In-use Technology Phase

C-Gall: A randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of laparoscopic cholecystectomy compared with observation/conservative management for preventing recurrent symptoms and complications in adults with uncomplicated symptomatic gallstones

Gallstones are common but only one in three people develop symptoms (severe abdominal pain, nausea and vomiting). These are sometimes accompanied by inflammation of the gallbladder (cholecystitis). Painkillers, anti-inflammatory medicines and antibiotics are usually prescribed initially and surgery to remove the gallbladder (cholecystectomy) is advised for medically fit patients. Approximately 70,000 cholecystectomies are performed every year in the UK, with significant costs for the NHS. However, it is known that some patients do not have any more symptoms after the initial episode of pain and that surgery might not be necessary.

This study will identify, across 20 UK hospitals, 430 patients that will be randomly allocated to either receive surgery or conservative management. Participants will be followed for 18 months and the primary outcome measure will be quality of life throughout that period (measured by the area under the curve using the SF-36 instrument).

This study will include a full economic evaluation. We will also consider a model to extend the analysis beyond the clinical follow-up period. The primary economic outcome measure will be incremental cost per QALY.

C-GALL Project websites

• Centre for Healthcare Randomised Trials (CHaRT)
• National Institute for Health Research (NIHR)

HERU researchers involved in this research project: Rodolfo Hernández

External collaborators: I Ahmed (NHS Grampian); C Ramsay, J Norrie, K Gillies, A Avenell, M Brazzelli (HSRU, University of Aberdeen) and P Murchie (Other Applied Health Sciences, University of Aberdeen)

Endometriosis is a chronic and often debilitating condition affecting 1 in 10 women in the UK. The condition arises when cells similar to those found in the womb are found elsewhere in the body. Each month, these cells build-up, break down and bleed causing severe symptoms such as chronic pain and infertility.

Occasionally, the endometrial cells grow deeper into tissues and organs, such as the bowel, bladder and vagina, causing a severe form of the condition called deep endometriosis (DE). DE can be treated by taking hormones such as the combined contraceptive pill, that can shrink areas of endometriosis, or by using keyhole (laparoscopic) surgery to remove areas of endometriosis.

The limited research that has been done suggests that for some women with DE who are not considering immediate pregnancy, hormonal treatment over many months could be just as effective as surgery in relieving pain. Clinical guidelines state that either hormones or surgery can be used but are unable to recommend one over the other in the absence of research directly comparing them.

Funded by the National Institute for Health Research (NIHR), the DIAMOND trial is comparing laparoscopic surgery to medical (hormonal) management for the treatment for DE. The economic evaluation will include a within trial assessment of cost-effectiveness at 18 months post randomisation, and modelling to assess cost-effectiveness up to the time of menopause.

HERU researchers involved in this research project: Graham Scotland and Charlotte Kennedy

External collaborators: Cooper, K. (NHS Grampian); Clark, J. (Birmingham Women's NHS Foundation Trust); Amer, S. (University of Nottingham); MacLennan, G., Gillies, K., Murchie, P., Bhattacharya, S. (University of Aberdeen); Byrne, D. (Royal Cornwall Hospitals NHS Trust); Cox, E. (Endometriosis UK); Gamaleldin, I. (University of Bristol); Vashisht, A. (University College London); Horne, A. (University of Edinburgh).  

‘Wet’ or neovascular age-related macular degeneration (nAMD) is a leading cause of sight loss in older people. The EDNA study will evaluate five non-invasive diagnostic tests which are easily performed and routinely carried out in the NHS secondary care setting and which fall into two groups: functional and morphological.

The functional tests are visual acuity, Amsler test and self-reported quality of sight. The morphological tests are fundus examination and optical coherence tomography (OCT). The diagnostic accuracy of these tests will be assessed against a reference standard test (fluorescein angiography). The results from this prospective cohort study will be used to inform the development of a decision analytic model, which will model disease progression and the costs and consequences of using the alternative diagnostic test to monitor patients in secondary care. http://www.nets.nihr.ac.uk/projects/hta/1214207.

HERU researchers involved in this project: Graham Scotland

External collaborators: U Chakravarthy, R Hogg (Queen’s University Belfast); C Ramsay, K Bainster, J Cook, A Azuara-Blanco (HSRU, University of Aberdeen); S Sivaprasad (Moorfields Eye Hospital NHS Foundation Trust) and H Heimann (Royal Liverpool & Broadgreen University Hospitals NHS Trust).

Despite improvements in technology, IVF success rates remain low with an overall live birth rate of 25% per treatment. Additionally, there are concerns about health outcomes for mothers and babies conceived through IVF, particularly after fresh embryo transfer, including maternal ovarian hyperstimulation syndrome (OHSS) and perinatal morbidity. It is believed that high levels of ovarian hormones during ovarian stimulation could create a relatively hostile environment for embryo implantation whilst increasing the risk of OHSS. It has been suggested that electively freezing embryos with the intention of thawing and replacing them within the uterus at a later stage (thawed frozen embryo transfer), instead of fresh embryo transfer, may lead to improved pregnancy rates and fewer complications. This two-arm parallel group randomised controlled trial, across multiple IVF centres in the UK, aims to address this question: http://www.nets.nihr.ac.uk/projects/hta/1311582.

More information on the trial is available at the Trial website and on the NIHR project portfolio. The ISRCTN registry is 61225414 (DOI: 10.1186/ISRCTN61225414).

HERU researchers involved in this research project: Graham Scotland

External collaborators: Mahashwari, A. (NHS Grampian); Macklon, N. (University of Southampton); Khalaf, Y. (Guy’s and St Thomas Hospital); Lavery, S. (Hammersmith Hospital); Child, T., Juszczak, E., Hardy, P., Kurinczuk, J. (University of Oxford); Rajkohwa, M. (Birmingham’s Women’s Hospital); Coomarasamy, A. (University of Birmingham); Cutting, R. (University of Sheffield); Brison, D. (Central Manchester University Hospital NHS Trust); Troup, S. (Liverpool Women’s Hospital); Lewis-Jones, C. (Infertility Network, UK); Raine-Fenning, N. (University of Nottingham) and Bhattacharya, S. (Obstetrics & Gynaecology, University of Aberdeen.

Oral iron supplementation is the most common treatment for anaemia but it does not improve anaemia for all people and there are associated side effects. Three broad treatment strategies are possible yet there is no evidence regarding effectiveness or cost-effectiveness for them.

A pilot randomised controlled trial was undertaken to assess the feasibility of conducting a definitive comparative trial of the following three treatment options:

1. no treatment,
2. oral iron supplementation and
3. intravenous iron infusion.

HERU researchers involved with this research project: Paul McNamee

External Collaborators: Myint, P. (Other Applied Health Sciences, University of Aberdeen); Witham, M., Hands, K. (Ninewells Hospital Dundee); Lee, A. (Medical Statistics Team, University of Aberdeen).

Tooth decay is very common condition. Almost all adults have some decay in their back teeth. Where the tooth decay has spread deep into the nerve, and caused serious and irreversible damage, there are different treatments available. The most common treatments are to take out the tooth or use root canal treatment. Root canal treatment removes all the nerve and is very expensive, time consuming and technically demanding.

A possible alternative is to remove only the infected part of the nerve, which is an easier and quicker treatment. This technique is called pulpotomy. Research has already been conducted in children’s teeth that supports using pulpotomy instead of root canal treatment. However, there are gaps in knowledge about using pulpotomy in adult’s teeth.

The PIP clinical trial compares pulpotomy with root canal treatment in adult patients recruited from dental practices across Scotland and England. The research considers the pain experienced by patients, the impact of treatment on their lives, whether further treatment is needed due to infection and the time and financial costs incurred. Patient questionnaires, X-rays and data from dentists are used to evaluate the success of the two treatments. Dental staff and patients are also interviewed on their views on the two treatments.

HERU researchers involved in this research project: Marjon van der Pol and Dwayne Boyers

Co-Applicants: J. Clarkson - Joint Principal Investigator (University of Dundee); C. Ramsay - Joint Principal Investigator (Health Services Research Unit (HSRU), University of Aberdeen); S. Albadri, F. Jarad (University of Liverpool); A Banjeree, F. Mannocci, R. Moazzez (King's College London); D. Conway, D. Robertson (University of Glasgow); C. Deery, Z. Marshaman (University of Sheffield); A-M Glenny (University of Manchester); T. McGuff, D. Ricketts, C. Tait, T. Lamont (University of Dundee); L. Young (NHS Education for Scotland).

Kidney stone disease is very common and, although stones in the kidney do not always cause problems, most need treatment. They can cause serious problems, such as pain, infection and kidney failure, with burden to patients, the NHS and society. There are three treatment options in the NHS for stones in the lower part of the kidney: (1) flexible ureterorenoscopy with laser lithotripsy (FURS); (2) percutaneous nephrolithotomy (PNL); and (3) extracorporeal shockwave lithotripsy (ESWL). Each treatment has advantages and disadvantages (benefits and harms) and there is uncertainty about which of these treatments is best to free people from kidney stones and which is best value for patients and the NHS.

This study will randomly allocate 522 patients with smaller stones (diameter ≤ 10 mm) to be treated with either FURS or ESWL and 522 patients with larger stones (10 mm < diameter ≤ 25 mm ) to be treated with either FURS or PNL, with each participant followed up for one year.

The primary outcome is generic health status (EQ-5D-5L) area under the curve (AUC) to 12 weeks post-intervention. This study includes a full economic evaluation. A within trial analysis as well as a simple model to extend the analysis beyond the clinical study follow-up period will be considered. For further details please see: http://www.nets.nihr.ac.uk/projects/hta/1315202.

More information on the trial is available at the Trial website and on the NIHR project portfolio. The ISRCTN registry number is 98970319 (DOI: 10.1186/ISRCTN98970319)

HERU researchers involved in this research project: Rodolfo Hernández

External collaborators: S McClinton (NHS Grampian & University of Aberdeen); T Lam (University of Aberdeen); O Wiseman (Addenbrooke's NHS Trust); D Smith (University College London Hospital); B Turney (John Radcliffe Hospital NHS Trust); R Pickard (The Freeman Hospital & University of Newcastle); R Thomas, G MacLennan, J Norrie, S MacLennan, K Starr, CT Clark (HSRU, University of Aberdeen) and K Anson (St George's Healthcare NHS Trust)

REFLECt trial: A Randomised controlled trial to Evaluate the clinical and cost effectiveness of prescribing high concentration FLuoride toothpaste in preventing and treating dEntal Caries in high-risk older adulTs

The RELFECT study is a two arm, parallel group pragmatic open label randomised controlled trial with 36 month follow.  The trial will randomise participants from Manchester, Scotland and Northern Ireland.  The primary clinical outcome for the study is restoration or extraction due to caries.  The health economic outcomes for the study are NHS and patient perspective costs, willingness to pay and net benefit.  Two economic analyses will be completed, the first, a within trial analysis over a three year time horizon.  Discrete choice experiments will be used to value the trial outcomes within a cost-benefit analysis framework to reflect broader measures of value to patients.  The findings will be compared with a standard cost-utility analysis.  A micro-simulation modelling study will be conducted to extrapolate the findings of the trial over a participant’s lifetime.   This study will provide important information on the value of prescribing a treatment which is increasing in use, without any evidence to support its effectiveness or cost-effectiveness.

HERU researchers involved in this research project: Dwayne Boyers

External collaborators:  Tickle, M., Walsh, T., Worthington, H., Glenny, A-M., Pretty, I., Birch, S. (University of Manchester); Clarkson, J. (University of Dundee).

Endometriosis is a common, painful condition affecting one in ten women of childbearing age. It occurs when cells like those lining the womb grow outside it, causing internal bleeding, scarring and pain. Key hole surgery (laparoscopy) is commonly used to destroy areas of endometriosis. However, endometriosis returns in up to half of treated women within five years, and there is uncertainty about how best to treat women, particularly those who wish to preserve their fertility.

Repeat surgery is invasive, expensive and risky, without guaranteeing a cure. A less invasive treatment is monthly or three-monthly injections with Gonadotrophin Releasing hormone (GnRH) analogues. While effective in reducing pain, this type of hormonal treatment has generally only been used for up to a year because of the risk of side effects (hot flushes and night sweats) and concerns about osteoporosis. However, recent research suggests that giving small doses of hormone replacement therapy (HRT) with GnRH analogues can reduce the risk of side effects.

Funded by the National Institute for Health Research (NIHR), this trial will assess the clinical and cost-effectiveness of long-term GnRH analogues with added HRT compared to conservative key hole surgery in women who experience recurrence of pain after surgery but who wish to preserve their fertility.

HERU researchers involved in this research project: Graham Scotland

External collaborators: Saraswat, L. (NHS Grampian & University of Aberdeen); MacLennan, G., Gillies, K. (Health Services Research Unit (HSRU), University of Aberdeen); Bhattacharya, S. (Other Applied Health Sciences, University of Aberdeen).

Primary hypercholesterolaemia is a form of dyslipidemia characterised by abnormalities of lipoprotein transport associated with high concentrations of cholesterol in the blood. People with hypercholesterolaemia are at increased risk of cardiovascular disease (CVD) owing to the fact that long-term high concentrations of cholesterol are known to accelerate atherosclerosis, the build-up of fatty deposits in the arteries.

This project was carried out as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal Process. The company responsible for ezetimibe (Merck Sharp & Dohme Ltd) submitted an evidence review and an economic model assessing the cost-effectiveness of the drug, alone or in combination with statin treatment, against no treatment or statin alone for the treatment of primary hypercholesterolaemia. The Aberdeen HTA group were commissioned to act as the Evidence Review Group (ERG) for the project, and to provide an independent report reviewing the company’s evidence submission.

Outcome and Translation

Following consideration of the company submission and the ERG report, the NICE appraisal committee recommended ezetimibe as a treatment option for some people with heterozygous-familial and non-familial hypercholesterolaemia: http://www.nice.org.uk/guidance/ta385/chapter/1-Recommendations.

National Institute for Health and Care Excellence (2016) Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia, Technology Appraisal Guidance [TA385], London: NICE.

A parallel-group, randomised, controlled comparison of three forms of dental recall strategy (6-month recall, risk-based recall and 24-month recall) evaluated the effectiveness and cost-effectiveness of these dental recall strategies by assessing their impact on maintaining oral health. A cost–benefit analysis was undertaken to assess the efficiency of the alternative recall strategies. Willingness to pay was elicited using a discrete choice experiment.

Outcome and Translation

Publications are currently in development.

HERU researchers involved in this research project: Marjon van der Pol and Dwayne Boyers

External collaborators: N Pitts, J Clarkson, D Bonetti, R Freeman, D Ricketts (University of Dundee); C Ramsay, (HSRU, University of Aberdeen); H Worthington (University of Manchester); T Anderson, W McCombes, L Young (NHS Education for Scotland); F Burke, D White (University of Birmingham); G Douglas (University of Leeds); R Gorter (University of Amsterdam); R Herbert (University of Cardiff); P Hodge (University of Glasgow); G Humphris (University of St. Andrews); T Mettes (Radboud University, NIJMEJEN Medical Centre, The Netherlands); I Needleman (UCL Eastman Dental Institute) and M Ross (University of Edinburgh)

IQuaD: Improving the Quality of Dentistry: a randomised controlled trial comparing oral hygiene advice and periodontal instrumentation for the prevention and management of periodontal disease in dentate adults attending dental primary care

Periodontal disease is the most common oral disease affecting adults. This disease is preventable, yet it remains the major cause of poor oral health worldwide and is the primary cause of tooth loss in older adults. There is a lack of strong evidence to inform clinicians and policy makers of the relative effectiveness (if any) and cost-effectiveness of different types of oral hygiene advice (OHA). The economic evaluation conducted as part of this cluster randomised controlled trial elicited the costs of dental care to both the NHS and patients and equated the data with benefits to patients. Benefits to patients were estimated using a discrete choice experiment administered to a sample of the general population to provide a scoring algorithm with which to weight the outcomes for the patient participants in the trial.

Outcome and Translation

63 dental practices and 1877 participants were recruited. Under Intention To Treat (ITT) analysis there was no evidence of a difference in gingival inflammation/bleeding (the primary clinical effectiveness outcome measure) across any of the randomised groups. There was no clinical benefit from scheduling 6-monthly or 12-monthly scale and polish over not scheduling these treatments unless desired or recommended. Furthermore, there was no clinical benefit of personalised over routine oral hygiene advice in either gingival inflammation/bleeding or patient centred outcomes (including oral health related quality of life).

Compared to standard care, no scale and polish with personalised advice had the greatest NHS: -£15 (-£34 to +£4) and participant: -£64 (-£112 to -£16) cost savings. The DCE shows that the general population value these services greatly and were willing to pay for both scale and polish and personalised advice. WTP for scale and polish was higher than personalised advice. Overall, Personalised OHA with 6-monthly PI had the greatest incremental net benefit to society: +£48 (+£22 to +£74). Sensitivity analyses did not change conclusions. The results of the study provide a dilemma for NHS dental policy makers who must consider whether or not to fund services that are not clinically beneficial but are highly valued by the general population.

HERU researchers involved in this research project: Marjon van der Pol and Dwayne Boyers

External collaborators: J Clarkson, D Bonetti, N Pitts (University of Dundee); C Ramsay (HSRU, University of Aberdeen); J Burr (University of St. Andrews); H Worthington, C Jones, M Tickle (University of Manchester Dental Hospital); P Heasman, J Steele (University of Newcastle); L Young, I Madden, W McCombes (NHS Education for Scotland); P Hodge (University of Glasgow Dental School); M Ross (University of Edinburgh); D Ricketts, A Hall (Dundee Dental Care Hospital & School) and P Averley (Queensway Dental Practice)

Oral splints are placed by dentists working in the NHS for patients with orofacial signs of symptoms. It is unclear if oral splints are effective or cost-effective, and if they are, which type of splint is the most cost-effective (cheaper pre-fabricated splints or more expensive custom made ones). 

This project developed a Markov decision analysis model alongside a systematic review of the clinical effectiveness literature on the use of oral splints for temporomandibular disease (TMD).

Standard reporting methods were used to illustrate uncertainty in findings (deterministic and probabilistic sensitivity analysis). There was a dearth of high quality evidence to populate the model, particularly over the longer time period. An expected value of perfect information (EVPI) analysis explored the value for money of conducting additional research to resolve uncertainty in the cost-effectiveness evidence. Expected value of partial perfect information (EVPPI) analysis was used to identify the most important model parameters on which to obtain future data. The results of these analyses can help to prioritise key areas of future research from a cost-effectiveness view-point.

Outcome and Translation

Results of the trial are currently under submission to journals. 

HERU researchers involved in this research project: Dwayne Boyers and Elisabet Jacobsen

External collaborators: Worthington, H., Glenny, A-M. Riley, P. (University of Manchester); Robertson, C. (HSRU, University of Aberdeen).

A self-contained Appendix to the report is available. This Appendix is not part of the main report but informs the findings.

• Appendix: Custom-made vs. Prefabricated splints vs. none (Economic evaluation results), including VOI results.

ARCHIVED

Assessing and modelling the impact of HPV 16/18 immunisation on the performance of current cervical screening and the effectiveness of alternative cervical screening strategies to optimise cancer prevention in the HPV immunisation era

In Scotland, human papilloma virus (HPV) vaccination of females aged 12 to 13 years started, via a school immunisation programme, on 1 September 2008. A ‘catch-up campaign’, targeting females up to the age of 18, ran alongside this. Scotland now moves from the Scottish Cervical Screening Programme to a Scottish Cervical Cancer Prevention Programme, with the aim of further reducing cervical cancer mortality by primary prevention based on HPV immunisation and secondary prevention based on screening. Health Protection Scotland (HPS) is coordinating the introduction of the new immunisation programme, and also established an HPV immunisation project to monitor its impact. Many new questions need to be investigated to inform NHS policy on the future delivery of the combined screening and immunisation programme. Scotland is in a unique position to lead on new research as 16–17-year-olds were immunised in 2008 and become eligible for cervical screening from September 2010. Our research combined routinely collected data on screening and disease detection with data on HPV genotyping and screening test performance to model future screening performance.

Outcome and Translation

This study will inform NHS Scotland policy on future service delivery of the national cervical screening and immunisation programme. Scotland’s research networks and HPS can collaborate effectively using Scotland’s excellent data linkage facilities to further develop and deliver a composite population health intervention for cancer prevention, and improve health outcomes in Scotland.

• HERU researchers involved in this research project: Aileen Neilson

External collaborators: M Cruickshank (Department of Obstetrics and Gynaecology, University of Aberdeen); C Campbell, D Weller (University of Edinburgh); Y Choi (Health Protection Agency); H Cubie (Lothian University NHS Hospital Trust, Royal Infirmary of Edinburgh); K Cuschieri (Edinburgh Royal Infirmary); M Donaghy, C Robertson (Health Protection Scotland); J Imrie (Monklands District General Hospital) and F Sullivan (University of Dundee)

TISU: Therapeutic Interventions for Stones of the Ureter: a multicentre randomised controlled trial of extracorporeal shockwave lithotripsy, as first treatment option, compared with direct progression to ureteroscopic retrieval, for ureteric stones

Urinary stone disease is very common with an estimated prevalence among the general population of 2–3% (1.8 million people in the UK) with males forming stones three times as often as females. All symptomatic urinary tract stones, and ureteric stones in particular, are associated with severe pain and can have a significant impact on patients’ quality of life due to the detrimental effect on their ability to work and the need for hospitalisation. Most ureteric stones can be expected to pass spontaneously with supportive care (painkillers and fluids) possibly aided by drugs such as alpha blockers or calcium channel blockers (conservative management). However, between a fifth and a third of cases require an active intervention (stone removal) because of failure to pass the stone, continuing pain, infection or obstruction to urine drainage.

The two standard active intervention options are extracorporeal shockwave lithotripsy (ESWL) and ureteroscopic stone retrieval. Whilst both ESWL and ureteroscopy appear to be effective in terms of stone clearance they differ in terms of invasiveness, anaesthetic requirement, treatment setting, potentially the number of procedures required to clear the stone, complications, patient reported outcomes (such as severity and duration of pain after intervention, time off work and bothersome urinary symptoms), and cost. There is uncertainty around which is the most clinically effective in terms of stone clearance and the true cost to the NHS and to society (in terms of impact on patient reported health and economic burden).

Outcome and Translation

The findings of this project will inform the decision makers on the most clinical and cost- effective  surgical intervention to use in the treatment of ureteric stones. The project will also inform the national guidance on the treatment of patients that present with ureteric stones.

ISRCTN registry: ISRCTN92289221

TISU Project website (Centre for Healthcare Randomised Trials)

HERU researchers involved in this research project: Mary Kilonzo

External collaborators: S McClinton, L Kurban (NHS Grampian); J N’Dow, S MacLennan, T Lam (Academic Urology Unit, University of Aberdeen); G MacLennan, J Norrie, R Thomas, K Starr (HSRU, University of Aberdeen); F Keely (Southmead Hospital); K Anson (St Georges NHS Trust); C Clark (Service User); R Pickard (Newcastle University) and N Burgess (Norfolk and Norwich University Hospital)