Claire Cochran

The effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle-closure glaucoma (EAGLE): Study protocol for a randomized controlled trial

BackgroundGlaucoma is the leading cause of irreversible blindness. Although primary open-angle glaucoma is more common, primary angle-closure glaucoma (PACG) is more likely to result in irreversible blindness. By 2020, 5·3 million people worldwide will be blind because of PACG. The current standard care for PACG is a stepped approach of a combination of laser iridotomy surgery (to open the drainage angle) and medical treatment (to reduce intraocular pressure). If these treatments fail, glaucoma surgery (eg, trabeculectomy) is indicated. It has been proposed that, because the lens of the eye plays a major role in the mechanisms leading to PACG, early clear lens extraction will improve glaucoma control by opening the drainage angle. This procedure might reduce the need for drugs and glaucoma surgery, maintain good visual acuity, and improve quality of life compared with standard care.EAGLE aims to evaluate whether early lens extraction improves patient-reported, clinical outcomes, and cost-effectiveness, compared with standard care.Methods/DesignEAGLE is a multicentre pragmatic randomized trial. All people presenting to the recruitment centres in the UK and east Asia with newly diagnosed PACG and who are at least 50 years old are eligible.The primary outcomes are EQ-5D, intraocular pressure, and incremental cost per quality adjusted life year (QALY) gained. Other outcomes are: vision and glaucoma-specific patient-reported outcomes, visual acuity, visual field, angle closure, number of medications, additional surgery (e.g., trabeculectomy), costs to the health services and patients, and adverse events.A single main analysis will be done at the end of the trial, after three years of follow-up. The analysis will be based on all participants as randomized (intention to treat). 400 participants (200 in each group) will be recruited, to have 90% power at 5% significance level to detect a difference in EQ-5D score between the two groups of 0·05, and a mean difference in intraocular pressure of 1·75 mm Hg. The study will have 80% power to detect a difference of 15% in the glaucoma surgery rate. Trial Registration: ISRCTN44464607.

Biopsy and selective recall compared with immediate large loop excision in management of women with low grade abnormal cervical cytology referred for colposcopy: multicentre randomised controlled trial

Objectives To compare the effectiveness of punch biopsy and selective recall for treatment versus a policy of immediate treatment by large loop excision in the management of women with low grade abnormal cervical cytology referred for colposcopy. Design Multicentre individually randomised controlled trial, nested within the NHS cervical screening programmes. Setting Grampian, Tayside, and Nottingham. Participants 1983 women, aged 20-59, with cytology showing borderline nuclear abnormalities or mild dyskaryosis, October 1999-October 2002. Interventions Immediate large loop excision or up to four targeted punch biopsies taken immediately with recall for treatment (by large loop excision) if these showed cervical intraepithelial neoplasia grade II or III or worse. Participants were followed for three years, concluding with an exit colposcopy. Main outcome measures Clinical end points: cumulative incidence of cervical intraepithelial neoplasia grade II or worse and grade III or worse at three years. Clinically significant anxiety and depression and self reported after effects assessed six weeks after colposcopy, biopsies, or large loop excision. Results 879 women (44%) had a normal transformation zone at colposcopy and had no further procedures at that time. Colposcopists were less likely to classify the transformation zone as abnormal when the allocation was large loop excision (603 (60%) in the biopsy and selective recall group; 501 (51%) in the immediate large loop excision group). Of women randomised to biopsy and recall, 157 (16%) required a second clinic visit for treatment. Specimens from almost 60% (n=296) of women who underwent immediate large loop excision showed no cervical intraepithelial neoplasia (31%; n=156) or showed cervical intraepithelial neoplasia grade I (28%; n=140). The percentages of women diagnosed with grade II or worse up to and including the exit examination were 22% (n=216) in the biopsy and recall arm and 23% (n=228) in the immediate large loop excision arm. There was no significant difference between the arms in cumulative incidence of cervical intraepithelial neoplasia grade II or worse (adjusted relative for risk large loop excision v biopsy 1.04, 95% confidence interval 0.86 to 1.25) or grade III or worse (1.03, 0.79 to 1.34). A greater proportion of disease was detected at initial investigation and less during follow-up and at exit in the immediate large loop excision arm, but time of detection did not differ significantly between arms. Levels of anxiety and depression and reported pain did not differ between arms. Higher proportions of women randomised to large loop excision reported moderate or more severe bleeding and discharge. Conclusion A policy of targeted punch biopsies with subsequent treatment for cervical intraepithelial neoplasia grade II or III and cytological surveillance for grade I or less provides the best balance between benefits and harms for the management of women with low grade abnormal cytology referred for colposcopy. Immediate large loop excision results in overtreatment and more after effects and should not be recommended. Trial Registration ISRCTN 34841617.

Developing a pelvic floor muscle training regimen for use in a trial intervention

This paper explains the rationale behind the intervention used for a large multi-centred randomised controlled trial for men following transurethral resection of prostate or radical prostatectomy. It shows the content of the protocol used and explains why this particular protocol of pelvic floor muscle exercises and urge suppression techniques was chosen for men in the intervention group. The trial will evaluate whether this intervention will be effective for men with urinary incontinence and sexual dysfunction after prostate surgery. ISRCTN number: ISRCTN87696430.

Conservative treatment for urinary incontinence in Men After Prostate Surgery (MAPS): two parallel randomised controlled trials.

OBJECTIVE To determine the clinical effectiveness and cost-effectiveness of active conservative treatment, compared with standard management, in regaining urinary continence at 12 months in men with urinary incontinence at 6 weeks after a radical prostatectomy or a transurethral resection of the prostate (TURP). BACKGROUND Urinary incontinence after radical prostate surgery is common immediately after surgery, although the chance of incontinence is less after TURP than following radical prostatectomy. DESIGN Two multicentre, UK, parallel randomised controlled trials (RCTs) comparing active conservative treatment [pelvic floor muscle training (PFMT) delivered by a specialist continence physiotherapist or a specialist continence nurse] with standard management in men after radial prostatectomy and TURP. SETTING Men having prostate surgery were identified in 34 centres across the UK. If they had urinary incontinence, they were invited to enroll in the RCT. PARTICIPANTS Men with urinary incontinence at 6 weeks after prostate surgery were eligible to be randomised if they consented and were able to comply with the intervention. INTERVENTIONS Eligible men were randomised to attend four sessions with a therapist over a 3-month period. The therapists provided standardised PFMT and bladder training for male urinary incontinence and erectile dysfunction. The control group continued with standard management. MAIN OUTCOME MEASURES The primary outcome of clinical effectiveness was urinary incontinence at 12 months after randomisation, and the primary measure of cost-effectiveness was incremental cost per quality-adjusted life-year (QALY). Outcome data were collected by postal questionnaires at 3, 6, 9 and 12 months. RESULTS Within the radical group (n = 411), 92% of the men in the intervention group attended at least one therapy visit and were more likely than those in the control group to be carrying out any PFMT at 12 months {adjusted risk ratio (RR) 1.30 [95% confidence interval (CI) 1.09 to 1.53]}. The absolute risk difference in urinary incontinence rates at 12 months between the intervention (75.5%) and control (77.4%) groups was -1.9% (95% CI -10% to 6%). NHS costs were higher in the intervention group [£ 181.02 (95% CI £ 107 to £ 255)] but there was no evidence of a difference in societal costs, and QALYs were virtually identical for both groups. Within the TURP group (n = 442), over 85% of men in the intervention group attended at least one therapy visit and were more likely to be carrying out any PFMT at 12 months after randomisation [adjusted RR 3.20 (95% CI 2.37 to 4.32)]. The absolute risk difference in urinary incontinence rates at 12 months between the intervention (64.9%) and control (61.5%) groups for the unadjusted intention-to-treat analysis was 3.4% (95% CI -6% to 13%). NHS costs [£ 209 (95% CI £ 147 to £ 271)] and societal costs [£ 420 (95% CI £ 54 to £ 785)] were statistically significantly higher in the intervention group but QALYs were virtually identical. CONCLUSIONS The provision of one-to-one conservative physical therapy for men with urinary incontinence after prostate surgery is unlikely to be effective or cost-effective compared with standard care that includes the provision of information about conducting PFMT. Future work should include research into the value of different surgical options in controlling urinary incontinence.

After-effects reported by women having follow-up cervical cytology tests in primary care: a cohort study within the TOMBOLA trial

BACKGROUND Although it is recognised that some women experience pain or bleeding during a cervical cytology test, few studies have quantified physical after-effects of these tests. AIM To investigate the frequency, severity, and duration of after-effects in women undergoing follow-up cervical cytology tests, and to identify subgroups with higher frequencies in Grampian, Tayside, and Nottingham. DESIGN Cohort study nested with a multi-centre individually randomised controlled trial. METHOD The cohort included 1120 women, aged 20-59 years, with low-grade abnormal cervical cytology who completed a baseline sociodemographic questionnaire and had a follow-up cervical cytology test in primary care 6 months later. Six weeks after this test, women completed a postal questionnaire on pain, bleeding, and discharge experienced after the test, including duration and severity. The adjusted prevalence of each after-effect was computed using logistic regression. RESULTS A total of 884 women (79%) completed the after-effects questionnaire; 30% of women experienced one or more after-effect: 15% reported pain, 16% bleeding, and 7% discharge. The duration of discharge was ≤2 days for 66%, 3-6 days for 22%, and ≥7 days for 11% of women. Pain or bleeding lasted ≤2 days in more than 80% of women. Severe after-effects were reported by <1% of women. The prevalence of pain decreased with increasing age. Bleeding was more frequent among nulliparous women. Discharge was more common among oral contraceptive users. CONCLUSION Pain, bleeding, and discharge are not uncommon in women having follow-up cervical cytology tests. Informing women about possible after-effects could better prepare them and provide reassurance, thereby minimising potential non-adherence with follow-up or non-participation with screening in the future.

Early lens extraction with intraocular lens implantation for the treatment of primary angle closure glaucoma: An economic evaluation based on data from the EAGLE trial

Objective To investigate the cost-effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle closure glaucoma (PACG) compared to standard care. Design Cost-effectiveness analysis alongside a multicentre pragmatic two-arm randomised controlled trial. Patients were followed-up for 36 months, and data on health service usage and health state utility were collected and analysed within the trial time horizon. A Markov model was developed to extrapolate the results over a 5-year and 10-year time horizon. Setting 22 hospital eye services in the UK. Population Males and females aged 50 years or over with newly diagnosed PACG or primary angle closure (PAC). Interventions Lens extraction compared to standard care (ie, laser iridotomy followed by medical therapy and glaucoma surgery). Outcome measures Costs of primary and secondary healthcare usage (UK NHS perspective), quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) for lens extraction versus standard care. Results The mean age of participants was 67.5 (8.42), 57.5% were women, 44.6% had both eyes eligible, 1.4% were of Asian ethnicity and 35.4% had PAC. The mean health service costs were higher in patients randomised to lens extraction: £2467 vs £1486. The mean adjusted QALYs were also higher with early lens extraction: 2.602 vs 2.533. The ICER for lens extraction versus standard care was £14 284 per QALY gained at three years. Modelling suggests that the ICER may drop to £7090 per QALY gained by 5 years and that lens extraction may be cost saving by 10 years. Our results are generally robust to changes in the key input parameters and assumptions. Conclusions We find that lens extraction has a 67–89% chance of being cost-effective at 3 years and that it may be cost saving by 10 years. Trial registration number ISRCTN44464607; Results.

'No collaboration, no trial; why collaborator opinion matters'

For a trial to be successful, site personnel must retain high commitment to a trial often over long periods of time. Little evidence exists, however, to guide what type of communication/training activities should be adopted to help promote long-term collaboration. In this presentation, we report the role of focus groups to inform the appropriate choice of communication/training activities for a large international study. EAGLE (Effectiveness, in Angle closure Glaucoma, of Lens Extraction) is an international multi-centre, pragmatic, randomised controlled trial (RCT). Within EAGLE trial data from participant questionnaires and clinical case report forms are uploaded onto the bespoke EAGLE website by collaborators at 31 sites worldwide. In order to elicit useful experiences and opinions from collaborators to inform future trial procedures, focus groups were conducted during a trial training event. Group training days, rather than individual visits, were preferred as they provide an opportunity to network with peers and focus on the trial away from distraction of the everyday environment. Collaborator newsletters remain a popular way of maintaining trial profile at a group level; at individual level distributing tasks by regular brief emails encourages engagement. Web based data entry gives collaborators a sense of ownership over the data they collect, but thoughtful website design and (telephone) support is key to maintaining data quality. Collaborators like trials that mimic standard clinical care; they are perceived easier to recruit and retain patients than other explanatory trials. Barriers included complexity of the inclusion and exclusion criteria, and issues with local financial support.