Prophylactic zoledronic acid therapy to prevent or modify Paget’s disease of bone progression in adults with SQSTM1 mutations: the ZiPP RCT

Background:Paget’s disease of bone is characterised by focal abnormalities of bone turnover resulting in various complications. It often presents at an advanced stage with irreversible bone damage. At this point, the symptomatic benefits of treatment are blunted. Paget’s disease of bone has a strong genetic component and the most important susceptibility gene is SQSTM1. Carriers of SQSTM1 mutations have more severe disease with an earlier age of onset than non-carriers and about 80% develop Paget’s disease of bone by the seventh decade.Objectives:The primary objective was to determine if zoledronic acid could prevent new Paget’s disease of bone-like bone lesions in SQSTM1 mutation carriers. Secondary objectives were to assess if zoledronic acid could: modify existing Paget’s disease of bone lesions, markers of bone turnover, quality of life, bone pain, anxiety, depression or the risk of complications.Design:This was a multicentre, double-blind placebo-controlled trial. Genetic screening of the SQSTM1 gene was offered to people with a family history of Paget’s disease of bone, identifying 222 mutation carriers who consented to participate. At baseline, a radionuclide bone scan was performed; biochemical markers of bone turnover were measured and questionnaires on pain, quality of life and mental health were completed. Participants completed annual biochemical markers measurements and questionnaires. Adverse events were recorded on a continuous basis. At the end of study, the bone scan was repeated, along with biochemical markers and questionnaires.Setting:This was a multicentre trial that was conducted at 27 secondary care referral centres for bone disease in 7 countries. All the visits were conducted within a secondary healthcare setting.Participants Interventions:Participants were randomly allocated to receive a single infusion of the bisphosphonate zoledronic acid 5 mg or an identical placebo.Main outcome measures:The study’s primary outcome measure was defined as the total number of participants who developed new bone lesions on radionuclide bone scans with the characteristics of PDB between the baseline visit and the final end-of-study visit. The secondary outcomes included the number of new PDB bone lesions on radionuclide bone scans, change in the activity of existing PDB bone lesions at the end of study assessed by radionuclide scans; changes in plasma type I collagen C-telopeptides (CTX); plasma procollagen type I amino-terminal propeptide (PINP); serum bone-specific alkaline phosphatase (BAP); quality of life assessed by SF-36, BPI, HADS questionnaires; the presence and severity of localized bone pain assessed by the BPI pain manikin; and the development of PDB-related skeletal events (PDRSE) in SQSTM1 mutation carriers including new lesions, complications (fractures, deformity), or the need for treatment of PDB.Methods:This was a multicentre, double-blind placebo-controlled trial. Genetic screening of the SQSTM1 gene was offered to people with a family history of Paget’s disease of bone, identifying 222 mutation carriers who consented to participate. At baseline, a radionuclide bone scan was performed; biochemical markers of bone turnover were measured and questionnaires on pain, quality of life and mental health were completed. Participants were randomly allocated to receive a single infusion of the bisphosphonate zoledronic acid 5 mg or an identical placebo. Participants completed annual biochemical markers measurements and questionnaires. Adverse events were recorded on a continuous basis. At the end of study, the bone scan was repeated, along with biochemical markers and questionnaires.Results:At baseline, 21/222 individuals (9.5%) had evidence of Paget’s disease of bone on bone scans. In the placebo group, 2/90 individuals (2.2%) developed new bone lesions compared with 0/90 (0%) in the zoledronic acid group (odds ratio 0.41, 95% confidence interval 0.00 to 3.43; p = 0.25). Eight participants in the placebo group had a poor outcome (new/unchanged/progressing lesions) compared with none in the zoledronic acid group (odds ratio 0.08, 95% confidence interval 0.00 to 0.42; p = 0.003). With placebo, 1/29 (3.4%) lesions disappeared compared with 13/15 (86.6%) with zoledronic acid (p &lt; 0.0001). One participant allocated to placebo required treatment with zoledronic acid due to a complication of Paget’s disease of bone. Significant reductions were observed for serum C-terminal telopeptide (p &lt; 0.0001), bone-specific alkaline phosphatase (p = 0.0003) and N-terminal propeptide of type I procollagen (p &lt; 0.0001) in the zoledronic acid group compared with placebo. There was no significant difference between groups in quality of life, pain, anxiety or depression.Conclusion:Genetic testing for SQSTM1 mutations coupled with bone scan examination can detect early Paget’s disease of bone in those with a family history of the disorder and zoledronic acid treatment can favourably modify its evolution.The study had some limitations. First, 9.5% of participants already had Paget’s disease of bone, reducing power. Second, only two participants developed new lesions compared to the 15% expected. The small number of events meant the study was underpowered for the primary outcome and we were unable to adjust analyses for co-variates or family clustering.An extended follow-up in the zoledronic acid in the prevention of Paget’s disease – long-term extension study is in progress and will provide valuable information on the duration of effects of a single zoledronic acid infusion. It will be important to consider a health economic analysis to model the effects of genetic testing, scanning and zoledronic acid treatment, to evaluate long-term clinical and symptomatic benefits.<br/

Measuring the association between body mass index and all-cause mortality in the presence of missing data: analyses from the Scottish national diabetes register:Missing data in the Scottish diabetes register

Incorrectly handling missing data can lead to imprecise and biased estimates. We describe the effect of applying different approaches to handling missing data in an analysis of the association between body mass index and all-cause mortality in people with type 2 diabetes. Data from the Scottish diabetes register linked to hospital admissions data and death registrations were used. The analysis was based on people diagnosed with type 2 diabetes between 2004 and 2011 with follow-up until 2014. The association between body mass index and mortality was investigated using Cox proportional hazard models with comparison of findings using four different missing data methods; complete case analysis, two multiple imputation models and nearest neighbour imputation. There were 124,451 cases of type 2 diabetes, among which there were 17,085 deaths during 787,275 person-years of follow-up. Patients with missing data (24.8%) had higher mortality than those without (Adjusted hazard ratio: 1.36 [95% confidence interval: 1.31-1.41]). A U-shaped relationship between body mass index and mortality was observed, with the lowest hazard ratios occurring amongst moderately obese people, regardless of the chosen approach for handling missing data. Missing data may affect absolute and relative risk estimates differently and should be considered in analyses of routine data

Post stroke intervention trial in fatigue (POSITIF):Randomised multicentre feasibility trial

OBJECTIVE: To test the feasibility of a telephone delivered intervention, informed by cognitive behavioural principles, for post-stroke fatigue, and estimated its effect on fatigue and other outcomes. DESIGN: Randomised controlled parallel group trial. SETTING: Three Scottish stroke services. SUBJECTS: Stroke survivors with fatigue three months to two years post-stroke onset. INTERVENTIONS: Seven telephone calls (fortnightly then a ‘booster session’ at 16 weeks) of a manualised intervention, plus information about fatigue, versus information only. MAIN MEASURES: Feasibility of trial methods, and collected outcome measures (fatigue, mood, anxiety, social participation, quality of life, return to work) just before randomisation, at the end of treatment (four months after randomisation) and at six months after randomisation. RESULTS: Between October 2018 and January 2020, we invited 886 stroke survivors to participate in postal screening: 188/886 (21%) returned questionnaires and consented, of whom 76/188 (40%) were eligible and returned baseline forms; 64/76 (84%) returned six month follow-up questionnaires. Of the 39 allocated the intervention, 23 (59%) attended at least four sessions. At six months, there were no significant differences between the groups (adjusted mean differences in Fatigue Assessment Scale −0.619 (95% CI −4.9631, 3.694; p = 0.768), the Generalised Anxiety Disorder 7 −0.178 (95% CI −3.823, 3.467, p = 0.92), and the Patient Health Questionnaire −0.247 (95% CI −2.935, 2.442, p = 0.851). There were no between-group differences in quality of life, social participation or return to work. CONCLUSION: Patients can be recruited to a trial of this design. These data will inform the design of further trials in post-stroke fatigue

Current recommendations/practices for anonymising data from clinical trials in order to make it available for sharing:A scoping review

BACKGROUND/AIMS: There are increasing pressures for anonymised datasets from clinical trials to be shared across the scientific community, and differing recommendations exist on how to perform anonymisation prior to sharing. We aimed to systematically identify, describe and synthesise existing recommendations for anonymising clinical trial datasets to prepare for data sharing. METHODS: We systematically searched MEDLINE(®), EMBASE and Web of Science from inception to 8 February 2021. We also searched other resources to ensure the comprehensiveness of our search. Any publication reporting recommendations on anonymisation to enable data sharing from clinical trials was included. Two reviewers independently screened titles, abstracts and full text for eligibility. One reviewer extracted data from included papers using thematic synthesis, which then was sense-checked by a second reviewer. Results were summarised by narrative analysis. RESULTS: Fifty-nine articles (from 43 studies) were eligible for inclusion. Three distinct themes are emerging: anonymisation, de-identification and pseudonymisation. The most commonly used anonymisation techniques are: removal of direct patient identifiers; and careful evaluation and modification of indirect identifiers to minimise the risk of identification. Anonymised datasets joined with controlled access was the preferred method for data sharing. CONCLUSIONS: There is no single standardised set of recommendations on how to anonymise clinical trial datasets for sharing. However, this systematic review shows a developing consensus on techniques used to achieve anonymisation. Researchers in clinical trials still consider that anonymisation techniques by themselves are insufficient to protect patient privacy, and they need to be paired with controlled access

Physiological deterioration in the Emergency Department: the SNAP40-ED study

Continuous novel ambulatory monitoring may detect deterioration in Emergency Department (ED) patients more rapidly, prompting treatment and preventing adverse events. Single-centre, open-label, prospective, observational cohort study recruiting high/medium acuity (Manchester triage category 2 and 3) participants, aged over 16 years, presenting to ED. Participants were fitted with a novel wearable monitoring device alongside standard clinical care (wired monitoring and/or manual clinical staff vital sign recording) and observed for up to 4 hours in the ED. Primary outcome was time to detection of deterioration. Two-hundred and fifty (250) patients were enrolled. In 82 patients (32.8%) with standard monitoring (wired monitoring and/or manual clinical staff vital sign recording), deterioration in at least one vital sign was noted during their four-hour ED stay. Overall, the novel device detected deterioration a median of 34 minutes earlier than wired monitoring (Q1, Q3 67,194; n=73, mean difference 39.48, p<0.0001). The novel device detected deterioration a median of 24 minutes (Q1, Q3 2,43; n=42) earlier than wired monitoring and 65 minutes (Q1, Q3 28,114; n=31) earlier than manual vital signs. Deterioration in physiology was common in ED patients. ED staff spent a significant amount of time performing observations and responding to alarms, with many not escalated. The novel device detected deterioration significantly earlier than standard care

GALA: an international multicentre randomised trial comparing general anaesthesia versus local anaesthesia for carotid surgery

Background: Patients who have severe narrowing at or near the origin of the internal carotid artery as a result of atherosclerosis have a high risk of ischaemic stroke ipsilateral to the arterial lesion. Previous trials have shown that carotid endarterectomy improves long-term outcomes, particularly when performed soon after a prior transient ischaemic attack or mild ischaemic stroke. However, complications may occur during or soon after surgery, the most serious of which is stroke, which can be fatal. It has been suggested that performing the operation under local anaesthesia, rather than general anaesthesia, may be safer. Therefore, a prospective, randomised trial of local versus general anaesthesia for carotid endarterectomy was proposed to determine whether type of anaesthesia influences peri-operative morbidity and mortality, quality of life and longer term outcome in terms of stroke-free survival. Methods/design: A two-arm, parallel group, multicentre randomised controlled trial with a recruitment target of 5000 patients. For entry into the study, in the opinion of the responsible clinician, the patient requiring an endarterectomy must be suitable for either local or general anaesthesia, and have no clear indication for either type. All patients with symptomatic or asymptomatic internal carotid stenosis for whom open surgery is advised are eligible. There is no upper age limit. Exclusion criteria are: no informed consent; definite preference for local or general anaesthetic by the clinician or patient; patient unlikely to be able to co-operate with awake testing during local anaesthesia; patient requiring simultaneous bilateral carotid endarterectomy; carotid endarterectomy combined with another operation such as coronary bypass surgery; and, the patient has been randomised into the trial previously. Patients are randomised to local or general anaesthesia by the central trial office. The primary outcome is the proportion of patients alive, stroke free ( including retinal infarction) and without myocardial infarction 30 days post-surgery. Secondary outcomes include the proportion of patients alive and stroke free at one year; health related quality of life at 30 days; surgical adverse events, re-operation and re-admission rates; the relative cost of the two methods of anaesthesia; length of stay and intensive and high dependency bed occupancy

Addressing barriers and identifying facilitators to support informed consent and recruitment in the Cavernous malformations A Randomised Effectiveness (CARE) pilot phase trial:insights from the integrated QuinteT recruitment intervention (QRI)

BackgroundIt was anticipated that recruitment to the Cavernous malformations: A Randomised Effectiveness (CARE) pilot randomised trial would be challenging. The trial compared medical management and surgery (neurosurgical resection or stereotactic radiosurgery) with medical management alone, for people with symptomatic cerebral cavernous malformation (ISRCTN41647111). Previous trials comparing surgical and medical management for intracranial vascular malformations failed to recruit to target. A QuinteT Recruitment Intervention was integrated during trial accrual, September 2021–April 2023 inclusive, to improve informed consent and recruitment.MethodsThe QuinteT Recruitment Intervention combined iterative collection and analysis of quantitative data (28 trial site screening logs recording numbers/proportions screened, eligible, approached and randomised) and qualitative data (79 audio-recorded recruitment discussions, 19 interviews with healthcare professionals, 11 interviews with patients, 2 investigator workshops, and observations of study meetings, all subject to thematic, content or conversation analysis). We triangulated quantitative and qualitative data to identify barriers and facilitators to recruitment and how and why these arose. Working with the chief investigators and trial management group, we addressed barriers and facilitators with corresponding actions to improve informed consent and recruitment.FindingsBarriers identified included how usual care practices made equipoise challenging, multi-disciplinary teams sometimes overrode recruiter equipoise and logistical issues rendered symptomatic cavernoma diagnosis and assessment for stereotactic radiosurgery challenging. Facilitators identified included the preparedness of some neurosurgeons’ to offer surgery to people otherwise offered medical management alone, multi-disciplinary team equipoise, and effective information provision presenting participation as a solution to equipoise regarding management. Actions, before and during recruitment, to improve inclusivity of site screening, approach and effectiveness of information provision resulted in 72 participants recruited following a 5-month extension, exceeding the target of 60 participants.InterpretationQuinteT Recruitment Intervention insights revealed barriers and facilitators, enabling identification of remedial actions. Recruitment to a definitive trial would benefit from further training/support to encourage clinicians to be comfortable approaching patients to whom medical management is usually offered, and broadening the pool of neurosurgeons and multi-disciplinary team members prepared to offer surgery, particularly stereotactic radiosurgery