Golimumab induction and maintenance for moderate to severe ulcerative colitis: results from GO-COLITIS (Golimumab: a Phase 4, UK, open label, single arm study on its utilization and impact in ulcerative Colitis).

OBJECTIVE: GO-COLITIS aimed to measure the effectiveness of subcutaneous golimumab in tumour necrosis factor-α antagonist-naive patients with moderate to severe ulcerative colitis (UC) despite conventional treatment. DESIGN: GO-COLITIS was an open label, single arm, phase 4 study with a pragmatic design which reflected UK clinical practice. Adult patients were eligible if diagnosed with UC ≥3 months, partial Mayo score (PMS) 4-9. Patients received subcutaneous golimumab induction (200 mg initially and 100 mg at week 2) followed at week 6 by 50 mg or 100 mg (depending on weight) every 4 weeks until week 54 with a 12-week follow-up. Efficacy was measured by PMS at baseline, week 6, 30, 54 and 66. Health-related quality of life (HRQoL; Inflammatory Bowel Disease Questionnaire (IBDQ) and EuroQol Group 5 Dimensions Health Questionnaire (EQ-5D)) was assessed at baseline, week 6 and week 54. All safety adverse events (AEs) were recorded. RESULTS: 207 patients were enrolled and 205 received golimumab (full analysis set (FAS)205). At week 6, 68.8% (95% CI 62.0% to 75.1%) and 38.5% (95% CI 31.8% to 45.6%) of patients were in response and remission, respectively, using PMS. At the end of the induction phase, 140/141 patients in clinical response continued into the maintenance phase (Maintenance FAS). Sustained clinical response through week 54 was achieved in 51/205 (24.9%) of the FAS205 population and 51/140 (36.4%) of the Maintenance FAS population. Statistically significant improvements from baseline to week 6 were observed for the IBDQ total score and for each IBDQ domain score (bowel symptoms, emotional function, systemic symptoms and social function), as well as the EQ-5D index score and associated visual analogue scale score (p<0.0001). Improvement of HRQoL was sustained through week 54. Serious AEs leading to treatment discontinuation occurred in 8.8% of patients. CONCLUSION: In this study measuring patient-reported outcomes in patients with moderate to severe UC, golimumab induced and maintained response as measured by PMS and significantly improved quality of life measures. TRIAL REGISTRATION NUMBER: NCT02092285; 2013-004583-56.

Concordance between plasma apolipoprotein B levels and cholesterol indices among patients receiving statins and nonstatin treatment: Post-hoc analyses from the U.K. InPractice study.

BACKGROUND: Apolipoprotein B (ApoB) is a superior predictor of low-density-lipoprotein (LDL) particle number and cardiovascular disease (CVD) risk compared with LDL-cholesterol (LDL-C) levels. Current evidence has shown a degree of discordance between LDL-C with ApoB levels among patients not receiving lipid-lowering therapy. The extent of this discordance among patients receiving LDL-lowering therapies however is less clear. METHODS: We performed a post hoc analysis of the InPractice data looking at the concordance between LDL-C, non-high density lipoprotein-cholesterol (nonHDL-C) and total cholesterol with ApoB values. The study involved 786 high-risk CVD patients from 34 primary care centers initially treated with simvastatin (S) 40 mg at baseline subsequently randomized to adding ezetimibe 10 mg to S 40 mg (E/S40) or changed to atorvastatin (A) 40 mg or to rosuvastatin (R) 5-10 mg for 6 weeks. RESULTS: At 6 weeks after treatment, the association between LDL-C and ApoB values for the different treatment regimes were similar; Pearson's correlation coefficients between LDL-C and ApoB were 0.84 (E/S40), 0.82 (A), and 0.83 (R). Overall, ApoB appeared to have a slightly greater correlation with nonHDL-C than with LDL-C across all treatment groups, for baseline and posttreatment values. The analysis of quintile frequencies showed a similar pattern; the proportion of patients who had values that fell in the same quintile post treatment for ApoB and LDL-C levels were 52.2% (E/S40), 44.5% (A), and 49.4% (R). Concordance between ApoB and nonHDL-C was 60.6% (E/S40), 62.4% (A), and 61.8% (R). Kappa analysis confirmed fair agreement between LDL-C and ApoB levels for all treatment groups; 0.59 (E/S40), 0.54 (A), and 0.56(R). CONCLUSION: We showed that the association between ApoB and LDL-C is similar across different lipid-lowering treatment regimes, which suggests that the use of different lipid-lowering agent confers similar ability to predict ApoB levels. When determining CVD risk at an individual patient level, limitation exists when using LDL-C or nonHDL-C per se as risk markers. In the absence of ApoB measurement, we believe that information from both LDL-C and nonHDL-C should be used together to improve the estimation of residual CVD risk among patients who are already receiving lipid lowering therapy.

Statistical approaches for conducting network meta-analysis in drug development.

We introduce health technology assessment and evidence synthesis briefly, and then concentrate on the statistical approaches used for conducting network meta-analysis (NMA) in the development and approval of new health technologies. NMA is an extension of standard meta-analysis where indirect as well as direct information is combined and can be seen as similar to the analysis of incomplete-block designs. We illustrate it with an example involving three treatments, using fixed-effects and random-effects models, and using frequentist and Bayesian approaches. As most statisticians in the pharmaceutical industry are familiar with SAS® software for analyzing clinical trials, we provide example code for each of the methods we illustrate. One issue that has been overlooked in the literature is the choice of constraints applied to random effects, and we show how this affects the estimates and standard errors and propose a symmetric set of constraints that is equivalent to most current practice. Finally, we discuss the role of statisticians in planning and carrying out NMAs and the strategy for dealing with important issues such as heterogeneity.

Docetaxel in combination with doxorubicin and cyclophosphamide as adjuvant treatment for early node-positive breast cancer: a cost-effectiveness and cost-utility analysis.

PURPOSE: To estimate the cost effectiveness of TAC (docetaxel, doxorubicin, and cyclophosphamide) compared with FAC (fluorouracil, doxorubicin, and cyclophosphamide) when administered as adjuvant therapy to women with node-positive early breast cancer in the United Kingdom (UK), both with and without primary prophylaxis with granulocyte colony-stimulating factor (G-CSF). METHODS: A standard health economic Markov model estimated the cost and outcome for node-positive early breast cancer patients, from initiation of adjuvant chemotherapy to death. Patient-level data were used from the Breast Cancer International Research Group (BCIRG) 001 trial for estimates of the effect of chemotherapy on toxicity and outcome, and an observational data set collected from a UK university hospital provided estimates of resource use and outcome for patients with relapsed disease. RESULTS: Over a 10-year analysis timeframe, the incremental cost per life-year saved associated with the use of TAC rather than FAC was estimated as pound 15,418 (95% CI, pound 13,734 to pound 17,997) and the incremental cost per quality-adjusted life-year gained (IC/QALY) was pound 18,188 (95% CI, pound 14,161 to pound 32,422). The addition of primary G-CSF (lenograstim or filgrastim) to the TAC regimen resulted in an IC/QALY of pound 20,432. The results were most sensitive to the quality-of-life (QOL) score for patients in remission postchemotherapy. However, even if QOL was assumed to be as poor as for patients with metastatic disease, the IC/QALY estimate rose only to pound 32,430. CONCLUSION: The use of adjuvant TAC rather than FAC for node-positive early breast cancer patients is cost effective, despite the increased drug and toxicity treatment costs, and when primary G-CSF prophylaxis is given to all patients.

Effects of montelukast compared to double dose budesonide on airway inflammation and asthma control.

Many patients with asthma remain symptomatic with impaired airway function on inhaled steroids. This study investigates the relationship between the clinical effect seen in response to additional treatment and the effect on airway inflammatory indices. Seventy-five adult asthmatic patients, incompletely controlled on 800 mcg budesonide/day, were randomised following a 4 week run-in period, to a double-blind, multi-centre controlled clinical trial of doubling inhaled corticosteroid (budesonide 1600 mcg/day) or adding 10mg montelukast for 12 weeks. Induced sputum was collected at baseline and end of treatment and analysed for eosinophil and neutrophil percentages, leukotrienes C4, D4 and E4, IL-8, Eosinophil Cationic Protein (ECP) and histamine. Sputum evidence of inflammation (2.0% eosinophils) was seen in only 29% of these patients and the percentage of eosinophils and other markers of airway inflammation did not change over the study period in either treatment group. There were significant improvements in am PEF (montelukast: 31.7 L/min, budesonide: 32.3 L/min) and quality of life with both treatments. We conclude that while both treatments showed similar improvements in lung function and quality of life, there was no evidence from these sputum markers measured that the effects were mediated via a reduction in airway inflammation or that the level of pre-treatment markers was associated with outcome.

Ethnicity, socio-economic status, overweight and underweight in East London adolescents.

BACKGROUND: The developed world is experiencing an 'epidemic' of childhood obesity but little is known about the prevalence of obesity, or underweight, amongst adolescents from minority ethnic groups in the UK. An understanding of the prevalence of obesity and overweight in these populations is important since some ethnic groups may be particularly vulnerable to the adverse health effects associated with obesity. STUDY OBJECTIVES: To examine levels of extreme obesity, obesity, overweight and underweight amongst a representative sample of adolescents from different ethnic groups in East London and to explore the association between socio-economic status and body mass index (BMI). DESIGN: A school-based survey of adolescents aged 11-14. Obesity and overweight were estimated using the 1990 UK growth reference (UK 90) and the International Obesity Task Force (IOTF) cut-off points. Extreme obesity was defined as a BMI more than three SD above the UK 90 mean. Underweight was examined by looking at those with a BMI below the 15th or the 5th UK 90 percentiles. MAIN RESULTS: A total of 2,482 adolescents were surveyed (response rate 84%), 73% from non-white ethnic groups. Although there were significant differences in BMI between ethnic groups, high levels of overweight were seen in all ethnic groups. More than one-third were overweight and one-fifth were obese using the UK 90; and over a quarter were overweight and almost one-tenth were obese using the IOTF cut-offs. Two per cent were extremely obese. Indian males were at higher risk of being overweight than white British males. The prevalence of obesity and overweight was similar in white British and Bangladeshi males. Overall the prevalence of underweight was slightly lower than that predicted by the UK 90, but South Asian ethnic groups, especially males, had a higher prevalence of underweight than other groups. No associations between BMI and measures of socio-economic status were found in this relatively deprived population. CONCLUSIONS: The 'epidemic' of childhood obesity observed in the UK involves adolescents from all ethnic groups, although there are some differences between ethnic groups in the prevalence of overweight. Indian males appear to be at increased risk of being overweight. There is no evidence of a simultaneous increase in underweight amongst this population overall, but Bangladeshi, Indian and Pakistani boys appear to be at increased risk of being underweight.

The national montelukast survey.

BACKGROUND: Randomized controlled trials have demonstrated the efficacy of montelukast for treating asthma; whether this can be extrapolated to clinical effectiveness in routine practice has yet to be established. OBJECTIVE: To examine the use, effectiveness, and tolerability of montelukast in clinical practice for treating asthma and to explore prognostic factors that could predict a favorable response to the drug. METHODS: This was a retrospective, cross-sectional, observational study of clinical outcomes seen in patients prescribed montelukast for asthma that used routinely collected clinical information. Data were collected on all consenting patients who had been prescribed montelukast for asthma irrespective of the continuation or duration of treatment. Independent observers, treating physicians, and patients assessed certain outcomes after the initiation of montelukast, including the general asthma response and changes in activity-related symptoms. RESULTS: Fifty-six centers in the United Kingdom (20 primary care and 36 secondary care) participated. The analysis was based on 1351 eligible patients for whom essential data were available. Eight hundred thirty patients (66.4%; 95% CI, 63.8% to 69.0%) were recorded as having shown an improvement in their asthma control, and 103 (8.2%; 95% CI, 6.8% to 9.9%) experienced a dramatic improvement. The greatest proportion of patients responding was seen in those with mild to moderate asthma. Montelukast was well tolerated; no new adverse events were recorded. CONCLUSIONS: Montelukast is an effective, well-tolerated treatment for asthma in routine practice. The overall response rate and tolerability seen in this survey are similar to those reported in randomized clinical trials.

Evaluating the effectiveness of asthma treatment in real-life practice.

RATIONALE, AIMS AND OBJECTIVES: The randomized controlled trial (RCT) is considered the gold standard methodology for determining the efficacy and tolerability of new treatments. However, RCTs cannot provide information on the effectiveness of interventions as they are used in real life. This study was conducted to investigate the effectiveness of montelukast, a leukotriene receptor antagonist, in the real-world management of asthma, through a large-scale, retrospective, observational study: the National Montelukast Survey. METHODS: In order to ensure a robust methodology for the National Montelukast Survey we performed three pilot studies involving a total of almost 400 patients. During the pilots, the design of the study was extensively modified from a simple prescriber questionnaire used in the first pilot to the 'triangulated' methodology encompassing the perspectives of patient, prescriber and independent observer used in the National Montelukast Survey. Good levels of interobserver agreement confirmed the robustness of the final methodology. CONCLUSIONS: Achieving a robust methodology was dependent on the extensive piloting. It is possible to collect reliable observational data relating to treatment outcomes. We believe our methods are likely to have more widespread applicability and offer a potential improvement over postmarketing surveillance.

Specialist nurse intervention to reduce unscheduled asthma care in a deprived multiethnic area: the east London randomised controlled trial for high risk asthma (ELECTRA).

OBJECTIVE: To determine whether asthma specialist nurses, using a liaison model of care, reduce unscheduled care in a deprived multiethnic area. DESIGN: Cluster randomised controlled trial. SETTING: 44 general practices in two boroughs in east London. PARTICIPANTS: 324 people aged 4-60 years admitted to or attending hospital or the general practitioner out of hours service with acute asthma; 164 (50%) were South Asian patients, 108 (34%) were white patients, and 52 (16%) were from other, largely African and Afro-Caribbean, ethnicities. INTERVENTION: Patient review in a nurse led clinic and liaison with general practitioners and practice nurses comprising educational outreach, promotion of guidelines for high risk asthma, and ongoing clinical support. Control practices received a visit promoting standard asthma guidelines; control patients were checked for inhaler technique. MAIN OUTCOME MEASURES: Percentage of participants receiving unscheduled care for acute asthma over one year and time to first unscheduled attendance. RESULTS: Primary outcome data were available for 319 of 324 (98%) participants. Intervention delayed time to first attendance with acute asthma (hazard ratio 0.73, 95% confidence interval 0.54 to 1.00; median 194 days for intervention and 126 days for control) and reduced the percentage of participants attending with acute asthma (58% (101/174) v 68% (99/145); odds ratio 0.62, 0.38 to 1.01). In analyses of prespecified subgroups the difference in effect on ethnic groups was not significant, but results were consistent with greater benefit for white patients than for South Asian patients or those from other ethnic groups. CONCLUSION: Asthma specialist nurses using a liaison model of care reduced unscheduled care for asthma in a deprived multiethnic health district. Ethnic groups may not benefit equally from specialist nurse intervention.