Deposition on Surface-Modified ZSM-5

The mono(μ-oxo) dicopper cores present in the pores of Cu-ZSM-5 are active for the partial oxidation of methane to methanol. However, copper on the external surface reduces the ratio of active, selective sites to unselective sites. More efficient catalysts are obtained by controlling the copper deposition during synthesis. Herein, the external exchange sites of ZSM-5 samples were passivated by bis(trimethylsilyl) trifluoroacetamide (BSTFA) followed by calcination, promoting selective deposition of intraporous copper during aqueous copper ion exchange. At an optimum level of 1–2 wt % SiO2, IR studies showed a 64 % relative reduction in external copper species and temperature-programmed oxidation analysis showed an associated increase in the formation of methanol compared with unmodified Cu-ZSM-5 samples. It is, therefore, reported that the modified zeolites contained a significantly higher proportion of active, selective copper species than their unmodified counterparts with activity for partial methane oxidation to methanol.

Injurious tail biting in pigs: How can it be controlled in existing systems without tail docking?

Tail biting is a serious animal welfare and economic problem in pig production. Tail docking, which reduces but does not eliminate tail biting, remains widespread. However, in the EU tail docking may not be used routinely, and some 'alternative' forms of pig production and certain countries do not allow tail docking at all. Against this background, using a novel approach focusing on research where tail injuries were quantified, we review the measures that can be used to control tail biting in pigs without tail docking. Using this strict criterion, there was good evidence that manipulable substrates and feeder space affect damaging tail biting. Only epidemiological evidence was available for effects of temperature and season, and the effect of stocking density was unclear. Studies suggest that group size has little effect, and the effects of nutrition, disease and breed require further investigation. The review identifies a number of knowledge gaps and promising avenues for future research into prevention and mitigation. We illustrate the diversity of hypotheses concerning how different proposed risk factors might increase tail biting through their effect on each other or on the proposed underlying processes of tail biting. A quantitative comparison of the efficacy of different methods of provision of manipulable materials, and a review of current practices in countries and assurance schemes where tail docking is banned, both suggest that daily provision of small quantities of destructible, manipulable natural materials can be of considerable benefit. Further comparative research is needed into materials, such as ropes, which are compatible with slatted floors. Also, materials which double as fuel for anaerobic digesters could be utilised. As well as optimising housing and management to reduce risk, it is important to detect and treat tail biting as soon as it occurs. Early warning signs before the first bloody tails appear, such as pigs holding their tails tucked under, could in future be automatically detected using precision livestock farming methods enabling earlier reaction and prevention of tail damage. However, there is a lack of scientific studies on how best to respond to outbreaks: the effectiveness of, for example, removing biters and/or bitten pigs, increasing enrichment, or applying substances to tails should be investigated. Finally, some breeding companies are exploring options for reducing the genetic propensity to tail bite. If these various approaches to reduce tail biting are implemented we propose that the need for tail docking will be reduced. © 2014 The Animal Consortium.