Visual cycle modulators versus placebo or observation for the prevention and treatment of geographic atrophy due to age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a highly prevalent condition in an ever-increasing elderly population. Although insidious in the early stages, advanced AMD (neovascular and atrophic forms) can cause significant visual disability and economic burden on health systems worldwide. The most common form, geographic atrophy, has no effective treatment to date, whereas neovascular AMD can be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to assess treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials, reviewed herein. OBJECTIVES: To assess the efficacy and safety of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to AMD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); MEDLINE Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to 11 January 2020 with no language restrictions. We also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in people diagnosed with AMD (early, intermediate or geographic atrophy). DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. We resolved discrepancies through discussion. We graded the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included three RCTs from the USA; one of these had clinical sites in Germany. Two studies compared emixustat to placebo while the other compared fenretinide to placebo. All assigned one study eye per participant and, combined, have a total of 821 participants with a majority white ethnicity (97.6%). All participants were diagnosed with geographic atrophy due to AMD based on validated imaging modalities. All three studies have high risk of attrition bias mainly due to ocular adverse effects of emixustat and fenretinide. We considered only one study to be adequately conducted and reported with high risk of bias in only one domain (attrition bias). We considered the other two studies to be poorly reported and to have high risk of attrition bias and reporting bias. People with geographic atrophy treated with emixustat may not experience a clinically important change in best-corrected visual acuity (BCVA) between baseline and 24 months compared to people treated with placebo (mean difference (MD) 1.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (CI) -2.34 to 6.14, low-certainty evidence). Emixustat may also result in little or no difference in loss of 15 ETDRS letters or more of BCVA compared with placebo at 24 months (16.4% versus 18%) (risk ratio (RR) 0.91, 95% CI 0.59 to 1.4, low-certainty evidence). In terms of disease progression, emixustat may result in little or no difference in the annual growth rate of geographic atrophy compared with placebo (mean difference MD 0.09 mm2/year (95% CI -0.26 to 0.44, low-certainty evidence). All three studies reported adverse events of both drugs (emixustat: moderate-certainty evidence; fenretinide: low-certainty evidence). The main adverse events were ocular in nature and associated with the mechanism of action of the drugs. Delayed dark adaptation (emixustat: 54.5%; fenretinide: 39.3%) and chromatopsia (emixustat: 22.6%; fenretinide: 25.2%) were the most common adverse events reported, and were the most prevalent reasons for study dropout in emixustat trials. These effects were dose-dependent and resolved after drug cessation. No specific systemic adverse events were considered related to emixustat; only pruritus and rash were considered to be due to fenretinide. One emixustat study reported six deaths, none deemed related to the drug. None of the included RCTs reported the other pre-specified outcomes, including proportion of participants losing 10 letters or more, and mean change in macular sensitivity. We planned to investigate progression to advanced AMD (geographic atrophy or neovascular AMD) in prevention studies, including participants with early or intermediate AMD, but we identified no such studies. Two of the included studies reported an additional outcome - incidence of choroidal neovascularisation (CNV) - that was not in our published protocol. CNV onset may be reduced in those treated with emixustat but the evidence was uncertain (risk ratio (RR) 0.67, 95% CI 0.27 to 1.65, low-certainty evidence), or fenretinide (RR 0.5, 95% CI 0.26 to 0.98, low-certainty evidence) compared to placebo. A dose-dependent relationship was observed with emixustat. AUTHORS' CONCLUSIONS: There is limited evidence to support the use of visual cycle modulators (emixustat and fenretinide) for the treatment of established geographic atrophy due to AMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.

Incidence of sudden cardiac death in the young: a systematic review.

OBJECTIVE: To summarise studies describing incidence of sudden cardiac death in a general population of young individuals to inform screening policy. DESIGN: Systematic review. DATA SOURCES: Database searches of MEDLINE, EMBASE and the Cochrane library (all inception to current) on 29 April 2019 (updated 16 November 2019), and forward/backward citation tracking of eligible studies. STUDY ELIGIBILITY CRITERIA: All studies that reported incidence of sudden cardiac death in young individuals (12-39 years) in a general population, with no restriction on language or date. Planned subgroups were incidence by age, sex, race and athletic status (including military personnel). DATA EXTRACTION: Two reviewers independently assessed study eligibility, extracted study data and assessed risk of bias using the Joanna Briggs Institute critical appraisal checklist for prevalence studies. ANALYSIS: Reported incidence of sudden cardiac death in the young per 100 000 person-years. RESULTS: 38 studies that reported incidence across five continents. We identified substantial heterogeneity in population, sudden cardiac death definition, and case ascertainment methods, precluding meta-analysis. Median reported follow-up years was 6.97 million (IQR 2.34 million-23.70 million) and number of sudden cardiac death cases was 64 (IQR 40-251). In the general population, the median of reported incidence was 1.7 sudden cardiac death per 100 000 person-years (IQR 1.3-2.6, range 0.75-11.9). Most studies (n=14, 54%) reported an incidence between one and two cases per 100 000 person-years. Incidence was higher in males and older individuals. CONCLUSIONS: This systematic review identified variability in the reported incidence of sudden cardiac death in the young across studies. Most studies reported an incidence between one and two cases per 100 000 person-years. PROSPERO REGISTRATION NUMBER: CRD42019120563.

A Systematic Review of Economic Evaluations Assessing the Cost-Effectiveness of Licensed Drugs Used for Previously Treated Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) Negative Advanced/Metastatic Non-Small Cell Lung Cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers. There are many published studies of cost-effectiveness analyses of licensed treatments, but no study has compared these studies or their approaches simultaneously. OBJECTIVE: To investigate the methodology used in published economic analyses of licensed interventions for previously treated advanced/metastatic NSCLC in patients without anaplastic lymphoma kinase or epidermal growth factor receptor expression. METHODS: A systematic review was performed, including a systematic search of key databases (e.g. MEDLINE, EMBASE, Web of Knowledge, Cost-effectiveness Registry) limited to the period from 01 January 2001 to 26 July 2019. Two reviewers independently screened, extracted data and quality appraised identified studies. The reporting quality of the studies was assessed by using the Consolidated Health Economic Evaluation Reporting Standards and the Philips' checklists. RESULTS: Thirty-one published records met the inclusion criteria, which corresponded to 30 individual cost-effectiveness analyses. Analytical approaches included partitioned survival models (n = 14), state-transition models (n = 7) and retrospective analyses of new or published data (n = 8). Model structure was generally consistent, with pre-progression, post-progression and death health states used most commonly. Other characteristics varied more widely, including the perspective of analysis, discounting, time horizon, usually to align with the country that the analysis was set in. CONCLUSIONS: There are a wide range of approaches in the modelling of treatments for advanced NSCLC; however, the model structures are consistent. There is variation in the exploration of sensitivity analyses, with considerable uncertainty remaining in most evaluations. Improved reporting is necessary to ensure transparency in future analyses.

Comparative survival benefit of currently licensed second or third line treatments for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) negative advanced or metastatic non-small cell lung cancer: a systematic review and secondary analysis of trials.

BACKGROUND: A review of therapies for advanced cancers licenced by the EMA between 2009 and 2013 concluded that for more than half of these drugs there was little evidence of overall survival or quality of life benefit. Recent years have witnessed a growing number of licensed second-line pharmacotherapies for advanced/metastatic non-small cell lung cancer (NSCLC). With the aim of gauging patient survival benefit, we conducted a systematic review of randomised controlled trials (RCT) and compared survival outcomes from available licensed treatments for patients with advanced/metastatic NSCLC. METHODS: RCTs of second/third line treatments in participants with advanced/metastatic NSCLC and negative/low expression of Anaplastic Lymphoma Kinase (ALK) and of Epidermal Growth Factor Receptor (EGFR) were included. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 up to July, 2017. Two or more independent reviewers screened bibliographic records, extracted data, and assessed risk of bias of studies. Published Kaplan Meier plots for OS and PFS along with restricted-mean-survival methods and parametric modelling were used to estimate the survival outcomes as mean number of months of survival. Network meta-analysis was undertaken to rank interventions and to make indirect comparisons. RESULTS: We included 11 RCTs with data for 7581 participants that compared nine different drugs. In studies of patients regardless of histology groups, targeted drugs (ramucirumab and nintedanib) yielded small overall survival gains of < 2.5 months over docetaxel, erlotinib provided no benefit, while immunotherapies (atezolizumab and pembrolizumab) delivered 5 to 6 months gain. Studies with patients stratified by histology confirmed the apparent superiority of immunotherapy (nivolumab and atezolizumab) over targeted treatments (ramucirumab, nintedanib, afatinib) providing between about 4 to 8 months OS gain over docetaxel. In network analysis immunotherapies consistently ranked higher than alternatives irrespective of population histology and outcome measure. CONCLUSION: Our review indicates that nivolumab, pembrolizumab and atezolizumab provide superior survival benefits compared to other licensed drugs for late stage NSCLC. Patient gains from these immunotherapies are substantial compared to the expected average survival with chemotherapy (docetaxel) of < 1 year for people with squamous histology and about 1.25 year for those with non-squamous histology.

Meniscal allograft transplantation after meniscectomy: clinical effectiveness and cost-effectiveness.

PURPOSE: To assess the clinical effectiveness and cost-effectiveness of meniscal allograft transplantation (MAT) after meniscal injury and subsequent meniscectomy. METHODS: Systematic review of clinical effectiveness and cost-effectiveness analysis. RESULTS: There is considerable evidence from observational studies, of improvement in symptoms after meniscal allograft transplantation, but we found only one small pilot trial with a randomised comparison with a control group that received non-surgical care. MAT has not yet been proven to be chondroprotective. Cost-effectiveness analysis is not possible due to a lack of data on the effectiveness of MAT compared to non-surgical care. CONCLUSION: The benefits of MAT include symptomatic relief and restoration of at least some previous activities, which will be reflected in utility values and hence in quality-adjusted life years, and in the longer term, prevention or delay of osteoarthritis, and avoidance or postponement of some knee replacements, with resulting savings. It is likely to be cost-effective, but this cannot be proven on the basis of present evidence. LEVEL OF EVIDENCE: IV.

Allografts in reconstruction of the posterior cruciate ligament: a health economics perspective.

PURPOSE: To review the relative cost-effectiveness of allografts and autografts in reconstruction of the posterior cruciate ligament. METHODS: Systematic review and cost-effectiveness analysis. RESULTS: The available evidence does not show any significant difference in clinical effectiveness between autografts and allografts. Given that, only a cost analysis is provided, which shows that allografts are more costly. CONCLUSION: Given the lack of any benefit of allografts over autografts, autografts should be preferred on cost grounds, if available. However, there may be situations where an allograft is indicated, for example, in multiple ligament reconstructions. LEVEL OF EVIDENCE: IV.

Autograft or allograft for reconstruction of anterior cruciate ligament: a health economics perspective.

PURPOSE: To assess the clinical and cost-effectiveness of allografts versus autografts in the reconstruction of anterior cruciate ligaments. METHODS: Systematic review of comparative clinical effectiveness and cost-effectiveness analysis. RESULTS: Both autograft and allograft reconstruction are highly effective. Recent studies show little difference in failure rates between autografts and allografts (about 6% and 7%, respectively). In cost-effectiveness analysis, the price differential is the main factor, making autografts the first choice. However, there will be situations, particularly in revision ACL reconstruction, where an allograft may be preferred, or may be the only reasonable option available. CONCLUSION: In ACL reconstruction, clinical results with autografts are as good as or slightly better than with allografts. Allografts cost more, indicating that autografts are more cost-effective and should usually be first choice. LEVEL OF EVIDENCE: II.

The cost-effectiveness of osteochondral allograft transplantation in the knee.

PURPOSE: Osteochondral allografts (OCA) consist of a layer of hyaline cartilage and a layer of underlying bone. They are used to repair combined defects of articular cartilage and bone. Such defects often occur in people far too young to have knee arthroplasty, for whom the main alternative to OCA is conservative symptomatic care, which will not prevent development of osteoarthritis. The aim of this report was to assess the cost-effectiveness of osteochondral allograft transplantation in the knee. METHODS: Systematic review of evidence on clinical effectiveness and economic modelling. RESULTS: The evidence on osteochondral allograft transplantation comes from observational studies, but often based on good quality prospective registries of all patients having such surgery. Without controlled trials, it was necessary to use historical cohorts to assess the effect of osteochondral grafts. There is good evidence that OCA are clinically effective with a high graft survival rate over 20 years. If an OCA graft fails, there is some evidence that revision with a second OCA is also effective, though less so than primary OCA. Economic modelling showed that osteochondral allograft transplantation was highly cost-effective, with costs per quality adjusted life year much lower than many other treatments considered cost effective. CONCLUSIONS: Osteochondral allograft transplantation appears highly cost-effective though the cost per quality adjusted life year varies according to the widely varying costs of allografts. Based on one small study, revision OCA also appears very cost-effective, but more evidence is needed. LEVEL OF EVIDENCE: II.

Autologous Chondrocyte Implantation with Chondrosphere for Treating Articular Cartilage Defects in the Knee: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Chondrosphere (Spherox) is a form of autologous chondrocyte implantation (ACI). It is licensed for repair of symptomatic articular cartilage defects of the femoral condyle and the patella of the knee with defect sizes up to 10 cm2 in adults. In a single technology appraisal (STA) [TA508] undertaken by the National Institute of Health and Care Excellence (NICE), Warwick Evidence was the Evidence Review Group (ERG) invited to independently review the evidence submitted by the manufacturer, Co.Don. The clinical effectiveness data came from their COWISI randomised controlled trial (RCT), which compared Chondrosphere with microfracture (MF). The timing of this appraisal was unfortunate given that MF was no longer the most relevant comparator because NICE had contemporaneously published guidance approving ACI in place of MF. Moreover, the COWISI RCT enrolled mostly patients with small defect sizes. Evidence of clinical effectiveness for Chondrosphere used in people with larger defect size came from another RCT, which compared three doses of Chondrosphere and that by design could not provide evidence comparing Chondrosphere to any other forms of ACI. To estimate the relative clinical performance of Chondrosphere versus other ACI, Co.Don conducted an indirect treatment comparison by network meta-analyses (NMA). The NMA was flawed in that the distribution of population characteristics that are effect modifiers greatly differed across the treatment comparisons of the network. The ERG questioned both the appropriateness of the NMA and the validity of the resulting estimates. Co.Don estimated the cost-effectiveness of Chondrosphere using a lifetime Markov model with all patients receiving the first repair during the first cycle of the model then moving into one of three health states: success, no further repair (NFR), or a second repair, if necessary. Subsequent to the first cycle, those who were a success either remained a success or moved to second repair. All those in NFR remained in NFR. The cost-effectiveness of Chondrosphere compared to other ACI forms relied on the clinical effectiveness estimates of success and failure rates obtained from the company's indirect comparisons, the validity of which the ERG questioned. The company revised cost-effectiveness estimates for Chondrosphere versus MF and for Chondrosphere versus matrix-applied characterised autologous cultured chondrocyte implant (MACI) were £4360 and around £18,000 per quality-adjusted life year gained, respectively. NICE recommended ACI using Chondrosphere for treating symptomatic articular cartilage defects of the femoral condyle and patella of the knee in adults only if certain requirements were met.

Improving Uptake of Postnatal Checking of Blood Glucose in Women Who Had Gestational Diabetes Mellitus in Universal Healthcare Settings: A Systematic Review.

The aim of this systematic review is to look at the barriers to uptake and interventions to improve uptake of postnatal screening in women who have had gestational diabetes mellitus (GDM). Increasing postnatal screening rates could lead to timely interventions that could reduce the incidence of type 2 diabetes mellitus (T2DM), the associated long-term health complications, and the financial burden of T2DM. A systematic review of the literature was undertaken. PubMed, Embase, Medline, CINAHL and the Cochrane library databases were searched using well-defined search terms. Predefined inclusion and exclusion criteria were used to identify relevant manuscripts. Data extractions and quality assessments were performed by one reviewer and checked by a second reviewer. Eleven primary studies of various research design and three systematic reviews were included. We identified seven themes within these studies and these were described in two categories, barriers and interventions. There appeared to be no single intervention that would overcome all the identified barriers, however, reminders to women and healthcare professionals appear to be most effective. Uptake rates of testing for T2DM are low in women with GDM. Interventions developed with consideration of the identified barriers to uptake could promote greater numbers of women attending for follow-up.

Comparative efficacy and safety of licensed treatments for previously treated non-small cell lung cancer: A systematic review and network meta-analysis.

PURPOSE: This systematic review with network meta-analysis compared the efficacy and safety of currently licensed second-line treatments in patients with late stage non-small cell lung cancer (NSCLC). METHODS: Randomised controlled trials (RCTs) of participants with advanced/metastatic NSCLC receiving second/third line treatments were screened. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 to July, 2017. Two reviewers screened bibliographic records, extracted data, and assessed risk of bias of included studies. The outcomes were overall survival (OS), progression-free survival (PFS), and drug-related grade 3-5 adverse-events (AEs). We pooled study-specific hazard ratios (HR; for OS and PFS) and risk ratios (RR; for AEs) using conventional and network-meta-analyses, and ranked interventions by the surface under the cumulative ranking curve. FINDINGS: We included 11 RCTs (7,581 participants) comparing nine drugs. All drugs except for erlotinib significantly improved OS compared to docetaxel. Nivolumab was the highest ranking drug followed by atezolizumab and pembrolizumab. There was no significant difference in OS across these three drugs (HR = 0.98, 95% CI 0.79, 1.21 for nivolumab vs atezolizumab; HR = 0.98, 95% CI 0.77, 1.25 for nivolumab vs pembrolizumab). For PFS, ramucirumab + docetaxel and nivolumab were the drugs with the highest ranking. All interventions except ramucirumab + docetaxel had a reduced risk for severe drug-related AEs vs. docetaxel. Of the drugs with the highest ranking on AEs, nivolumab was significantly safer compared to atezolizumab (RR = 0.55, 95% CI 0.38, 0.79) or pembrolizumab (RR = 0.52, 95% CI 0.34, 0.81). IMPLICATIONS: Nivolumab, pembrolizumab and atezolizumab exhibited superior benefit/risk balance compared to other licensed drugs used late stage NSCLC. Our results indicate that the use of immunotherapies in people diagnosed with non-specific late stage NSCLC should be promoted. The use of docetaxel may now be judged irrelevant as a comparator intervention for approval of new drugs for second line treatment of NSCLC. STUDY REGISTRATION NUMBER: PROSPERO CRD42017065928.

Treatments for dry age-related macular degeneration and Stargardt disease: a systematic review.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of visual loss in older people. Advanced AMD takes two forms, neovascular (wet) and atrophic (dry). Stargardt disease (STGD) is the commonest form of inherited macular dystrophy. OBJECTIVE: To carry out a systematic review of treatments for dry AMD and STGD, and to identify emerging treatments where future NIHR research might be commissioned. DESIGN: Systematic review. METHODS: We searched MEDLINE, EMBASE, Web of Science and The Cochrane Library from 2005 to 13 July 2017 for reviews, journal articles and meeting abstracts. We looked for studies of interventions that aim to preserve or restore vision in people with dry AMD or STGD. The most important outcomes are those that matter to patients: visual acuity (VA), contrast sensitivity, reading speed, ability to drive, adverse effects of treatment, quality of life, progression of disease and patient preference. However, visual loss is a late event and intermediate predictors of future decline were accepted if there was good evidence that they are strong predictors of subsequent visual outcomes. These include changes detectable by investigation, but not necessarily noticed by people with AMD or STGD. ClinicalTrials.gov, the World Health Organization search portal and the UK Clinical Trials gateway were searched for ongoing and recently completed clinical trials. RESULTS: The titles and abstracts of 7948 articles were screened for inclusion. The full text of 398 articles were obtained for further screening and checking of references and 112 articles were included in the final report. Overall, there were disappointingly few good-quality studies (including of sufficient size and duration) reporting useful outcomes, particularly in STGD. However we did identify a number of promising research topics, including drug treatments, stem cells, new forms of laser treatment, and implantable intraocular lens telescopes. In many cases, research is already under way, funded by industry or governments. LIMITATIONS: In AMD, the main limitation came from the poor quality of much of the evidence. Many studies used VA as their main outcome despite not having sufficient duration to observe changes. The evidence on treatments for STGD is sparse. Most studies tested interventions with no comparison group, were far too short term, and the quality of some studies was poor. FUTURE WORK: We think that the topics on which the Health Technology Assessment (HTA) and Efficacy Mechanism and Evaluation (EME) programmes might consider commissioning primary research are in STGD, a HTA trial of fenretinide (ReVision Therapeutics, San Diego, CA, USA), a visual cycle inhibitor, and EME research into the value of lutein and zeaxanthin supplements, using short-term measures of retinal function. In AMD, we suggest trials of fenretinide and of a potent statin. There is epidemiological evidence from the USA that the drug, levodopa, used for treating Parkinson's disease, may reduce the incidence of AMD. We suggest that similar research should be carried out using the large general practice databases in the UK. Ideally, future research should be at earlier stages in both diseases, before vision is impaired, using sensitive measures of macular function. This may require early detection of AMD by screening. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016038708. FUNDING: The National Institute for Health Research HTA programme.

A cluster randomised trial, cost-effectiveness analysis and psychosocial evaluation of insulin pump therapy compared with multiple injections during flexible intensive insulin therapy for type 1 diabetes: the REPOSE Trial.

BACKGROUND: Insulin is generally administered to people with type 1 diabetes mellitus (T1DM) using multiple daily injections (MDIs), but can also be delivered using infusion pumps. In the UK, pumps are recommended for patients with the greatest need and adult use is less than in comparable countries. Previous trials have been small, of short duration and have failed to control for training in insulin adjustment. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of pump therapy compared with MDI for adults with T1DM, with both groups receiving equivalent structured training in flexible insulin therapy. DESIGN: Pragmatic, multicentre, open-label, parallel-group cluster randomised controlled trial, including economic and psychosocial evaluations. After participants were assigned a group training course, courses were randomly allocated in pairs to either pump or MDI. SETTING: Eight secondary care diabetes centres in the UK. PARTICIPANTS: Adults with T1DM for > 12 months, willing to undertake intensive insulin therapy, with no preference for pump or MDI, or a clinical indication for pumps. INTERVENTIONS: Pump or MDI structured training in flexible insulin therapy, followed up for 2 years. MDI participants used insulin analogues. Pump participants used a Medtronic Paradigm® VeoTM (Medtronic, Watford, UK) with insulin aspart (NovoRapid, Novo Nordisk, Gatwick, UK). MAIN OUTCOME MEASURES: Primary outcome - change in glycated haemoglobin (HbA1c) at 2 years in participants whose baseline HbA1c was ≥ 7.5% (58 mmol/mol). Key secondary outcome - proportion of participants with HbA1c ≤ 7.5% at 2 years. Other outcomes at 6, 12 and 24 months - moderate and severe hypoglycaemia; insulin dose; body weight; proteinuria; diabetic ketoacidosis; quality of life (QoL); fear of hypoglycaemia; treatment satisfaction; emotional well-being; qualitative interviews with participants and staff (2 weeks), and participants (6 months); and ICERs in trial and modelled estimates of cost-effectiveness. RESULTS: We randomised 46 courses comprising 317 participants: 267 attended a Dose Adjustment For Normal Eating course (132 pump; 135 MDI); 260 were included in the intention-to-treat analysis, of which 235 (119 pump; 116 MDI) had baseline HbA1c of ≥ 7.5%. HbA1c and severe hypoglycaemia improved in both groups. The drop in HbA1c% at 2 years was 0.85 on pump and 0.42 on MDI. The mean difference (MD) in HbA1c change at 2 years, at which the baseline HbA1c was ≥ 7.5%, was -0.24% [95% confidence interval (CI) -0.53% to 0.05%] in favour of the pump (p = 0.098). The per-protocol analysis showed a MD in change of -0.36% (95% CI -0.64% to -0.07%) favouring pumps (p = 0.015). Pumps were not cost-effective in the base case and all of the sensitivity analyses. The pump group had greater improvement in diabetes-specific QoL diet restrictions, daily hassle plus treatment satisfaction, statistically significant at 12 and 24 months and supported by qualitative interviews. LIMITATION: Blinding of pump therapy was not possible, although an objective primary outcome was used. CONCLUSION: Adding pump therapy to structured training in flexible insulin therapy did not significantly enhance glycaemic control or psychosocial outcomes in adults with T1DM. RESEARCH PRIORITY: To understand why few patients achieve a HbA1c of < 7.5%, particularly as glycaemic control is worse in the UK than in other European countries. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61215213. 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. 21, No. 20. See the NIHR Journals Library website for further project information.

Autologous chondrocyte implantation in the knee: systematic review and economic evaluation.

BACKGROUND: The surfaces of the bones in the knee are covered with articular cartilage, a rubber-like substance that is very smooth, allowing frictionless movement in the joint and acting as a shock absorber. The cells that form the cartilage are called chondrocytes. Natural cartilage is called hyaline cartilage. Articular cartilage has very little capacity for self-repair, so damage may be permanent. Various methods have been used to try to repair cartilage. Autologous chondrocyte implantation (ACI) involves laboratory culture of cartilage-producing cells from the knee and then implanting them into the chondral defect. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of ACI in chondral defects in the knee, compared with microfracture (MF). DATA SOURCES: A broad search was done in MEDLINE, EMBASE, The Cochrane Library, NHS Economic Evaluation Database and Web of Science, for studies published since the last Health Technology Assessment review. REVIEW METHODS: Systematic review of recent reviews, trials, long-term observational studies and economic evaluations of the use of ACI and MF for repairing symptomatic articular cartilage defects of the knee. A new economic model was constructed. Submissions from two manufacturers and the ACTIVE (Autologous Chondrocyte Transplantation/Implantation Versus Existing Treatment) trial group were reviewed. Survival analysis was based on long-term observational studies. RESULTS: Four randomised controlled trials (RCTs) published since the last appraisal provided evidence on the efficacy of ACI. The SUMMIT (Superiority of Matrix-induced autologous chondrocyte implant versus Microfracture for Treatment of symptomatic articular cartilage defects) trial compared matrix-applied chondrocyte implantation (MACI®) against MF. The TIG/ACT/01/2000 (TIG/ACT) trial compared ACI with characterised chondrocytes against MF. The ACTIVE trial compared several forms of ACI against standard treatments, mainly MF. In the SUMMIT trial, improvements in knee injury and osteoarthritis outcome scores (KOOSs), and the proportion of responders, were greater in the MACI group than in the MF group. In the TIG/ACT trial there was improvement in the KOOS at 60 months, but no difference between ACI and MF overall. Patients with onset of symptoms < 3 years' duration did better with ACI. Results from ACTIVE have not yet been published. Survival analysis suggests that long-term results are better with ACI than with MF. Economic modelling suggested that ACI was cost-effective compared with MF across a range of scenarios. LIMITATIONS: The main limitation is the lack of RCT data beyond 5 years of follow-up. A second is that the techniques of ACI are evolving, so long-term data come from trials using forms of ACI that are now superseded. In the modelling, we therefore assumed that durability of cartilage repair as seen in studies of older forms of ACI could be applied in modelling of newer forms. A third is that the high list prices of chondrocytes are reduced by confidential discounting. The main research needs are for longer-term follow-up and for trials of the next generation of ACI. CONCLUSIONS: The evidence base for ACI has improved since the last appraisal by the National Institute for Health and Care Excellence. In most analyses, the incremental cost-effectiveness ratios for ACI compared with MF appear to be within a range usually considered acceptable. Research is needed into long-term results of new forms of ACI. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013083. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation.

BACKGROUND: Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. OBJECTIVE: To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin. SOURCES: MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions. METHODS: Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers. RESULTS: We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP). LIMITATIONS: There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking. CONCLUSIONS: Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Boehringer Ingelheim, Bracknell, UK). FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Indirect effects of childhood pneumococcal conjugate vaccination on invasive pneumococcal disease: a systematic review and meta-analysis.

BACKGROUND: The full extent to which childhood pneumococcal conjugate vaccines (PCV) can indirectly reduce illness in unvaccinated populations is not known. We aimed to estimate the magnitude and timing of indirect effects of PCVs on invasive pneumococcal disease. METHODS: In this systematic review and meta-analysis, we searched bibliographic databases for non-randomised quasi-experimental or observational studies reporting invasive pneumococcal disease changes following PCV introduction in unvaccinated populations (studies published Sept 1, 2010, to Jan 6, 2016), updating the previous systematic review of the same topic (studies published Jan 1, 1994, to Sept 30, 2010). Two reviewers extracted summary data by consensus. We used a Bayesian mixed-effects model to account for between-study heterogeneity to estimate temporal indirect effects by pooling of invasive pneumococcal disease changes by serotype and serogroup. FINDINGS: Data were extracted from 70 studies included in the previous review and 172 additional studies, covering 27 high-income and seven middle-income countries. The predicted mean times to attaining a 90% reduction in invasive pneumococcal disease were 8·9 years (95% credible interval [CrI] 7·8-10·3) for grouped serotypes contained in the seven-valent PCV (PCV7), and 9·5 years (6·1-16·6) for the grouped six additional serotypes contained in the 13-valent PCV (PCV13) but not in PCV7. Disease due to grouped serotypes contained in the 23-valent pneumococcal polysaccharide vaccine (PPV23) decreased at similar rates per year in adults aged 19-64 years (relative risk [RR] 0·85, 95% CrI 0·75-0·95) and 65 years and older (0·87, 0·84-0·90). However, we noted no changes in either group in invasive pneumococcal disease caused by the additional 11 serotypes covered by PPV23 but not PCV13. INTERPRETATION: Population childhood PCV programmes will lead, on average, to substantial protection across the whole population within a decade. This large indirect protection should be considered when assessing vaccination of older age groups. FUNDING: Policy Research Programme of the Department of Health, England.

Macular disease research in the United Kingdom 2011-2014: a bibliometric analysis of outputs, performance and coverage.

BACKGROUND: Bibliometric indicators, based on measuring patterns of publications and citations, are widely used by universities and research funders to assess research performance. Our aims were to: (1) perform a bibliometric analysis of UK macular disease research publications from 2011 to 2014 and compare this with the other countries producing major output in the area, and (2) compare the pattern of UK macular disease publication with the priorities for age-related macular degeneration (AMD) developed by the Sight Loss and Vision Priority Setting Partnership (SLV-PSP). METHODS: We used the Scopus database to retrieve macular disease articles published from 2011 to 2014. Citations to articles from 2011 to 2013 and journal impact factors (JIFs) for 2014 articles were obtained. Articles with UK authors were allocated to the 10 SLV-PSP priorities for age-related macular degeneration (AMD), where possible. RESULTS: The UK, USA, and Germany and China were the top four producers of macular disease research from 2011 to 2013. All except China had a higher proportion of citations than articles. There were 421 articles with UK authors published from 2011 to 2014, of which 49% had international collaborators. The UK produced 9.7% of the world's output of macular disease articles from 2011 to 2013, but received 14.2% of the world's share of citations. UK authors' share of the world's top 10% of cited publications from 2011 to 2013 was 16.2%. In 2014, 13.2% of UK articles were in journals in the top 10% when ranked by Journal Impact Factors (JIFs), while the overall UK article share for that year was 9.9%. UK articles did not show a strong correlation between citations and JIFs. The SLV-PSP published a set of 10 priorities for research into age-related macular degeneration in October 2103. Only 8% of the UK's 2011-2014 publications matched the SLV-PSP top priority (treatment to stop dry AMD progressing) and 34% did not match any of the SLV-PSP priorities, mainly because the priorities did not include invasive treatment of wet AMD. CONCLUSIONS: The UK is performing well in macular research, based on bibliometric indicators. The distribution of past research topics does not match the priorities set by the SLV-PSP.

Pan-retinal photocoagulation and other forms of laser treatment and drug therapies for non-proliferative diabetic retinopathy: systematic review and economic evaluation.

BACKGROUND: Diabetic retinopathy is an important cause of visual loss. Laser photocoagulation preserves vision in diabetic retinopathy but is currently used at the stage of proliferative diabetic retinopathy (PDR). OBJECTIVES: The primary aim was to assess the clinical effectiveness and cost-effectiveness of pan-retinal photocoagulation (PRP) given at the non-proliferative stage of diabetic retinopathy (NPDR) compared with waiting until the high-risk PDR (HR-PDR) stage was reached. There have been recent advances in laser photocoagulation techniques, and in the use of laser treatments combined with anti-vascular endothelial growth factor (VEGF) drugs or injected steroids. Our secondary questions were: (1) If PRP were to be used in NPDR, which form of laser treatment should be used? and (2) Is adjuvant therapy with intravitreal drugs clinically effective and cost-effective in PRP? ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) for efficacy but other designs also used. DATA SOURCES: MEDLINE and EMBASE to February 2014, Web of Science. REVIEW METHODS: Systematic review and economic modelling. RESULTS: The Early Treatment Diabetic Retinopathy Study (ETDRS), published in 1991, was the only trial designed to determine the best time to initiate PRP. It randomised one eye of 3711 patients with mild-to-severe NPDR or early PDR to early photocoagulation, and the other to deferral of PRP until HR-PDR developed. The risk of severe visual loss after 5 years for eyes assigned to PRP for NPDR or early PDR compared with deferral of PRP was reduced by 23% (relative risk 0.77, 99% confidence interval 0.56 to 1.06). However, the ETDRS did not provide results separately for NPDR and early PDR. In economic modelling, the base case found that early PRP could be more effective and less costly than deferred PRP. Sensitivity analyses gave similar results, with early PRP continuing to dominate or having low incremental cost-effectiveness ratio. However, there are substantial uncertainties. For our secondary aims we found 12 trials of lasers in DR, with 982 patients in total, ranging from 40 to 150. Most were in PDR but five included some patients with severe NPDR. Three compared multi-spot pattern lasers against argon laser. RCTs comparing laser applied in a lighter manner (less-intensive burns) with conventional methods (more intense burns) reported little difference in efficacy but fewer adverse effects. One RCT suggested that selective laser treatment targeting only ischaemic areas was effective. Observational studies showed that the most important adverse effect of PRP was macular oedema (MO), which can cause visual impairment, usually temporary. Ten trials of laser and anti-VEGF or steroid drug combinations were consistent in reporting a reduction in risk of PRP-induced MO. LIMITATION: The current evidence is insufficient to recommend PRP for severe NPDR. CONCLUSIONS: There is, as yet, no convincing evidence that modern laser systems are more effective than the argon laser used in ETDRS, but they appear to have fewer adverse effects. We recommend a trial of PRP for severe NPDR and early PDR compared with deferring PRP till the HR-PDR stage. The trial would use modern laser technologies, and investigate the value adjuvant prophylactic anti-VEGF or steroid drugs. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005408. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Bibliometrics of NIHR HTA monographs and their related journal articles.

OBJECTIVES: A bibliometric analysis of the UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) monographs and their related journal articles by: (1) exploring the differences in citations to the HTA monographs in Google Scholar (GS), Scopus and Web of Science (WoS), and (2) comparing Scopus citations to the monographs with their related journal articles. SETTING: A study of 111 HTA monographs published in 2010 and 2011, and their external journal articles. MAIN OUTCOME MEASURES: Citations to the monographs in GS, Scopus and WoS, and to their external journal articles in Scopus. RESULTS: The number of citations varied among the three databases, with GS having the highest and WoS the lowest; however, the citation-based rankings among the databases were highly correlated. Overall, 56% of monographs had a related publication, with the highest proportion for primary research (76%) and lowest for evidence syntheses (43%). There was a large variation in how the monographs were cited, compared to journal articles, resulting in more frequent problems, with unlinked citations in Scopus and WoS. When comparing differences in the number of citations between monograph publications with their related journal articles from the same project, we found that monographs received more citations than their journal articles for evidence syntheses and methodology projects; by contrast, journal articles related to primary research monographs were more highly cited than their monograph. CONCLUSIONS: The numbers of citations to the HTA monographs differed considerably between the databases, but were highly correlated. When a HTA monograph had a journal article from the same study, there were more citations to the journal article for primary research, but more to the monographs for evidence syntheses. Citations to the related journal articles were more reliably recorded than citations to the HTA monographs.