Laith Alrubaiy

Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial

Summary Background Infliximab and ciclosporin are of similar efficacy in treating acute severe ulcerative colitis, but there has been no comparative evaluation of their relative clinical effectiveness and cost-effectiveness. Methods In this mixed methods, open-label, pragmatic randomised trial, we recruited consenting patients aged 18 years or older at 52 district general and teaching hospitals in England, Scotland, and Wales who had been admitted, unscheduled, with severe ulcerative colitis and failed to respond to intravenous hydrocortisone within about 5 days. Patients were randomly allocated (1:1) to receive either infliximab (5 mg/kg intravenous infusion given over 2 h at baseline, and again at 2 weeks and 6 weeks after the first infusion) or ciclosporin (2 mg/kg per day by continuous infusion for up to 7 days, followed by twice-daily tablets delivering 5·5 mg/kg per day for 12 weeks). Randomisation used a web-based password-protected site, with a dynamic algorithm to generate allocations on request, thus protecting against investigator preference or other subversion, while ensuring that each trial group was balanced by centre, which was the only stratification used. Local investigators and participants were aware of the treatment allocated, but the chief investigator and analysts were masked. Analysis was by treatment allocated. The primary outcome was quality-adjusted survival—ie, the area under the curve (AUC) of scores from the Crohns and Ulcerative Colitis Questionnaire (CUCQ) completed by participants at baseline, 3 months, and 6 months, then every 6 months from 1 year to 3 years. This trial is registered with the ISRCTN Registry, number ISRCTN22663589. Findings Between June 17, 2010, and Feb 26, 2013, 270 patients were recruited. 135 patients were allocated to the infliximab group and 135 to the ciclosporin group. 121 (90%) patients in each group were included in the analysis of the primary outcome. There was no significant difference between groups in quality-adjusted survival (mean AUC 564·0 [SD 241·9] in the infliximab group vs 587·0 [226·2] in the ciclosporin group; mean adjusted difference 7·9 [95% CI −22·0 to 37·8]; p=0·603). Likewise, there were no significant differences between groups in the secondary outcomes of CUCQ scores, EQ-5D, or SF-6D scores; frequency of colectomy (55 [41%] of 135 patients in the infliximab group vs 65 [48%] of 135 patients in the ciclosporin group; p=0·223); or mean time to colectomy (811 [95% CI 707–912] days in the infliximab group vs 744 [638–850] days in the ciclosporin group; p=0·251). There were no differences in serious adverse reactions (16 reactions in 14 participants receiving infliximab vs ten in nine patients receiving ciclosporin); serious adverse events (21 in 16 patients vs 25 in 17 patients); or deaths (three in the infliximab group vs none in the ciclosporin group). Interpretation There was no significant difference between ciclosporin and infliximab in clinical effectiveness. Funding NIHR Health Technology Assessment programme.

Randomised controlled trial. Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: Trial design and protocol (CONSTRUCT)

Introduction Many patients with ulcerative colitis (UC) present with acute exacerbations needing hospital admission. Treatment includes intravenous steroids but up to 40% of patients do not respond and require emergency colectomy. Mortality following emergency colectomy has fallen, but 10% of patients still die within 3 months of surgery. Infliximab and ciclosporin, both immunosuppressive drugs, offer hope for treating steroid-resistant UC as there is evidence of their short-term effectiveness. As there is little long-term evidence, this pragmatic randomised trial, known as Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: a Trial (CONSTRUCT), aims to compare the clinical and cost-effectiveness of infliximab and ciclosporin for steroid-resistant UC. Methods and analysis Between May 2010 and February 2013, 52 UK centres recruited 270 patients admitted with acute severe UC who failed to respond to intravenous steroids but did not need surgery. We allocated them at random in equal proportions between infliximab and ciclosporin.The primary clinical outcome measure is quality-adjusted survival, that is survival weighted by Crohns and Colitis Questionnaire (CCQ) participants’ scores, analysed by Cox regression. Secondary outcome measures include: the CCQ—an extension of the validated but community-focused UK Inflammatory Bowel Disease Questionnaire (IBDQ) to include patients with acute severe colitis and stoma; two general quality of life measures—EQ-5D and SF-12; mortality; survival weighted by EQ-5D; emergency and planned colectomies; readmissions; incidence of adverse events including malignancies, serious infections and renal disorders; disease activity; National Health Service (NHS) costs and patient-borne costs. Interviews investigate participants’ views on therapies for acute severe UC and healthcare professionals’ views on the two drugs and their administration. Ethics and dissemination The Research Ethics Committee for Wales has given ethical approval (Ref. 08/MRE09/42); each participating Trust or Health Board has given NHS Reseach & Development approval. We plan to present trial findings at international and national conferences and publish in high-impact peer-reviewed journals. Trial registration number ISRCTN: 22663589; EudraCT number: 2008-001968-36

Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT)

BACKGROUND The efficacy of infliximab and ciclosporin in treating severe ulcerative colitis (UC) is proven, but there has been no comparative evaluation of effectiveness. OBJECTIVE To compare the clinical effectiveness and cost-effectiveness of infliximab and ciclosporin in treating steroid-resistant acute severe UC. METHOD Between May 2010 and February 2013 we recruited 270 participants from 52 hospitals in England, Scotland and Wales to an open-label parallel-group, pragmatic randomised trial. Consented patients admitted with severe colitis completed baseline quality-of-life questionnaires before receiving intravenous hydrocortisone. If they failed to respond within about 5 days, and met other inclusion criteria, we invited them to participate and used a web-based adaptive randomisation algorithm to allocate them in equal proportions between 5 mg/kg of intravenous infliximab at 0, 2 and 6 weeks or 2 mg/kg/day of intravenous ciclosporin for 7 days followed by 5.5 mg/kg/day of oral ciclosporin until 12 weeks from randomisation. Further treatment was at the discretion of physicians responsible for clinical management. The primary outcome was quality-adjusted survival (QAS): the area under the curve (AUC) of scores derived from Crohns and Ulcerative Colitis Questionnaires completed by participants at 3 and 6 months, and then 6-monthly over 1-3 years, more frequently after surgery. Secondary outcomes collected simultaneously included European Quality of Life-5 Dimensions (EQ-5D) scores and NHS resource use to estimate cost-effectiveness. Blinding was possible only for data analysts. We interviewed 20 trial participants and 23 participating professionals. Funded data collection finished in March 2014. Most participants consented to complete annual questionnaires and for us to analyse their routinely collected health data over 10 years. RESULTS The 135 participants in each group were well matched at baseline. In 121 participants analysed in each group, we found no significant difference between infliximab and ciclosporin in QAS [mean difference in AUC/day 0.0297 favouring ciclosporin, 95% confidence interval (CI) -0.0088 to 0.0682; p = 0.129]; EQ-5D scores (quality-adjusted life-year mean difference 0.021 favouring ciclosporin, 95% CI -0.032 to 0.096; p = 0.350); Short Form questionnaire-6 Dimensions scores (mean difference 0.0051 favouring ciclosporin, 95% CI -0.0250 to 0.0353; p = 0.737). There was no statistically significant difference in colectomy rates [odds ratio (OR) 1.350 favouring infliximab, 95% CI 0.832 to 2.188; p = 0.223]; numbers of serious adverse reactions (event ratio = 0.938 favouring ciclosporin, 95% CI 0.590 to 1.493; p = 0.788); participants with serious adverse reactions (OR 0.660 favouring ciclosporin, 95% CI 0.282 to 1.546; p = 0.338); numbers of serious adverse events (event ratio 1.075 favouring infliximab, 95% CI 0.603 to 1.917; p = 0.807); participants with serious adverse events (OR 0.999 favouring infliximab, 95% CI 0.473 to 2.114; p = 0.998); deaths (all three who died received infliximab; p = 0.247) or concomitant use of immunosuppressants. The lower cost of ciclosporin led to lower total NHS costs (mean difference -£5632, 95% CI -£8305 to -£2773; p < 0.001). Interviews highlighted the debilitating effect of UC; participants were more positive about infliximab than ciclosporin. Professionals reported advantages and disadvantages with both drugs, but nurses disliked the intravenous ciclosporin. CONCLUSIONS Total cost to the NHS was considerably higher for infliximab than ciclosporin. Nevertheless, there was no significant difference between the two drugs in clinical effectiveness, colectomy rates, incidence of SAEs or reactions, or mortality, when measured 1-3 years post treatment. To assess long-term outcome participants will be followed up for 10 years post randomisation, using questionnaires and routinely collected data. Further studies will be needed to evaluate the efficacy and effectiveness of new anti-tumour necrosis factor drugs and formulations of ciclosporin. TRIAL REGISTRATION Current Controlled Trials ISRCTN22663589. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 44. See the NIHR Journals Library website for further project information.

Development of a Short Questionnaire to Assess the Quality of Life in Crohn’s Disease and Ulcerative Colitis

BACKGROUND AND AIMS Most of the disease-specific quality of life (QoL) measures for inflammatory bowel disease (IBD) are lengthy and time consuming. None have been established for routine use in clinical practice. We designed this study to develop a short QoL measure in IBD. METHODS A 32-item questionnaire, the Crohns and ulcerative colitis questionnaire (CUCQ)-32 was developed by reviewing the literature of the previously validated questionnaires and by consultation with patients and experts. Construct validity was carried out using the Short Form 12 and the EuroQol 5 dimensions questionnaires and two disease severity measures (the Simple Clinical Colitis Activity Index and the Harvey-Bradshaw Index). Test-retest analysis was done by asking patients to complete the CUCQ questionnaire twice within a period of two weeks. RESULTS Data were obtained from 205 patients with IBD who completed the CUCQ-32. Psychometric analysis showed that Cronbachs α was 0.88, item-total correlations were good, and there were no ceiling or flooring effects. Stepwise regression identified eight items that accounted for >95% of the variance in the CUCQ-32. The resulting CUCQ-8 demonstrated good internal consistency (Cronbachs α = 0.84), had good reproducibility (intraclass correlation coefficient = 0.94), was well correlated with the EuroQol 5 dimensions questionnaire (r = 0.58) and the Short Form-12 (r = 0.65 for physical component and r = 0.63 for mental component), and was responsive to change (responsiveness ratio was 0.64, p-value < 0.05). CONCLUSIONS CUCQ-8 is a short questionnaire that has the potential to be an efficient tool for assessing the QoL of all patients with IBD in clinical practice.

Assessing patient reported outcome measures: A practical guide for gastroenterologists

Gastrointestinal illnesses cause physical, emotional and social impact on patients. Patient reported outcome measures (PROMs) are increasingly used in clinical decision-making, clinical research and approval of new therapies. In the last decade, there has been a rapid increase in the number of PROMs in gastroenterology and, therefore, the choice between which of these PROMs to use can be difficult. Not all PROM instruments currently used in research and clinical practice in gastroenterology have gone through a rigorous development methodology. New drugs and therapies will not have access to the market if the PROMs used in their clinical trials are not validated according to the guidelines of the international agencies. Therefore, it is important to know the required properties of PROMs when choosing or evaluating a drug or a clinical intervention. This paper reviews the current literature on how to assess the validity and reliability of PROMs. It summarises the required properties into a practical guide for gastroenterologists to use in assessing an instrument for use in clinical practice or research.

Systematic Review of the Clinical Disease Severity Indices for Inflammatory Bowel Disease

Background:Clinical disease severity indices are increasingly being used in choosing treatment and monitoring the response of patients with inflammatory bowel disease (IBD). The aim of this study was to systematically review the clinical disease severity indices in IBD and to appraise their measurement properties and methodological quality. Methods:We searched the MEDLINE, Embase, and PsycINFO databases for original articles describing the development and/or evaluation of one or more of the measurement properties of clinical disease severity indices used in IBD. We assessed these properties (e.g., internal consistency, reliability, validity, responsiveness) using a standardized checklist. Results:We examined the full text of 142 articles that we deemed potentially eligible and identified 22 clinical disease severity indices in IBD. No clinical disease index has met all the required measurement properties. All of the validation studies were not descriptive enough to allow assessment of their methodology. Conclusions:Although commonly used in multiple clinical trials, none of the clinical disease severity indices in IBD had all the required measurement properties. Further validation studies are required.

Colectomy rates in patients with ulcerative colitis following treatment with infliximab or ciclosporin: a systematic literature review.

This review aimed to compile all available published data on colectomy rates following treatment using infliximab or ciclosporin in adult ulcerative colitis patients and to analyse colectomy rates, timing to colectomy and postcolectomy mortality for each treatment. We systematically reviewed the literature after 1990 reporting colectomy rates in ulcerative colitis patients treated with infliximab or ciclosporin, excluding articles on paediatric patients, patients with indeterminate colitis or Crohn’s disease and bowel surgery not related to ulcerative colitis. We presented weighted mean colectomy rates and mortality rates. Cox’s regression was used to assess time to colectomy adjusting for colitis severity, patient age and sex. We tabulated 78 studies reporting on ciclosporin and/or infliximab and colectomy rates or postcolectomy mortality rates. Not all studies reported data in a standardized manner. Infliximab had a significantly lower colectomy rate than ciclosporin at 36 months when analysing all studies, studies directly comparing infliximab and ciclosporin and studies using severe colitis patients, but not at 3, 12 or 24 months. Severity and age were key indicators in the likelihood of undergoing colectomy after treatment. Postcolectomy mortality rates were less than 1.5% for both drugs. This review indicates that long-term colectomy rates following infliximab are significantly lower than ciclosporin in the longer term, and that postcolectomy mortality following infliximab and ciclosporin is very low. However, many key data items were missing from research articles, reducing our ability to establish with more confidence the actual impact of these two drugs on colectomy rates and postcolectomy mortality rates.

Prevalence of hepatitis B seromarkers and hepatitis C antibodies in blood donors in Basra, Iraq

Background Transfusion-caused hepatitis remains a major problem in Iraq. Therefore, testing for hepatitis B surface antigen (HBsAg), antibodies to hepatitis B core antigen (anti-HBc) and antibodies to hepatitis C antigen (anti-HCV) is a very important preventative measure. The objective of this study was to establish the prevalence of hepatitis B and C virus seromarkers among blood donors as a foundation for safe blood transfusion in Iraq. Methods A cross-sectional observational study was conducted in the blood banks in Basra, Iraq from 1 January to 31 December 2013. Blood samples were collected and were tested for HBsAg, anti-HBc and anti-HCV using standard laboratory techniques. Results A total of 69 915 blood donors were enrolled for the study. A total of 1625 (2.3%) donors have shown serological evidence for hepatitis B virus infection; of those donors, 125 (0.2%) showed a positive test result for both anti-HBc and HBsAg while 1475 (2.1%) had positive anti-HBc results as the only positive test for HBV infection. There was no significant difference between males and females (p=0.28). The prevalence of anti-HCV was 0.1%. Conclusions This is the first large population study of its kind in Basra, Iraq. The prevalence of hepatitis B and C among blood donors is very low in Basra. Around 2% of blood donors had anti-HBc as the only serological evidence of HBV infection. Inclusion of anti-HBc in routine screening of blood donors in Iraq should be encouraged.

Patient-Reported Outcome Measures in Routine Clinical Care: The PROMise of a Better Future?

Most health-care providers treat patients with the goal of improving patients’ health based on biochemical, histological, radiological, and clinical assessments. From the patient’s perspective, treatment should be based on symptomatology and focus on the experience of the patient in order to better refine interventions. Such data are best gathered from patients rather than from the laboratory or the imaging suite [1]. In contrast, the usual endpoints measured in clinical trials are the relatively uncommon outcomes of death, infection, or readmission [1]. Moreover, some symptoms reported by patients may be undetected or underestimated by clinicians [2] and some conditions may fail to manifest with clinical or biochemical abnormalities, complicating clinical assessment. Patient-reported outcome measures (PROMs) are patient-completed tools that assess the patients’ perception of their disease severity, quality of life or well-being, or a combination of these. Since PROMs were initially developed for research use, many regulatory authorities advocate their use [3, 4]. As more proactive clinicians recognized their benefit to clinical management, PROMs have gained additional use in routine clinical practice [5]. The medical profession is now increasingly recognizing that as well as measuring clinical outcomes, that it is also important to measure PROMs as part of patient assessment. Consequentially, an increase in the development, validation, and use of PROMs has occurred. The King’s Fund report reflects on this as ‘‘a growing recognition throughout the world that the patient’s perspective is highly relevant to efforts to improve the quality and effectiveness of health care’’ and that PROMs are likely to become ‘‘a key part of how all health care is funded, provided, and managed’’ [1]. In 2009, the UK Government implemented the routine collection of PROMs in England for four routine elective surgical procedures—hip and knee replacement, groin hernia repair, and varicose vein surgery (http://content. digital.nhs.uk/proms) in order to compare performance. It is likely that this will be extended to more conditions in the future. In order to provide meaningful information, PROMs need to be appropriately developed and validated according to robust criteria [6]. PROMs are normally used to examine the impact a disease state has on a patient’s emotional, physical, social, functional, and family well-being. As the population ages, there are increasing numbers of patients living with the consequences of diseases and their treatment. It is therefore becoming more important to assess the impact of the disease from the patient perspective and to evaluate how a disease affects the patient at any juncture, enabling better targeted treatment and care. Although the benefit of using PROMs as part of routine clinical care is apparent, there are practical challenges that may limit its widespread integration into clinical practice. The first of these relates to the most appropriate tool to apply to the patient population. Although a plethora of PROMs exist for many conditions, many PROMs: are not robustly validated; may have limited generalizability; may not be sensitive enough to detect changes in a patient’s condition; are long and require excessive time to complete; use terms that are difficult to understand for patients; or have detailed scoring systems complicating application to short clinical consultation. Furthermore, collecting this information also presupposes that the patients can complete & Hayley A. Hutchings h.a.hutchings@swansea.ac.uk

Psychometric development of the Gastrointestinal Symptom Rating Questionnaire (GSRQ) demonstrated good validity

OBJECTIVES To develop and validate a gastrointestinal (GI) symptom rating questionnaire for patients with luminal GI symptoms including where no diagnosis has been made. STUDY DESIGN AND SETTING We developed and validated the Gastrointestinal Symptom Rating Questionnaire (GSRQ) in three stages: (1) item generation to identify the relevant items for scale inclusion; (2) development and piloting on patients with a known GI disorder; and (3) testing in a sample of trial patients. We examined the underlying dimensions of the scale, internal consistency, validity, reproducibility, and responsiveness. RESULTS We identified four interpretable factors on the GSRQ. The GSRQ had good internal consistency (corrected item-subscale correlations between 0.4 and 0.8) and Cronbachs alpha greater than 0.7 for each subscale. Construct validity was demonstrated by modest but significant correlations with the Short Form 36 and the EQ5D index value. We demonstrated good reproducibility with intraclass correlations for test-retest scores between 0.71 and 0.77, and significant responsiveness ratios for all subscales in patients who had improved, and in two of the subscales in patients who had deteriorated. CONCLUSION The GSRQ could be a useful tool to monitor quality of life in various luminal GI conditions and where a formal diagnosis has not been made.