SaFaRI: sacral nerve stimulation versus the FENIX magnetic sphincter augmentation for adult faecal incontinence: a randomised investigation.

PURPOSE: Faecal incontinence is a physically, psychologically and socially disabling condition. NICE guidance (2007) recommends surgical intervention, including sacral nerve stimulation (SNS), after failed conservative therapies. The FENIX magnetic sphincter augmentation (MSA) device is a novel continence device consisting of a flexible band of interlinked titanium beads with magnetic cores that is placed around the anal canal to augment anal sphincter tone through passive attraction of the beads. Preliminary studies suggest the FENIX MSA is safe, but efficacy data is limited. Rigorous evaluation is required prior to widespread adoption. METHOD AND DESIGN: The SaFaRI trial is a National Institute of Health Research (NIHR) Health Technology Assessment (HTA)-funded UK multi-site, parallel group, randomised controlled, unblinded trial that will investigate the use of the FENIX MSA, as compared to SNS, for adult faecal incontinence resistant to conservative management. Twenty sites across the UK, experienced in the treatment of faecal incontinence, will recruit 350 patients randomised equally to receive either SNS or FENIX MSA. Participants will be followed-up at 2 weeks post-surgery and at 6, 12 and 18 months post-randomisation. The primary endpoint is success, as defined by device in use and ≥50 % improvement in the Cleveland Clinic Incontinence Score (CCIS) at 18 months post-randomisation. Secondary endpoints include complications, quality of life and cost effectiveness. DISCUSSION: SaFaRI will rigorously evaluate a new technology for faecal incontinence, the FENIX™ MSA, allowing its safe and controlled introduction into current clinical practice. These results will inform the future surgical management of adult faecal incontinence.

Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial.

BACKGROUND: Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer. METHODS: In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m(2) intravenous irinotecan every 3 weeks (300 mg/m(2) if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876. RESULTS: Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12-13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83-1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64-0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 [21]% vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group. INTERPRETATION: Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents. FUNDING: Cancer Research UK, Amgen Inc.

Acceptance and Commitment Therapy to support medication decision-making and quality of life in women with breast cancer: protocol for a pilot randomised controlled trial.

BACKGROUND: Adherence to adjuvant endocrine therapy is affected by medication side-effects and associated distress. Previous interventions focused on educating women to enhance adherence have proved minimally effective. We co-designed an Acceptance and Commitment Therapy (ACT) intervention to enhance medication decision-making and quality of life by targeting a broader range of factors, including side-effect management and psychological flexibility. This study aims to establish key trial parameters, assess the acceptability of the intervention and the extent to which it can be delivered with fidelity, and to demonstrate "proof of principle" regarding its efficacy on primary and process outcomes. METHODS: The ACTION intervention includes an individual 1:1 ACT session followed by three group sessions involving 8-10 women and two practitioner psychologists. Participants are also provided with access to a website containing evidence-based methods for self-managing side-effects. The ACT sessions were adapted during the COVID-19 pandemic to be remotely delivered via video conferencing software. To evaluate the feasibility and acceptability of this intervention, a multi-site, exploratory, two-arm, individually randomised external pilot trial with a nested qualitative study will be undertaken. Eighty women with early stage breast cancer prescribed adjuvant endocrine therapy will be randomised (1:1) to receive treatment as usual or treatment as usual plus the ACTION intervention. The planned future primary outcome is medication adherence assessed by the ASK-12 measure. Progression to a phase III RCT will be based on criteria related to recruitment and follow-up rates, acceptability to patients, competency and fidelity of delivery, and proof of principle for change in medication adherence. DISCUSSION: This external pilot trial will be used to ascertain the feasibility of undertaking a future phase III RCT to definitively evaluate an ACT-based intervention to support medication taking behaviour and quality of life in women with early stage breast cancer on adjuvant endocrine therapy. TRIAL REGISTRATION: ISRCTN: 12027752. Registered 24 December 2020, https://doi.org/10.1186/ISRCTN12027752.

Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial.

BACKGROUND: MRI might improve diagnosis of breast cancer, reducing rates of reoperation. We assessed the clinical efficacy of contrast-enhanced MRI in women with primary breast cancer. METHODS: We undertook an open, parallel group trial in 45 UK centres, with 1623 women aged 18 years or older with biopsy-proven primary breast cancer who were scheduled for wide local excision after triple assessment. Patients were randomly assigned to receive either MRI (n=816) or no further imaging (807), with use of a minimisation algorithm incorporating a random element. The primary endpoint was the proportion of patients undergoing a repeat operation or further mastectomy within 6 months of random assignment, or a pathologically avoidable mastectomy at initial operation. Analysis was by intention to treat. This study is registered, ISRCTN number 57474502. FINDINGS: 816 patients were randomly assigned to MRI and 807 to no MRI. Addition of MRI to conventional triple assessment was not significantly associated with reduced a reoperation rate, with 153 (19%) needing reoperation in the MRI group versus 156 (19%) in the no MRI group, (odds ratio 0.96, 95% CI 0.75-1.24; p=0.77). INTERPRETATION: Our findings are of benefit to the NHS because they show that MRI might be unnecessary in this population of patients to reduce repeat operation rates, and could assist in improved use of NHS services. FUNDING: National Institute for Health Research's Health Technology Assessment Programme.

Clinical trial recruiters' experiences working with trial eligibility criteria: results of an exploratory, cross-sectional, online survey in the UK.

BACKGROUND: Eligibility criteria are a fundamental element of clinical trial design, defining who can and who should not participate in a trial. Problems with the design or application of criteria are known to occur and pose risks to participants' safety and trial integrity, sometimes also negatively impacting on trial recruitment and generalisability. We conducted a short, exploratory survey to gather evidence on UK recruiters' experiences interpreting and applying eligibility criteria and their views on how criteria are communicated and developed. METHODS: Our survey included topics informed by a wider programme of work at the Clinical Trials Research Unit, University of Leeds, on assuring eligibility criteria quality. Respondents were asked to answer based on all their trial experience, not only on experiences with our trials. The survey was disseminated to recruiters collaborating on trials run at our trials unit, and via other mailing lists and social media. The quantitative responses were descriptively analysed, with inductive analysis of free-text responses to identify themes. RESULTS: A total of 823 eligible respondents participated. In total, 79% of respondents reported finding problems with eligibility criteria in some trials, and 9% in most trials. The main themes in the types of problems experienced were criteria clarity (67% of comments), feasibility (34%), and suitability (14%). In total, 27% of those reporting some level of problem said these problems had led to patients being incorrectly included in trials; 40% said they had led to incorrect exclusions. Most respondents (56%) reported accessing eligibility criteria mainly in the trial protocol. Most respondents (74%) supported the idea of recruiter review of eligibility criteria earlier in the protocol development process. CONCLUSIONS: Our survey corroborates other evidence about the existence of suboptimal trial eligibility criteria. Problems with clarity were the most often reported, but the number of comments on feasibility and suitability suggest some recruiters feel eligibility criteria and associated assessments can hinder recruitment to trials. Our proposal for more recruiter involvement in protocol development has strong support and some potential benefits, but questions remain about how best to implement this. We invite other trialists to consider our other suggestions for how to assure quality in trial eligibility criteria.

Sacral nerve stimulation versus the magnetic sphincter augmentation device for adult faecal incontinence: the SaFaRI RCT.

BACKGROUND: Preliminary studies using the FENIX™ (Torax Medical, Minneapolis, MN, USA) magnetic sphincter augmentation device suggest that it is safe to use for the treatment of adult faecal incontinence, but efficacy data are limited. OBJECTIVE: To compare FENIX with sacral nerve stimulation for the treatment of adult faecal incontinence in terms of safety, efficacy, quality of life and cost-effectiveness. DESIGN, SETTING AND PARTICIPANTS: Multicentre, parallel-group, unblinded, randomised trial comparing FENIX with sacral nerve stimulation in participants suffering moderate to severe faecal incontinence. INTERVENTIONS: Participants were randomised on an equal basis to either sacral nerve stimulation or FENIX. Follow-up occurred 2 weeks postoperatively and at 6, 12 and 18 months post randomisation. MAIN OUTCOME AND MEASURE: The primary outcome was success, defined as device in use and ≥ 50% improvement in Cleveland Clinic Incontinence Score at 18 months post randomisation. Secondary outcomes included complication rates, quality of life and cost-effectiveness. Between 30 October 2014 and 23 March 2017, 99 participants were randomised across 18 NHS sites (50 participants to FENIX vs. 49 participants to sacral nerve stimulation). The median time from randomisation to FENIX implantation was 57.0 days (range 4.0-416.0 days), and the median time from randomisation to permanent sacral nerve stimulation was 371.0 days (range 86.0-918.0 days). A total of 45 out of 50 participants underwent FENIX implantation and 29 out of 49 participants continued to permanent sacral nerve stimulation. The following results are reported, excluding participants for whom the corresponding outcome was not evaluable. Overall, there was success for 10 out of 80 (12.5%) participants, with no statistically significant difference between the two groups [FENIX 6/41 (14.6%) participants vs. sacral nerve stimulation 4/39 (10.3%) participants]. At least one postoperative complication was experienced by 33 out of 45 (73.3%) participants in the FENIX group and 9 out of 40 (22.5%) participants in the sacral nerve stimulation group. A total of 15 out of 50 (30%) participants in the FENIX group ultimately had to have their device explanted. Slightly higher costs and quality-adjusted life-years (incremental = £305.50 and 0.005, respectively) were observed in the FENIX group than in the sacral nerve stimulation group. This was reversed over the lifetime horizon (incremental = -£1306 and -0.23 for costs and quality-adjusted life-years, respectively), when sacral nerve stimulation was the optimal option (net monetary benefit = -£3283), with only a 45% chance of FENIX being cost-effective. LIMITATIONS: The SaFaRI study was terminated in 2017, having recruited 99 participants of the target sample size of 350 participants. The study is, therefore, substantially underpowered to detect differences between the treatment groups, with significant uncertainty in the cost-effectiveness analysis. CONCLUSIONS: The SaFaRI study revealed inefficiencies in the treatment pathways for faecal incontinence, particularly for sacral nerve stimulation. The success of both FENIX and sacral nerve stimulation was much lower than previously reported, with high postoperative morbidity in the FENIX group. FUTURE WORK: Further research is needed to clarify the treatment pathways for sacral nerve stimulation and to determine its true clinical and cost-effectiveness. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16077538. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 18. See the NIHR Journals Library website for further project information.

Faecal incontinence is a distressing condition for patients, and surgery is recommended if symptoms are having an effect on quality of life. One of the treatments recommended for faecal incontinence by the National Institute for Health and Care Excellence is sacral nerve stimulation, which aims to improve continence by stimulating the nerves to the back passage. A newer treatment involves surgery to implant a string of magnetic beads around the anal canal using the FENIX™ device (Torax Medical, Minneapolis, MN, USA). The aim of this study was to assess the benefits and risks of the FENIX device compared with sacral nerve stimulation. The SaFaRI study aimed to recruit 350 participants with faecal incontinence, but was stopped early because of the manufacturer withdrawing the FENIX device for strategic reasons. In total, we recruited 99 participants. Fifty participants were allocated to receive the FENIX device and 49 participants were allocated to receive sacral nerve stimulation. The observed success rates with both devices were low: at 18 months following their entry into the study, 6 out of 41 (14.6%) participants in the FENIX group and 4 out of 39 (10.3%) participants in the sacral nerve stimulation group had the device both in use and producing a benefit. A total of 5 out of 50 (10.0%) participants allocated to receive the FENIX device did not have a device implanted, and 15 out of 45 (33.3%) participants who did have the FENIX device implanted needed to have it removed because of complications during the 18-month follow-up period. A total of 21 out of 49 (42.9%) participants allocated to receive sacral nerve stimulation did not have a permanent sacral nerve stimulation device implanted, and 0 of the 28 who did have a permanent sacral nerve stimulation device implanted needed to have it removed during the 18-month follow-up period. The costs associated with the FENIX device were higher because of a greater number of participants experiencing complications, meaning that the FENIX device is unlikely to be cost-effective in the treatment of faecal incontinence compared with sacral nerve stimulation.

Liver resection surgery versus thermal ablation for colorectal LiVer MetAstases (LAVA): study protocol for a randomised controlled trial.

BACKGROUND: Although surgical resection has been considered the only curative option for colorectal liver metastases (CLM), thermal ablation has recently been suggested as an alternative curative treatment. A prospective randomised trial is required to define the efficacy of resection vs ablation for the treatment of colorectal liver metastases. METHODS: Design and setting: This is a multicentre, open, randomised controlled non-inferiority trial design with internal pilot and will be performed in tertiary liver centres in UK and The Netherlands. PARTICIPANTS: Eligible patients will be those with colorectal liver metastases at high surgical risk because of their age, co-morbidities or tumour burden and who would be suitable for liver resection or thermal ablation. INTERVENTION: Thermal ablation as per local policy. CONTROL: Surgical liver resection performed as per centre protocol. Co-interventions: Further chemotherapy will be offered to patients as per current practice. Outcomes Pilot study: Same as main study and in addition patients and clinicians' acceptability of the trial to assist in optimisation of recruitment. PRIMARY OUTCOME: Disease-free survival (DFS) at two years post randomisation. SECONDARY OUTCOMES: Overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, DFS measured from end of intervention. FOLLOW-UP: 24 months from randomisation; five-year follow-up for overall survival. SAMPLE SIZE: 330 patients to demonstrate non-inferiority of thermal ablation. DISCUSSION: This trial will determine the effectiveness and cost-effectiveness of thermal ablation vs surgical resection for high-risk people with colorectal liver metastases, and guide the optimal treatment for these patients. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN52040363 . Registered on 9 March 2016.

Comparative costs and activity from a sample of UK clinical trials units.

BACKGROUND: The costs of medical research are a concern. Clinical Trials Units (CTUs) need to better understand variations in the costs of their activities. METHODS: Representatives of ten CTUs and two grant-awarding bodies pooled their experiences in discussions over 1.5 years. Five of the CTUs provided estimates of, and written justification for, costs associated with CTU activities required to implement an identical protocol. The protocol described a 5.5-year, nonpharmacological randomized controlled trial (RCT) conducted at 20 centres. Direct and indirect costs, the number of full time equivalents (FTEs) and the FTEs attracting overheads were compared and qualitative methods (unstructured interviews and thematic analysis) were used to interpret the results. Four members of the group (funding-body representatives or award panel members) reviewed the justification statements for transparency and information content. Separately, 163 activities common to trials were assigned to roles used by nine CTUs; the consistency of role delineation was assessed by Cohen's κ. RESULTS: Median full economic cost of CTU activities was £769,637 (range: £661,112 to £1,383,323). Indirect costs varied considerably, accounting for between 15% and 59% (median 35%) of the full economic cost of the grant. Excluding one CTU, which used external statisticians, the total number of FTEs ranged from 2.0 to 3.0; total FTEs attracting overheads ranged from 0.3 to 2.0. Variation in directly incurred staff costs depended on whether CTUs: supported particular roles from core funding rather than grants; opted not to cost certain activities into the grant; assigned clerical or data management tasks to research or administrative staff; employed extensive on-site monitoring strategies (also the main source of variation in non-staff costs). Funders preferred written justifications of costs that described both FTEs and indicative tasks for funded roles, with itemised non-staff costs. Consistency in role delineation was fair (κ = 0.21-0.40) for statisticians/data managers and poor for other roles (κ < 0.20). CONCLUSIONS: Some variation in costs is due to factors outside the control of CTUs such as access to core funding and levels of indirect costs levied by host institutions. Research is needed on strategies to control costs appropriately, especially the implementation of risk-based monitoring strategies.

Psychometric properties of the Body Image Scale in women with benign gynaecological conditions.

OBJECTIVES: To evaluate the psychometric properties of the Body Image Scale (originally designed for use in cancer) in women with benign gynaecological conditions. STUDY DESIGN: Prospective completion of the Body Image Scale by women participating in the EVALUATE Hysterectomy Trial. The scale was completed pre-operatively, then 6 weeks, 4 and 12 months post-operatively. The psychometric properties were evaluated by assessing the reliability, response prevalence, discriminant validity and sensitivity to change. Factor analysis was also conducted to determine the scale structure. RESULTS: The Body Image Scale showed good reliability and clinical validity. Differences between sub-groups of women were detected, demonstrating good discriminant validity. The Body Image Scale was shown to be responsive to changes in body image. CONCLUSIONS: The Body Image Scale was shown to be a reliable and valid tool for assessing body image in women with benign gynaecological conditions and for use in clinical trials involving such women.

A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO).

BACKGROUND: The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan. METHODS: Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation. RESULTS: The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference. INTERPRETATION: The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC. FUNDING: The trial was funded by Cancer Research UK and supported by Amgen Pharma.

The eVALuate study: two parallel randomised trials, one comparing laparoscopic with abdominal hysterectomy, the other comparing laparoscopic with vaginal hysterectomy.

OBJECTIVE: To compare the effects of laparoscopic hysterectomy and abdominal hysterectomy in the abdominal trial, and laparoscopic hysterectomy and vaginal hysterectomy in the vaginal trial. DESIGN: Two parallel, multicentre, randomised trials. SETTING: 28 UK centres and two South African centres. PARTICIPANTS: 1380 women were recruited; 1346 had surgery; 937 were followed up at one year. Primary outcome Rate of major complications. RESULTS: In the abdominal trial laparoscopic hysterectomy was associated with a higher rate of major complications than abdominal hysterectomy (11.1% v 6.2%, P = 0.02; difference 4.9%, 95% confidence interval 0.9% to 9.1%) and the number needed to treat to harm was 20. Laparoscopic hysterectomy also took longer to perform (84 minutes v 50 minutes) but was less painful (visual analogue scale 3.51 v 3.88, P = 0.01) and resulted in a shorter stay in hospital after the operation (3 days v 4 days). Six weeks after the operation, laparoscopic hysterectomy was associated with less pain and better quality of life than abdominal hysterectomy (SF-12, body image scale, and sexual activity questionnaires). In the vaginal trial we found no evidence of a difference in major complication rates between laparoscopic hysterectomy and vaginal hysterectomy (9.8% v 9.5%, P = 0.92; difference 0.3%, -5.2% to 5.8%), and the number needed to treat to harm was 333. We found no evidence of other differences between laparoscopic hysterectomy and vaginal hysterectomy except that laparoscopic hysterectomy took longer to perform (72 minutes v 39 minutes) and was associated with a higher rate of detecting unexpected pathology (16.4% v 4.8%, P = < 0.01). However, this trial was underpowered. CONCLUSIONS: Laparoscopic hysterectomy was associated with a significantly higher rate of major complications than abdominal hysterectomy. It also took longer to perform but was associated with less pain, quicker recovery, and better short term quality of life. The trial comparing vaginal hysterectomy with laparoscopic hysterectomy was underpowered and is inconclusive on the rate of major complications; however, vaginal hysterectomy took less time.