Two parallel,pragmatic, UK multicentre,randomised controlled trials comparing surgical options for upper compartment (vault or uterine) pelvic organ prolapse (the VUE Study): study protocol for a randomised controlled trial

BackgroundOne in three women who have a prolapse operation will go on to have another operation, though not necessarily in the same compartment. Surgery can result in greater impairment of quality of life than the original prolapse itself (such as the development of new-onset urinary incontinence, or prolapse at a different site). Anterior and posterior prolapse surgery is most common (90 % of operations), but around 43 % of women also have a uterine (34 %) or vault (9 %) procedure at the same time. There is not enough evidence from randomised controlled trials (RCTs) to guide management of vault or uterine prolapse. The Vault or Uterine prolapse surgery Evaluation (VUE) study aims to assess the surgical management of upper compartment pelvic organ prolapse (POP) in terms of clinical effectiveness, cost-effectiveness and adverse events.Methods/designVUE is two parallel, pragmatic, UK multicentre, RCTs (Uterine Trial and Vault Trial). Eligible for inclusion are women with vault or uterine prolapse: requiring a surgical procedure, suitable for randomisation and willing to be randomised. Randomisation will be computer-allocated separately for each trial, minimised on: requiring concomitant anterior and/or posterior POP surgery or not, concomitant incontinence surgery or not, age (under 60 years or 60 years and older) and surgeon. Participants will be randomly assigned, with equal probability to intervention or control arms in either the Uterine Trial or the Vault Trial. Uterine Trial participants will receive either a vaginal hysterectomy or a uterine preservation procedure. Vault Trial participants will receive either a vaginal sacrospinous fixation or an abdominal sacrocolpopexy. Participants will be followed up by postal questionnaires (6 months post surgery and 12 months post randomisation) and also reviewed in clinic 12 months post surgery. The primary outcome is the participant-reported Pelvic Organ Prolapse Symptom Score (POP-SS) at 12 months post randomisation.DiscussionDemonstrating the efficacy of vault and uterine prolapse surgeries is relevant not only to patients and clinicians but also to health care providers, both in the UK and globally.

Trial registration

Current controlled trials ISRCTN86784244 (assigned 19 October 2012), and the first subject was randomly assigned on 1 May 2013 

Electronic supplementary material

The online version of this article (doi:10.1186/s13063-016-1576-x) contains supplementary material, which is available to authorized users.     

The Cessation in Pregnancy Incentives Trial (CPIT): study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Seventy percent of women in Scotland have at least one baby, making pregnancy an opportunity to help most young women quit smoking before their own health is irreparably compromised. By quitting during pregnancy their infants will be protected from miscarriage and still birth as well as low birth weight, asthma, attention deficit disorder and adult cardiovascular disease. In the UK, the NICE guidelines: 'How to stop smoking in pregnancy and following childbirth' (June 2010) highlighted that little evidence exists in the literature to confirm the efficacy of financial incentives to help pregnant smokers to quit. Its first research recommendation was to determine: Within a UK context, are incentives an acceptable, effective and cost-effective way to help pregnant women who smoke to quit? Design and Methods This study is a phase II exploratory individually randomised controlled trial comparing standard care for pregnant smokers with standard care plus the additional offer of financial voucher incentives to engage with specialist cessation services and/or to quit smoking during pregnancy. Participants (n=600) will be pregnant smokers identified at maternity booking who when contacted by specialist cessation services agree to having their details passed to the NHS Smokefree Pregnancy Study Helpline to discuss the trial. The NHS Smokefree Pregnancy Study Helpline will be responsible for telephone consent and follow-up in late pregnancy. The primary outcome will be self reported smoking in late pregnancy verified by cotinine measurement. An economic evaluation will refine cost data collection and assess potential cost-effectiveness while qualitative research interviews with clients and health professionals will assess the level of acceptance of this form of incentive payment. Research questions What is the likely therapeutic efficacy? Are incentives potentially cost-effective? Is individual randomisation an efficient trial design without introducing outcome bias? Can incentives be introduced in a way that is feasible and acceptable? DISCUSSION: This phase II trial will establish a workable design to reduce the risks associated with a future definitive phase III multicentre randomised controlled trial and establish a framework to assess the costs and benefits of financial incentives to help pregnant smokers to quit. Trial registration: Current Controlled Trials ISRCTN87508788 350 words.     

The addition of a goal-based motivational interview to standardised treatment as usual to reduce dropouts in a service for patients with personality disorder: a feasibility study

Background

Verrucae are a common, infectious and sometimes painful problem. The optimal treatment for verrucae is unclear due to a lack of high quality randomised controlled trials. The primary objective of this study is to compare the clinical effectiveness of two common treatments for verrucae: cryotherapy using liquid nitrogen versus salicylic acid. Secondary objectives include a comparison of the cost-effectiveness of the treatments, and an investigation of time to clearance of verrucae, recurrence/clearance of verrucae at six months, patient satisfaction with treatment, pain associated with treatment, and use of painkillers for the treatments.

Methods/Design

This is an open, pragmatic, multicentre, randomised controlled trial with two parallel groups: cryotherapy using liquid nitrogen delivered by a healthcare professional for a maximum of 4 treatments (treatments 2-3 weeks apart) or daily self-treatment with 50% salicylic acid for a maximum of 8 weeks. Two hundred and sixty-six patients aged 12 years and over with a verruca are being enrolled into the study. The primary outcome is complete clearance of all verrucae as observed on digital photographs taken at 12 weeks compared with baseline and assessed by an independent healthcare professional. Secondary outcomes include self-reported time to clearance of verrucae, self-reported clearance of verrucae at 6 months, cost-effectiveness of the treatments compared to one another, and patient acceptability of both treatments including possible side effects such as pain. The primary analysis will be intention to treat. It is planned that recruitment will be completed by December 2009 and results will be available by June 2010.

Trial registration

Current Controlled Trials ISRCTN18994246.     

A cluster randomised controlled trial of an occupational therapy intervention for residents with stroke living in UK care homes (OTCH): study protocol

ABSTRACT: BACKGROUND: The occupational therapy (OT) in care homes study (OTCH) aims to investigate the effect of a targeted course of individual OT (with task training, provision of adaptive equipment, minor environmental adaptations and staff education) for stroke survivors living in care homes, compared to usual care. METHODS/DESIGN: A cluster randomised controlled trial of United Kingdom (UK) care homes (n?=?90) with residents (n?=?900) who have suffered a stroke or transient ischaemic attack (TIA), and who are not receiving end-of-life care. Homes will be stratified by centre and by type of care provided and randomised (50:50) using computer generated blocked randomisation within strata to receive either the OT intervention (3 months intervention from an occupational therapist) or control (usual care). Staff training on facilitating independence and mobility and the use of adaptive equipment, will be delivered to every home, with control homes receiving this after the 12 month follow-up.Allocation will be concealed from the independent assessors, but the treating therapists, and residents will not be masked to the intervention. Measurements are taken at baseline prior to randomisation and at 3, 6 and 12 months post randomisation. The primary outcome measure is independence in self-care activities of daily living (Barthel Activities of Daily Living Index). Secondary outcome measures are mobility (Rivermead Mobility Index), mood (Geriatric Depression Scale), preference based quality of life measured from EQ-5D and costs associated with each intervention group. Quality adjusted life years (QALYs) will be derived based on the EQ-5D scores. Cost effectiveness analysis will be estimated and measured by incremental cost effectiveness ratio. Adverse events will be recorded. DISCUSSION: This study will be the largest cluster randomised controlled trial of OT in care homes to date and will clarify the currently inconclusive literature on the efficacy of OT for stroke and TIA survivors residing in care homes. TRIAL REGISTRATION: ISRCTN00757750.     

Study protocol: The Adherence and Intensification of Medications (AIM) study - a cluster randomized controlled effectiveness study

Background

Each year, worldwide about 530,000 women die from causes related to pregnancy and childbirth. Of the deaths 99% are in low and middle income countries. Obstetric haemorrhage is the leading cause of maternal mortality, most occurring in the postpartum period. Systemic antifibrinolytic agents are widely used in surgery to prevent clot breakdown (fibrinolysis) in order to reduce surgical blood loss. At present there is little reliable evidence from randomised trials on the effectiveness of tranexamic acid in the treatment of postpartum haemorrhage.

Methods

The Trial aims to determine the effect of early administration of tranexamic acid on mortality, hysterectomy and other morbidities (surgical interventions, blood transfusion, risk of non-fatal vascular events) in women with clinically diagnosed postpartum haemorrhage. The use of health services and safety, especially thromboembolic effect, on breastfed babies will also be assessed. The trial will be a large, pragmatic, randomised, double blind, placebo controlled trial among 15,000 women with a clinical diagnosis of postpartum haemorrhage. All legally adult women with clinically diagnosed postpartum haemorrhage following vaginal delivery of a baby or caesarean section will potentially be eligible. The fundamental eligibility criterion is the responsible clinician's 'uncertainty' as to whether or not to use an antifibrinolytic agent in a particular woman with postpartum haemorrhage. Treatment will entail a dose of tranexamic acid (1 gram by intravenous injection) or placebo (sodium chloride 0.9%) will be given as soon as possible after randomisation. A second dose may be given if after 30 minutes bleeding continues, or if it stops and restarts within 24 hours after the first dose. The main analyses will be on an 'intention to treat' basis, irrespective of whether the allocated treatment was received or not. Subgroup analyses for the primary outcome will be based on type of delivery; administration or not of prophylactic uterotonics; and on whether the clinical decision to consider trial entry was based primarily on estimated blood loss alone or on haemodynamic instability. A study with 15,000 women will have over 90% power to detect a 25% reduction from 4% to 3% in the primary endpoint of mortality or hysterectomy.

Trial registration

Current Controlled Trials: ISRCTN76912190 and Clinicaltrials.gov ID: NCT00872469     

Gabapentin for the Management of Chronic Pelvic Pain in Women (GaPP1): A Pilot Randomised Controlled Trial

Chronic pelvic pain (CPP) affects 2.1–24% of women. Frequently, no underlying pathology is identified, and the pain is difficult to manage. Gabapentin is prescribed for CPP despite no robust evidence of efficacy. We performed a pilot trial in two UK centres to inform the planning of a future multicentre RCT to evaluate gabapentin in CPP management. Our primary objective was to determine levels of participant recruitment and retention. Secondary objectives included estimating potential effectiveness, acceptability to participants of trial methodology, and cost-effectiveness of gabapentin. Women with CPP and no obvious pelvic pathology were assigned to an increasing regimen of gabapentin (300-2700mg daily) or placebo. We calculated the proportion of eligible women randomised, and of randomised participants who were followed up to six months. The analyses by treatment group were by intention-to-treat. Interviews were conducted to evaluate women’s experiences of the trial. A probabilistic decision analytical model was used to estimate cost-effectiveness. Between September 2012–2013, 47 women (34% of those eligible) were randomised (22 to gabapentin, 25 to placebo), and 25 (53%) completed six-month follow-up. Participants on gabapentin had less pain (BPI difference 1.72 points, 95% CI:0.07–3.36), and an improvement in mood (HADS difference 4.35 points, 95% CI:1.97–6.73) at six months than those allocated placebo. The majority of participants described their trial experience favorably. At the UK threshold for willingness-to-pay, the probabilities of gabapentin or no treatment being cost-effective are similar. A pilot trial assessing gabapentin for CPP was feasible, but uncertainty remains, highlighting the need for a large definitive trial.

Trial registration

Controlled-Trials.com ISRCTN45178534     

The effects of continuous prostacyclin infusion on regional blood flow and cerebral vasospasm following subarachnoid haemorrhage: study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: One of the main causes of mortality and morbidity following subarachnoid haemorrhage (SAH) is the development of cerebral vasospasm, a frequent complication arising in the weeks after the initial bleeding. Despite extensive research, to date no effective treatment of vasospasm exists. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. In vitro models have shown a relaxing effect of prostacyclin after induced contraction in cerebral arteries and a recent pilot trial showed positive effect on cerebral vasospasm in a clinical setting. No randomised, clinical trials have been conducted, investigating the possible pharmacodynamic effects of prostacyclin on the human brain following SAH. METHODS: This trial is a single-center, randomised, placebo controlled, parallel group, blinded, clinical, pilot trial. A total of 90 patients with SAH will be randomised to one of 3 intervention arms; epoprostenol 1 ng/kg/min, epoprostenol 2 ng/kg/min or placebo in addition to standard treatment. Trial medication will start day 5 after SAH and continue to day 10. Primary outcome measure is changes in regional cerebral blood flow from baseline in the arterial territories of the anterior cerebral artery, medial cerebral artery and the posterior cerebral artery, measured by CT perfusion scan. The secondary outcomes will be vasospasm measured by CT angiography, ischaemic parameters measured by brain microdialysis, flow velocities in the medial cerebral artery, clinical parameters and outcome (Glasgow Outcome Scale) at 3 months. CONCLUSION: The trial is an explorative, pilot trial designed to investigate the feasibility and possible effects of low-dose prostacyclin on a primary outcome of regional blood flow and vasospasm in the human brain following SAH. Trial registration: Clinicaltrials.gov NCT01447095.     

Microbicides Development Programme: design of a phase III trial to measure the efficacy of the vaginal microbicide PRO 2000/5 for HIV prevention

Background

Non-pharmacological, non-surgical interventions are recommended as the first line of treatment for osteoarthritis (OA) of the hip and knee. There is evidence that exercise therapy is effective for reducing pain and improving function in patients with knee OA, some evidence that exercise therapy is effective for hip OA, and early indications that manual therapy may be efficacious for hip and knee OA. There is little evidence as to which approach is more effective, if benefits endure, or if providing these therapies is cost-effective for the management of this disorder. The MOA Trial (Management of OsteoArthritis) aims to test the effectiveness of two physiotherapy interventions for improving disability and pain in adults with hip or knee OA in New Zealand. Specifically, our primary objectives are to investigate whether: 1. Exercise therapy versus no exercise therapy improves disability at 12 months; 2. Manual physiotherapy versus no manual therapy improves disability at 12 months; 3. Providing physiotherapy programmes in addition to usual care is more cost-effective than usual care alone in the management of osteoarthritis at 24 months.

Methods

This is a 2 × 2 factorial randomised controlled trial. We plan to recruit 224 participants with hip or knee OA. Eligible participants will be randomly allocated to receive either: (a) a supervised multi-modal exercise therapy programme; (b) an individualised manual therapy programme; (c) both exercise therapy and manual therapy; or, (d) no trial physiotherapy. All participants will continue to receive usual medical care. The outcome assessors, orthopaedic surgeons, general medical practitioners, and statistician will be blind to group allocation until the statistical analysis is completed. The trial is funded by Health Research Council of New Zealand Project Grants (Project numbers 07/199, 07/200).

Discussion

The MOA Trial will be the first to investigate the effectiveness and cost-effectiveness of providing physiotherapy programmes of this kind, for the management of pain and disability in adults with hip or knee OA.

Trial registration

Australian New Zealand Clinical Trials Registry ref: ACTRN12608000130369.     

Cluster-randomised controlled trial of community mobilisation in Mumbai slums to improve care during pregnancy, delivery, postpartum and for the newborn

Background

Chronic back pain is a major public health problem and the primary reason patients seek acupuncture treatment. Therefore, an objective assessment of acupuncture efficacy is critical for making informed decisions about its appropriate role for patients with this common condition. This study addresses methodological shortcomings that have plagued previous studies evaluating acupuncture for chronic low back pain.

Methods and Design

A total of 640 participants (160 in each of four arms) between the ages of 18 and 70 years of age who have low back pain lasting at least 3 months will be recruited from integrated health care delivery systems in Seattle and Oakland. They will be randomized to one of two forms of Traditional Chinese Medical (TCM) acupuncture needling (individualized or standardized), a "control" group (simulated acupuncture), or to continued usual medical care. Ten treatments will be provided over 7 weeks. Study participants and the "Diagnostician" acupuncturists who evaluate participants and propose individualized treatments will be masked to the acupuncture treatment actually assigned each participant. The "Therapist" acupuncturists providing the treatments will not be masked but will have limited verbal interaction with participants. The primary outcomes, standard measures of dysfunction and bothersomeness of low back pain, will be assessed at baseline, and after 8, 26, and 52 weeks by telephone interviewers masked to treatment assignment. General health status, satisfaction with back care, days of back-related disability, and use and costs of healthcare services for back pain will also be measured. The primary analysis comparing outcomes by randomized treatment assignment will be analysis of covariance adjusted for baseline value. For both primary outcome measures, this trial will have 99% power to detect the presence of a minimal clinically significant difference among all four treatment groups and over 80% power for most pairwise comparisons. Secondary analyses will compare the proportions of participants in each group that improve by a clinically meaningful amount.

Conclusion

Results of this trial will help clarify the value of acupuncture needling as a treatment for chronic low back pain.

Trial registration

Clinical Trials.gov NCT00065585.     

Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal

Background

This paper presents the study protocol for a pragmatic randomised controlled trial to evaluate the impact of a school based program developed to prevent teenage pregnancy. The program includes students taking care of an Infant Simulator; despite growing popularity and an increasing global presence of such programs, there is no published evidence of their long-term impact. The aim of this trial is to evaluate the Virtual Infant Parenting (VIP) program by investigating pre-conceptual health and risk behaviours, teen pregnancy and the resultant birth outcomes, early child health and maternal health.

Methods and Design

Fifty-seven schools (86% of 66 eligible secondary schools) in Perth, Australia were recruited to the clustered (by school) randomised trial, with even randomisation to the intervention and control arms. Between 2003 and 2006, the VIP program was administered to 1,267 participants in the intervention schools, while 1,567 participants in the non-intervention schools received standard curriculum. Participants were all female and aged between 13-15 years upon recruitment. Pre and post-intervention questionnaires measured short-term impact and participants are now being followed through their teenage years via data linkage to hospital medical records, abortion clinics and education records. Participants who have a live birth are interviewed by face-to-face interview. Kaplan-Meier survival analysis and proportional hazards regression will test for differences in pregnancy, birth and abortion rates during the teenage years between the study arms.

Discussion

This protocol paper provides a detailed overview of the trial design as well as initial results in the form of participant flow. The authors describe the intervention and its delivery within the natural school setting and discuss the practical issues in the conduct of the trial, including recruitment. The trial is pragmatic and will directly inform those who provide Infant Simulator based programs in school settings.

Trial registration

ISRCTN24952438     

Duration of luteal support (DOLS) with progesterone pessaries to improve the success rates in assisted conception: study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Luteal phase support has been shown by a meta analysis of prospective randomised studies, to be beneficial in establishing a pregnancy after IVF. The optimal length of treatment is unresolved at present and it remains unclear how long to treat women receiving luteal supplementation. It has been used for as little as 2 weeks and for as long as 12 weeks of gestation. OBJECTIVE: To conduct a prospective randomised double blind study to investigate the effect of the duration of luteal support with progesterone in IVF cycles. Trial design: Following 2 weeks of standard treatment and a positive biochemical pregnancy test, this randomised control trial will allocate women to a supplementary 8 weeks of treatment of vaginal progesterone or 8 weeks of placebo. Eligibility: All women presenting to the Hewitt Centre for Reproductive Medicine, Liverpool Women's NHS Foundation Trust, for assisted conception with a positive biochemical pregnancy test at 2 weeks post embryo transfer are eligible to enter the trial. Primary outcome measure:The primary outcome measure is the proportion of all randomised women that continue successfully to a viable pregnancy (at least one fetus with FHR >100 beats minute) on transabdominal / transvaginal ultrasound at 10 weeks post embryo transfer / 12 weeks gestation (i.e. at the end of 8 weeks supplementary trial treatment).     

Efficacy and mode of action of mesalazine in the treatment of diarrhoea-predominant irritable bowel syndrome (IBS-D): study protocol for a randomised controlled trial

Background

Irritable bowel syndrome (IBS) is reported by one in ten of the population accounting for up to 40% of new referrals to gastroenterology outpatients. Patients characteristically have abdominal discomfort and disturbed bowel habit. Diarrhoea-predominant IBS is characterised by frequent loose stools with associated urgency and abdominal cramps. Current symptomatic treatments can reduce bowel frequency but often fail to reduce discomfort. Mesalazine is an anti-inflammatory drug used to treat patients with inflammatory bowel disease. There is one pilot study suggesting it may be beneficial to patients who have diarrhoea-predominant IBS but these findings need to be confirmed in a larger trial. The current study aims to test the effectiveness of mesalazine to reduce symptoms in diarrhoea-predominant IBS patients. The study will also investigate the mode of action of the drug, especially its impact on mast cell activation.

Methods/design

This is a multicentre randomised, double-blind, placebo-controlled trial using a parallel group design. At least 108 participants with diarrhoea-predominant IBS will be recruited through at least six hospitals. The intervention is a 12-week course of 2g mesalazine granules taken up to twice a day. The comparator is a blinded placebo granule formulation. Outcome measures include stool diaries, symptom questionnaires, stool and blood samples together with rectal mucosal biopsies. The daily stool diary will record stool frequency and form, urgency, bloating, abdominal pain and a global satisfaction with control of IBS scored each week. The questionnaires will assess bowel symptoms, while the samples and biopsies will be used to analyse underlying mechanisms of any response. Primary outcome will be the average stool frequency during weeks 11 and 12 of the treatment period and will be compared between treatment arms using an analysis of covariance in the form of a general linear model incorporating baseline characteristics that are thought a priori to strongly predict outcome. The primary efficacy parameter will be the difference in mean frequency between treatment arms.

Discussion

This report describes a randomised controlled trial that will provide evidence of any benefit of treating diarrhoea-predominant IBS patients with mesalazine. The results will be available toward the end of 2013.

Trial registration

ISRCTN76612274     

Efficacy of vision restoration therapy after optic neuritis (VISION study): study protocol for a randomized controlled trial

Background

One of the main causes of mortality and morbidity following subarachnoid haemorrhage (SAH) is the development of cerebral vasospasm, a frequent complication arising in the weeks after the initial bleeding. Despite extensive research, to date no effective treatment of vasospasm exists. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. In vitro models have shown a relaxing effect of prostacyclin after induced contraction in cerebral arteries, and a recent pilot trial showed a positive effect on cerebral vasospasm in a clinical setting. No randomised, clinical trials have been conducted, investigating the possible pharmacodynamic effects of prostacyclin on the human brain following SAH.

Methods

This trial is a single-centre, randomised, placebo-controlled, parallel group, blinded, clinical, pilot trial. A total of 90 patients with SAH will be randomised to one of three intervention arms: epoprostenol 1?ng/kg/min, epoprostenol 2?ng/kg/min or placebo in addition to standard treatment. Trial medication will start day 5 after SAH and continue to day 10. The primary outcome measure is changes in regional cerebral blood flow from baseline in the arterial territories of the anterior cerebral artery, medial cerebral artery and the posterior cerebral artery, measured by CT perfusion scan. The secondary outcomes will be vasospasm measured by CT angiography, ischaemic parameters measured by brain microdialysis, flow velocities in the medial cerebral artery, clinical parameters and outcome (Glasgow Outcome Scale) at 3?months.

Trial registration

Clinicaltrials.gov NCT01447095.     

Common definition for categories of clinical research: a prerequisite for a survey on regulatory requirements by the European Clinical Research Infrastructures Network (ECRIN)

Background

Idiopathic recurrent miscarriage is defined as 3 consecutive pregnancy losses with no contributing features found on investigations. At present there are no treatments of proven efficacy for idiopathic recurrent miscarriage. Uterine natural killer (uNK) cells, the most predominant leucocyte in the endometrium are adjacent to foetal trophoblast cells and thought to be involved in implantation. The exact mechanisms of how uNK cells affect implantation are not clear but are probably through the regulation of angiogenesis. Multiple studies have shown an association between high density of uterine natural killer cells and recurrent miscarriage. We have shown that prednisolone reduces the number of uNK cells in the endometrium. The question remains as to whether reducing the number of uNK cells improves pregnancy outcome.

Methods

We propose a randomised, double-blind, placebo controlled trial of prednisolone with a pilot phase to assess feasibility of recruitment, integrity of trial procedures, and to generate data to base future power calculations. The primary aim is to investigate whether prednisolone therapy during the first trimester of pregnancy is able to improve live birth rates in patients with idiopathic recurrent miscarriage and raised uNK cells in the endometrium. Secondary outcomes include conception rate, karyotype of miscarriage, miscarriages (first and second trimester), stillbirths, pregnancy complications, gestational age at delivery, congenital abnormality and side effects of steroids. The trial has 2 stages: i) screening of non-pregnant women and ii) randomisation of the pregnant cohort. All patients who fit the inclusion criteria (<40 years old, ≥3 consecutive miscarriages with no cause found and no contraindications to prednisolone therapy) will be asked to consent to an endometrial biopsy in the mid-luteal phase to assess their levels of uNK cells. Women with high levels of uNK cells (≥5%), will be randomised to either prednisolone or placebo when a pregnancy is confirmed. Follow-up includes 2 weekly ultrasound scans in the first trimester, an anomaly scan at 20 weeks gestation, growth scans at 28 and 34 weeks gestation and a postnatal follow-up at 6 weeks.

Trial Registration

Current Controlled Trials ISRCTN28090716     

Prospective controlled randomized trial on prevention of postoperative abdominal adhesions by Icodextrin 4% solution after laparotomic operation for small bowel obstruction caused by adherences [POPA study: Prevention of Postoperative Adhesions on behalf of the World Society of Emergency Surgery]

Background

In some randomized trials successful laparoscopic cholecystectomy for cholecystitis is associated with an earlier recovery and shorter hospital stay when compared with open cholecystectomy. Other studies did not confirm these results and showed that the potential advantages of laparoscopic cholecystectomy for cholecystitis can be offset by a high conversion rate to open surgery. Moreover in these studies a similar postoperative programme to optimize recovery comparing laparoscopic and open approaches was not standardized. These studies also do not report all eligible patients and are not double blinded.

Design

The present study project is a prospective, randomized investigation. The study will be performed in the Department of General, Emergency and Transplant Surgery St Orsola-Malpighi University Hospital (Bologna, Italy), a large teaching institutions, with the participation of all surgeons who accept to be involved in (and together with other selected centers). The patients will be divided in two groups: in the first group the patient will be submitted to laparoscopic cholecystectomy within 72 hours after the diagnosis while in the second group will be submitted to laparotomic cholecystectomy within 72 hours after the diagnosis.

Trial Registration

TRIAL REGISTRATION NUMBER ISRCTN27929536 – The ACTIVE (Acute Cholecystitis Trial Invasive Versus Endoscopic) study. A multicentre randomised, double-blind, controlled trial of laparoscopic versus open surgery for acute cholecystitis in adults.     

Acupuncture for chronic prostatitis/chronic pelvic pain syndrome: study protocol for a randomized controlled trial

Background

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition affecting men of all ages. Acupuncture may be an effective treatment option for CP/CPPS, but evidence is limited. We propose to evaluate the effectiveness of acupuncture in a rigorously conducted trial.

Methods

Ten hospitals will recruit 440 participants with CP/CPPS in China from October 2017 to December 2019. Participants will be randomly allocated to acupuncture or sham acupuncture with a 1:1 ratio using computerized simple random sampling. The whole study consists of 2-week baseline, 8-week treatment, and 24-week follow up. Twenty 30-mintute sessions of acupuncture or sham acupuncture treatment will be provided between week 1 and 8. The two co-primary outcomes are the proportion of responders at week 8 and week 32. Secondary outcomes include proportion of responders in the two groups at different time points; change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score; change in the NIH-CPSI subscales; change in the International Prostate Symptom Score; change in the Hospital Anxiety and Depression Scale; expectation assessments; proportions of participants in each response category of the Global Response Assessment; change in the International Index of Erectile Function 5; change in the five-level EuroQol five-dimensional questionnaire and a visual analogue scale; and changes in peak and average urinary flow rate.

Discussion

This study will provide robust evidence on whether acupuncture is effective for relieving symptoms of CP/CPPS.

Trials registration

ClinicalTrials.gov, NCT03213938. Registered on 5 July 2017.

     

A randomised, double-masked phase III/IV study of the efficacy and safety of Avastin® (Bevacizumab) intravitreal injections compared to standard therapy in subjects with choroidal neovascularisation secondary to age-related macular degeneration: clinical trial design

Background

The management of neovascular age-related macular degeneration (nAMD) has been transformed by the introduction of agents delivered by intravitreal injection which block the action of vascular endothelial growth factor-A (anti-VEGF agents). One such agent in widespread use is bevacizumab which was initially developed for use in oncology. Most of the evidence supporting the use of bevacizumab for nAMD has come from interventional case series and this clinical trial was initiated because of the increasing and widespread use of this agent in the treatment of nAMD (an off-label indication) despite a lack of definitive unbiased safety and efficacy data.

Methods and design

The Avastin^® (bevacizumab) for choroidal neovascularisation (ABC) trial is a double-masked randomised controlled trial comparing intravitreal bevacizumab injections to standard therapy in the treatment of nAMD. Patients are randomised to intravitreal bevacizumab or standard therapy available at the time of trial initiation (verteporfin photodynamic therapy, intravitreal pegaptanib or sham treatment). Ranibizumab treatment was not included in the control arm as it had not been licensed for use at the start of recruitment for this trial. The primary outcome is the proportion of patients gaining ≥ 15 letters of visual acuity at 1 year and secondary outcomes include the proportion of patients with stable vision and mean visual acuity change.

Discussion

The ABC Trial is the first double-masked randomised control trial to investigate the efficacy and safety of intravitreal bevacizumab in the treatment of nAMD. This trial fully recruited in November 2007 and results should be available in early 2009. Important design issues for this clinical trial include (a) defining the control group (b) use of gain in vision as primary efficacy end-point and (c) use of pro re nata treatment using intravitreal bevacizumab rather than continuous therapy.

Trial registration

Current controlled trials ISRCTN83325075     

Influence of Control Group on Effect Size in Trials of Acupuncture for Chronic Pain: A Secondary Analysis of an Individual Patient Data Meta-Analysis

Background

In a recent individual patient data meta-analysis, acupuncture was found to be superior to both sham and non-sham controls in patients with chronic pain. In this paper we identify variations in types of sham and non-sham controls used and analyze their impact on the effect size of acupuncture.

Methods

Based on literature searches of acupuncture trials involving patients with headache and migraine, osteoarthritis, and back, neck and shoulder pain, 29 trials met inclusion criteria, 20 involving sham controls (n = 5,230) and 18 non-sham controls (n = 14,597). For sham controls, we analysed non-needle sham, penetrating sham needles and non-penetrating sham needles. For non-sham controls, we analysed non-specified routine care and protocol-guided care. Using meta-regression we explored impact of choice of control on effect of acupuncture.

Findings

Acupuncture was significantly superior to all categories of control group. For trials that used penetrating needles for sham control, acupuncture had smaller effect sizes than for trials with non-penetrating sham or sham control without needles. The difference in effect size was −0.45 (95% C.I. −0.78, −0.12; p = 0.007), or −0.19 (95% C.I. −0.39, 0.01; p = 0.058) after exclusion of outlying studies showing very large effects of acupuncture. In trials with non-sham controls, larger effect sizes associated with acupuncture vs. non-specified routine care than vs. protocol-guided care. Although the difference in effect size was large (0.26), it was not significant with a wide confidence interval (95% C.I. −0.05, 0.57, p = 0.1).

Conclusion

Acupuncture is significantly superior to control irrespective of the subtype of control. While the choice of control should be driven by the study question, our findings can help inform study design in acupuncture, particularly with respect to sample size. Penetrating needles appear to have important physiologic activity. We recommend that this type of sham be avoided.