Sundern Hachen, Germany
Home Versus Hospital Based NIV Care in MND
Phase
N/ASpan
134 weeksSponsor
Papworth Hospital NHS Foundation TrustCambridge
Recruiting
taRgeting bEtA-Cell Function To achIeVe Remission of Type 2 diAbeTEs
This is a single-centre, open-label, randomised, parallel design study comparing up to 12 weeks of fully closed-loop insulin delivery to standard care with a glucose sensor in adults with recent-onset type 2 diabetes. Recruitment will target up to 56 participants to allow for drop-outs. Participants will be recruited from outpatient clinics at Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, local GP surgeries, social media advertising or other established practices at the centre. Written informed consent will be obtained from all participants before any study related activities. After obtaining informed consent, the baseline visit (including mixed meal tolerance test) and a 2-3 week run-in period, participants will be randomised to either 12 weeks use of fully closed-loop insulin delivery or 12 weeks during which they will apply their standard diabetes therapy with a glucose sensor. Participants in both groups will receive diet and lifestyle advice with specific focus on the impact of diet and lifestyle choices on glucose sensor readings and trends. Following the 12 weeks intervention period (and repeat mixed meal tolerance test) all participants will continue with standard diabetes therapy for nine months of follow-up (and final mixed meal tolerance test). Diabetes therapies will be adjusted every 3 months based on HbA1c. The study includes up to 5 visits and 6 telephone/email contacts. Visits 2 and 3 may be combined. All participants will continue to be seen by their clinical team at frequencies as appropriate in line with usual clinical practice. All study visits will be scheduled in addition to routine clinical visits and will be performed by the research team. Maximum time in the study is 56 weeks.
Phase
N/ASpan
210 weeksSponsor
University of CambridgeCambridge, Cambridgeshire
Recruiting
Cambridge
Recruiting
Healthy Volunteers
The Biomechanical Outcomes of Autologous Chondrocyte Implantation
Knee joint articular cartilage is a primary load-bearing surface that endures repetitive high impact loading during activities of daily living. Individuals of any age can injure the knee's articular cartilage. However, as cartilage has an innate limited capacity to regenerate, surgical interventions that adopt tissue engineering techniques are often necessary to repair cartilage and preserve the joint. Autologous chondrocyte implantation (ACI) is a surgical procedure that is offered to some patients with focal cartilage injuries of the knee. The first pilot study on the use of ACI in humans was published by Brittberg and colleagues in 1994. By 2010 35,000 ACI procedures had been performed worldwide. Patient-reported outcomes and survivorship of ACI have been well reported in current literature. However, objective biomechanical and functional outcomes of ACI patients are not well understood. This knowledge is essential for optimising treatment, because poor functional outcome is known to worsen quality of life. This is particularly true for patients of working age who wish to return to an active and independent lifestyle. The applicant recently conducted and published a systematic review on the functional outcome of ACI. The review identified only 19 eligible articles of 20 ACI cohorts. The data showed that the average range of motion (ROM) improved with clinical (>5˚) and statistical significance (p < 0.05) postoperatively: 130.5± 14.8˚ to 136.1±10.2º, however only 7 studies reported both pre- and post-operative RoM. Knee strength significantly improved within the first two postoperative years but remained poorer than control groups at final follow-up (n=11). The review also found no statistical differences between ACI and control groups in their ability to perform functional activities like the 6-minute walk and hop tests post-operatively (n = 8). Only two papers had published on the kinematics of gait post-operatively. Both papers reported the outcomes of the same cohort, stating that there were no significant differences in spatio-temporal parameters between ACI patients and controls post-operatively. However, kinematic differences were observed during two specific phases of the gait cycle. Differences were also reported in peak knee adduction and peak knee extension moments. The limited literature identified by this review highlighted the urgent need for research into the functional outcomes of joint preservation surgeries like ACI to optimise functional outcome.
Phase
N/ASpan
90 weeksSponsor
University of ManchesterCambridge
Recruiting
EMPA-ESUS. a Randomised Control Trial to Investigate the Impact of Empagliflozin on Left Atrial Function in Patients with Embolic Stroke of Undetermined Source
Background: Individuals who suffer an embolic stoke of undermined source represent 17% of all ischaemic stroke patients. When they undergo continuous cardiac rhythm monitoring with a loop recorder, a large portion of the population have been noted to develop atrial fibrillation (AF). In our own centre, 48.6% of patients have found to develop AF. This is considerably more than the proportion seen in patients undergoing ILR implantation for other reasons. What remains unclear is whether this AF may have been responsible for the initial stroke, or is a reflection of an underlying atrial cardiopathy. Moreover, it is felt that this device detected AF is an important risk factor for stroke recurrence. Recent trials have suggested that whilst anticoagulation for device detected AF reduces future stroke, this is at the expense of a significant bleeding risk. Thus far, there have been no therapies that prevent the occurrence of AF, even in groups at high risk of AF development. Obviously such a strategy would negate the risk of bleeding associated with anticoagulation use. Such a strategy would reflect a paradigm shift in AF management. Whilst studies have tried to explore the significance of abnormal atrial function in ESUS, generally crude assessments such as P-wave terminal force in V1 and brain natriuretic peptide had been utilised. Our group deep phenotyped over 300 ESUS patients. This work highlighted an important predictive role of left atrial strain for future device detected AF. Left atrial strain has shown great promise as a marker of atrial dysfunction. There is growing evidence that sodium glucose 2 co-transporter inhibitors, such as empagliflozin, may prevent the development of AF. There have been over a dozen metaanalyses of the safety data from the large SGLT2i outcome trials, which have consistently shown that the SGLT2i arm was associated with lower incident AF compared to the control arm. Similar results were seen in cohort studies including in Taiwan and the Food and Drug Association's adverse events reporting system. It is this finding that prompted the interest in utilising empagliflozin as the intervention in the trial. Study aims and objectives: The aims of this study are to assess if: SGLT2 inhibitors can prevent adverse changes in left atrial function in patients who are felt to have an increased chance of AF development. A nested MRI substudy will be used to try and provide mechanistic insight into how SGLT2 inhibitors may exert an antiarrhythmic effect. Methods: Given that the use of SGLT2 inhibitors to prevent atrial change has not been investigated before, we aim to investigate the hypotheses with an early stage randomised controlled trial. For this, patients undergoing implantable loop recorder insertion for AF detection following an embolic stroke of undetermined source will be invited to participate. The participants will be randomised either to usual stroke care or to the intervention arm (use of SGLT2 inhibitor in addition to usual stroke care). They will be assessed at baseline and at 6-months following initiation of the medication. Both appointments will include echocardiography, electrocardiography and anthropometric assessments such as weight and grip strength. From each arm, 10 patients will under also undergo advanced MRI imaging including MR spectroscopy, to try and investigate possible mechanisms for any effect of the SGLT2 inhibitor.
Phase
2/3Span
228 weeksSponsor
University of East AngliaCambridge, Cambridgeshire
Recruiting
A First-time in Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics and Target Engagement of GSK4528287 in Healthy Participants
Phase
1Span
95 weeksSponsor
GlaxoSmithKlineCambridge
Recruiting
Healthy Volunteers
PARTial BREast RECONstruction With Chest Wall Perforator Flap
The Main Outcomes and Measures are: A) Patient Demographics and Tumour characteristics 1. Patient demographics: age, body mass index (BMI), comorbidities 2. Preoperative tumour characteristics and location influencing surgical planning B) Treatment characteristics 1. Surgical: operative data, including flap types and distribution 2. Oncological: systemic therapies (adjuvant and neoadjuvant), radiotherapy
Phase
N/ASpan
157 weeksSponsor
Cambridge University Hospitals NHS Foundation TrustCambridge, Cambridgeshire
Recruiting
Sotagliflozin in Patients With Heart Failure Symptoms and Type 1 Diabetes
BACKGROUND Intensive insulin therapy designed to near-normalize glucose levels in people with type 1 diabetes significantly reduces an individual's risk of long-term micro- and macrovascular complications. Unfortunately, glycaemic targets are not achieved by the majority of people with type 1 diabetes and as such overall life expectancy remains reduced compared to those without type 1 diabetes. Cardiovascular disease remains a major cause of morbidity and mortality in type 1 diabetes. There is growing recognition that heart failure (HF) is an increasing problem in type 1 diabetes. Diabetes itself is an independent risk factor for HF, causing structural and functional cardiac changes that predispose to HF (known as diabetic cardiomyopathy). HF is the end result of many cardiovascular diseases such as hypertension and myocardial infarction, and improved treatments for these conditions and changing demographic trends mean that many more people are surviving longer and developing HF. HF has a substantial healthcare burden. In the United States (US) and Europe, the prevalence of HF in the general population is around 1-2% - around 6 million adults in the US are estimated to be living with HF currently. In 2014 in the US there were ~1.1 million emergency department visits, 980 000 hospitalizations, and 84 000 deaths with HF as the primary cause, with an estimated cost of ~$11.3 billion (~$11,500/per patient for each hospitalisation). Despite advances in management of HF over the past 30 years, the incidence of mortality and HF hospitalisation in recent HF clinical trials remained high at ~20-30% over 2 years. The burden of HF in type 1 diabetes is less well characterised compared to HF in those with type 2 diabetes (and individuals without diabetes), however the data still indicate the substantial nature of this growing problem. One of the largest epidemiological studies was a Scottish national data study of 3.25 million individuals >30 years old, where the crude incidence of HF hospitalisation was over twice that of the population without diabetes. While the crude incidence was less than in type 2 diabetes, type 1 diabetes patients were on average 20 years younger. Despite their younger age, 30-day mortality following HF hospitalisation was higher in individuals with type 1 diabetes after adjustment for age, sex and socioeconomic status, indicating that outcomes are worse in HF patients with type 1 diabetes compared to those with either type 2 diabetes or without diabetes. Data from Scandinavia supports this finding and suggests that the risk of both incident HF and cardiovascular mortality was higher for individuals with type 1 diabetes compared to type 2 diabetes after adjustment for age. The overall prevalence of HF in this study at baseline was 3.1% - extrapolated to the US this would equate to 57,000 of the 1.9 million individuals with type 1 diabetes. A recent meta-analysis of all available data suggested that the incidence of HF was 3.1 times higher in individuals with type 1 diabetes compared to controls (typically the general population). Assuming a 5% incidence of HF hospitalisation/year, HF hospitalizations cost the US healthcare system ~$29 million per year. In summary, these data suggest that not only is HF a significant problem in individuals with type 1 diabetes, but there is evidence of an outcome disparity compared to individuals with type 2 diabetes or those without diabetes. Although there are some differences (e.g. presentation at a younger age), the pathophysiology of HF in type 1 diabetes is similar to type 2 diabetes. Risk factors are similar (e.g. glycaemic control, coronary artery disease and hypertension), leading to inflammation, endothelial dysfunction, fibrosis, and subsequent diastolic and systolic dysfunction. Given the pathophysiological similarities, there is little to suggest that HF therapies that have shown benefit in individuals with type 2 diabetes (or individuals without diabetes) would not also be efficacious in type 1 diabetes. In all current HF guidelines mainstay HF treatments (renin-angiotensin system blockers, beta-blockers, and mineralocorticoid receptor antagonists) are recommended for all patients with HF regardless of diabetes status. Sodium-glucose co-transporter inhibitors (SGLTi) were initially developed as oral add-on treatments for glycaemic control in type 2 diabetes. A consistent finding in large cardiovascular outcome trials was a significant ~30% risk reduction in hospitalisation for HF, as well as overall reductions in cardiovascular mortality. Subsequently, SGLTi in addition to guideline-directed HF therapy have been studied in HF patients either with type 2 diabetes or without diabetes and have again shown a consistent benefit compared to placebo, with significant reductions in mortality and HF hospitalisation irrespective of cardiac function left ventricular ejection fraction (LVEF) at baseline without any concerning safety signals. SGLTi also improve HF-related quality of life (QoL) and renal outcomes. This has led to the inclusion of SGLTi in the most recent HF treatment guidelines as a cornerstone of therapy in addition to established pharmacological agents (e.g., renin-angiotensin system inhibitors, beta-blockers and mineralocorticoid receptor antagonists). However, there is one key issue - individuals with type 1 diabetes have been excluded from these HF trials, in part due to concerns around safety. At present there is no evidence to support the use of these life-saving therapies in this population that already has worse outcomes than other groups with HF. In adult type 1 diabetes, Phase III trials with dapagliflozin, empagliflozin and sotagliflozin have been completed, collectively showing modest benefits of SGLT inhibition in terms of Haemoglobin A1c (HbA1c) reduction, increased time in range, reduced body weight and total insulin dose. However, SGLTi use in type 1 diabetes was also associated with an increased risk of diabetic ketoacidosis (DKA), which has limited their more widespread use in type 1 diabetes. Sotagliflozin is a dual SGLT1 and 2 inhibitor that is currently approved in the United Kingdom for use in individuals with type 1 diabetes with a body mass index (BMI) of ≥27kg/m2 and taking insulin doses of at least 0.5 units/kg of body weight in patients with inadequate glycaemic control. As with selective SGLT2i, sotagliflozin also improves HF-related outcomes. The key evidence for this comes from two clinical trials. In the Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease (SCORED) trial including 10,584 patients with type 2 diabetes, chronic kidney disease and cardiovascular risk factors, sotagliflozin caused a 26% relative risk reduction in the primary endpoint of cardiovascular death, HF hospitalisation or urgent HF visit compared to placebo. There was also a 33% relative risk reduction in HF hospitalisation or urgent HF visits, figures consistent with other SGLT2i trials. The second key trial was the Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure (SOLOIST-WHF) trial. In this trial 1,222 patients with type 2 diabetes and a recent HF hospitalisation were randomised to sotagliflozin 200mg once daily (with uptitration to 400mg once daily) or placebo. Patients were included regardless of left ventricular ejection fraction (LVEF) at baseline. The median follow-up duration was 9 months. Sotagliflozin caused a 33% relative risk reduction in the primary outcome of cardiovascular death, HF hospitalisation or urgent HF visit, with a 36% reduction in HF hospitalisation or urgent HF visits that met statistical significance. Sotagliflozin also significantly improved QoL at 4 months measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ). Rates of serious adverse events (SAEs) leading to study drug withdrawal were similar in both sotagliflozin and placebo groups, though severe hypoglycaemia was more common with sotagliflozin than placebo (9 individuals vs. 2). There was no significant increase in incidence of DKA with sotagliflozin compared to placebo (2 vs. 4). Taken together, these two trials confirm the benefit of sotagliflozin on HF related outcomes, consistent with selective SGLT2i. Again, individuals with type 1 diabetes were excluded from both of these trials. In summary, there is significant HF related morbidity and mortality in type 1 diabetes, and outcomes are worse than in HF patients with type 2 diabetes or without diabetes. Oral sotagliflozin 200mg daily is licensed for improving glycaemic control in type 1 diabetes in the UK. Although sotagliflozin improves HF related outcomes and QoL in patients with type 2 diabetes and patients with HF who do not have diabetes, studies are needed to determine whether these benefits might extend to patients with type 1 diabetes and heart failure. RATIONALE As outlined above, HF is a significant problem in type 1 diabetes, with an estimated prevalence of 3-5%. Outcomes for individuals with type 1 diabetes and HF are worse than in those with type 2 diabetes or without diabetes, with increased mortality and hospitalisation rates. Critically, patients with type 1 diabetes have been excluded from pivotal trials of the latest advance in HF treatment (SGLT2i), potentially exacerbating these outcome disparities further. The proposed trial will be the first to provide data on the efficacy and safety of sotagliflozin, in patients with type 1 diabetes and HF (regardless of LVEF). If a beneficial signal is found, this would provide strong support for extending the use of sotagliflozin in this group of patients with type 1 diabetes and adoption into clinical guidelines. A multi-centre, double-blind, randomised controlled trial to provide the strongest level of evidence for previous findings of the researchers will be conducted. Importantly, by choosing QoL measured using the KCCQ as the primary endpoint, an outcome that not only correlates strongly with mortality and hospitalisation but is also accepted by the US Food and Drug Administration (FDA) as a valid endpoint for regulatory approval has been selected. The KCCQ is a 23- item self-administered questionnaire that measures the patient's perception of their health status, including HF symptoms, impact on physical and social function, and how their HF impacts their QOL within the preceding 2 weeks. Improvements in KCCQ score map very well to reductions in mortality and hospitalisation and SGLT2i have consistently improved KCCQ scores. A 5-point increase in KCCQ score is traditionally considered clinically meaningful and is associated with a 7% reduction in mortality and HF hospitalisation. Given the prohibitive size of trial that would be required to demonstrate an improvement in mortality or HF hospitalizations with sotagliflozin in type 1 diabetes, the KCCQ represents an ideal endpoint for the trial. The proposed trial has the potential to be a high-impact, practice-changing trial.
Phase
2Span
74 weeksSponsor
University of DundeeCambridge
Recruiting
A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Clinical Activity of GSK5733584 for Injection in Participants With Advanced Solid Tumors
Phase
1Span
157 weeksSponsor
GlaxoSmithKlineCambridge
Recruiting
Useability and Acceptability of the CUE1 Device in Older People With Parkinson's Disease
Phase
N/ASpan
31 weeksSponsor
Dr Alistair MackettCambridge
Recruiting