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/

The GLP-1 receptor agonist, liraglutide, fails to slow disease progression in SOD1G93A and TDP-43Q331K transgenic mouse models of ALS

GLP-1 receptor agonists used for the treatment of diabetes, have shown some neuroprotective effects in cellular and animal models of Alzheimer’s disease (AD) and Parkinson’s disease (PD). There are currently few studies investigating GLP-1 receptor agonists in the treatment of ALS, where these neuroprotective effects may be beneficial. Here we investigate the effects of liraglutide, a GLP-1 receptor agonist, in two well characterised transgenic mouse models of ALS (SOD1G93A and TDP-43Q331K) to determine if liraglutide could be a potential treatment in ALS patients. Doses of liraglutide previously shown to have efficacy in AD and PD mouse models were used. Behavioural testing was carried out to ascertain the effect of liraglutide on disease progression. Immunohistochemical analysis of tissue was used to determine any neuroprotective effects on the CNS. We found that liraglutide dosed animals showed no significant differences in disease progression when compared to vehicle dosed animals in either the SOD1G93A or TDP-43Q331K mouse models of ALS. We also observed no changes in motor neuron counts or glial activation in lumbar spinal cords of liraglutide treated mice compared to vehicle dosed mice. Overall, we found no evidence to support clinical evaluation of liraglutide as a potential candidate for the treatment of ALS

Protocol of a randomised trial of teriparatide followed by zoledronic acid to reduce fracture risk in adults with osteogenesis imperfecta

Introduction: Osteogenesis imperfecta (OI) is a rare genetic disease associated with multiple fractures throughout life. It is often treated with osteoporosis medications but their effectiveness at preventing fractures is unknown. The Treatment of Osteogenesis Imperfecta with Parathyroid Hormone and Zoledronic Acid trial will determine if therapy with teriparatide (TPTD) followed by zoledronic acid (ZA) can reduce the risk of clinical fractures in OI. Methods and analysis: Individuals aged ≥18 years with a clinical diagnosis of OI are eligible to take part. At baseline, participants will undergo a spine X-ray, and have bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) at the spine and hip. Information on previous fractures and previous bone targeted treatments will be collected. Questionnaires will be completed to assess pain and other aspects of health-related quality of life (HRQoL). Participants will be randomised to receive a 2-year course of TPTD injections 20 µg daily followed by a single intravenous infusion of 5 mg ZA, or to receive standard care, which will exclude the use of bone anabolic drugs. Participants will be followed up annually, have a repeat DXA at 2 years and at the end of study. Spine X-rays will be repeated at the end of study. The duration of follow-up will range between 2 and 8 years. The primary endpoint will be new clinical fractures confirmed by X-ray or other imaging. Secondary endpoints will include participant reported fractures, BMD and changes in pain and HRQoL. Ethics and dissemination: The study received ethical approval in December 2016. Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results will inform clinical practice by determining if TPTD/ZA can reduce the risk of fractures in OI compared with standard care. Trial registration number: ISRCTN15313991

Sex-Specific Thresholds of High-Sensitivity Troponin in Patients With Suspected Acute Coronary Syndrome.

BACKGROUND: Major disparities between women and men in the diagnosis, management, and outcomes of acute coronary syndrome are well recognized. OBJECTIVES: The aim of this study was to evaluate the impact of implementing a high-sensitivity cardiac troponin I assay with sex-specific diagnostic thresholds for myocardial infarction in women and men with suspected acute coronary syndrome. METHODS: Consecutive patients with suspected acute coronary syndrome were enrolled in a stepped-wedge, cluster-randomized controlled trial across 10 hospitals. Myocardial injury was defined as high-sensitivity cardiac troponin I concentration >99th centile of 16 ng/l in women and 34 ng/l in men. The primary outcome was recurrent myocardial infarction or cardiovascular death at 1 year. RESULTS: A total of 48,282 patients (47% women) were included. Use of the high-sensitivity cardiac troponin I assay with sex-specific thresholds increased myocardial injury in women by 42% and in men by 6%. Following implementation, women with myocardial injury remained less likely than men to undergo coronary revascularization (15% vs. 34%) and to receive dual antiplatelet (26% vs. 43%), statin (16% vs. 26%), or other preventive therapies (p < 0.001 for all). The primary outcome occurred in 18% (369 of 2,072) and 17% (488 of 2,919) of women with myocardial injury before and after implementation, respectively (adjusted hazard ratio: 1.11; 95% confidence interval: 0.92 to 1.33), compared with 18% (370 of 2,044) and 15% (513 of 3,325) of men (adjusted hazard ratio: 0.85; 95% confidence interval: 0.71 to 1.01). CONCLUSIONS: Use of sex-specific thresholds identified 5 times more additional women than men with myocardial injury. Despite this increase, women received approximately one-half the number of treatments for coronary artery disease as men, and outcomes were not improved. (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome [High-STEACS]; NCT01852123)

Data sharing in clinical trials - practical guidance on anonymising trial datasets

Asthma UK Centre for Applied Research (AUKCAR

High-Sensitivity Cardiac Troponin and the Universal Definition of Myocardial Infarction.

Background: The introduction of more sensitive cardiac troponin assays has led to increased recognition of myocardial injury in acute illnesses other than acute coronary syndrome. The Universal Definition of Myocardial Infarction recommends high-sensitivity cardiac troponin (hs-cTn) testing and classification of patients with myocardial injury based on aetiology, but the clinical implications of implementing this guideline are not well understood. Methods: In a stepped-wedge cluster randomized controlled trial, we implemented a hs-cTn assay and the recommendations of the Universal Definition in 48,282 consecutive patients with suspected acute coronary syndrome. In a pre-specified secondary analysis, we compared the primary outcome of myocardial infarction or cardiovascular death and secondary outcome of non-cardiovascular death at one year across diagnostic categories. Results: Implementation increased the diagnosis of type 1 myocardial infarction by 11% (510/4,471), type 2 myocardial infarction by 22% (205/916), and acute and chronic myocardial injury by 36% (443/1,233) and 43% (389/898), respectively. Compared to those without myocardial injury, the rate of the primary outcome was highest in those with type 1 myocardial infarction (cause-specific hazard ratio [csHR] 5.64, 95% confidence interval [CI] 5.12 to 6.22), but was similar across diagnostic categories, whereas non-cardiovascular deaths were highest in those with acute myocardial injury (csHR 2.65, 95%CI 2.33 to 3.01). Despite modest increases in anti-platelet therapy and coronary revascularization after implementation in patients with type 1 myocardial infarction, the primary outcome was unchanged (csHR 1.00, 95%CI 0.82 to 1.21). Increased recognition of type 2 myocardial infarction and myocardial injury did not lead to changes in investigation, treatment or outcomes. Conclusions: Implementation of high-sensitivity cardiac troponin and the recommendations of the Universal Definition of Myocardial Infarction identified patients at high-risk of cardiovascular and non-cardiovascular events, but was not associated with consistent increases in treatment or improved outcomes. Trials of secondary prevention are urgently required to determine whether this risk is modifiable in patients without type 1 myocardial infarction. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT0185212

A restrictive versus liberal transfusion strategy to prevent myocardial injury in patients undergoing surgery for fractured neck of femur:a feasibility randomised controlled trial (RESULT-NOF)

BackgroundThe optimum transfusion strategy in patients with fractured neck of femur is uncertain, particularly if there is coexisting cardiovascular disease. MethodsWe conducted a prospective, single-centre, randomised feasibility trial of two transfusion strategies. We randomly assigned patients undergoing surgery for fractured neck of femur to a restrictive (haemoglobin, 70–90 g L −1) or liberal (haemoglobin, 90–110 g L −1) transfusion strategy throughout their hospitalisation. Feasibility outcomes included: enrolment rate, protocol compliance, difference in haemoglobin, and blood exposure. The primary clinical outcome was myocardial injury using troponin estimations. Secondary outcomes included major adverse cardiac events, postoperative complications, duration of hospitalisation, mortality, and quality of life. ResultsWe enrolled 200 (22%) of 907 eligible patients, and 62 (31%) showed decreased haemoglobin (to 90 g L −1 or less) and were thus exposed to the intervention. The overall protocol compliance was 81% in the liberal group and 64% in the restrictive group. Haemoglobin concentrations were similar preoperatively and at postoperative day 1 but lower in the restrictive group on day 2 (mean difference [MD], 7.0 g L −1; 95% confidence interval [CI], 1.6–12.4). Lowest haemoglobin within 30 days/before discharge was lower in the restrictive group (MD, 5.3 g L −1; 95% CI, 1.7–9.0). Overall, 58% of patients in the restrictive group received no transfusion compared with 4% in the liberal group (difference in proportion, 54.5%; 95% CI, 36.8–72.2). The proportion with the primary clinical outcome was 14/26 (54%, liberal) vs 24/34 (71%, restrictive), and the difference in proportion was –16.7% (95% CI, –41.3 to 7.8; P=0.18). ConclusionA clinical trial of two transfusion strategies in hip fracture with a clinically relevant cardiac outcome is feasible

Troponin in Acute Chest Pain to Risk Stratify and Guide Effective Use of Computed Tomography Coronary Angiography (TARGET-CTCA): A Randomised Controlled Trial

BACKGROUND: The majority of patients with suspected acute coronary syndrome presenting to the emergency department will be discharged once myocardial infarction has been ruled out, although a proportion will have unrecognised coronary artery disease. In this setting, high-sensitivity cardiac troponin identifies those at increased risk of future cardiac events. In patients with intermediate cardiac troponin concentrations in whom myocardial infarction has been ruled out, this trial aims to investigate whether outpatient computed tomography coronary angiography (CTCA) reduces subsequent myocardial infarction or cardiac death. METHODS: TARGET-CTCA is a multicentre prospective randomised open label with blinded endpoint parallel group event driven trial. After myocardial infarction and clear alternative diagnoses have been ruled out, participants with intermediate cardiac troponin concentrations (5 ng/L to 99th centile upper reference limit) will be randomised 1:1 to outpatient CTCA plus standard of care or standard of care alone. The primary endpoint is myocardial infarction or cardiac death. Secondary endpoints include clinical, patient-centred, process and cost-effectiveness. Recruitment of 2270 patients will give 90% power with a two-sided P value of 0.05 to detect a 40% relative risk reduction in the primary endpoint. Follow-up will continue until 97 primary outcome events have been accrued in the standard care arm with an estimated median follow-up of 36 months. DISCUSSION: This randomised controlled trial will determine whether high-sensitivity cardiac troponin-guided CTCA can improve outcomes and reduce subsequent major adverse cardiac events in patients presenting to the emergency department who do not have myocardial infarction