Simon Bond

Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial.

Summary Background Small studies suggest peanut oral immunotherapy (OIT) might be effective in the treatment of peanut allergy. We aimed to establish the efficacy of OIT for the desensitisation of children with allergy to peanuts. Methods We did a randomised controlled crossover trial to compare the efficacy of active OIT (using characterised peanut flour; protein doses of 2–800 mg/day) with control (peanut avoidance, the present standard of care) at the NIHR/Wellcome Trust Cambridge Clinical Research Facility (Cambridge, UK). Randomisation (1:1) was by use of an audited online system; group allocation was not masked. Eligible participants were aged 7–16 years with an immediate hypersensitivity reaction after peanut ingestion, positive skin prick test to peanuts, and positive by double-blind placebo-controlled food challenge (DBPCFC). We excluded participants if they had a major chronic illness, if the care provider or a present household member had suspected or diagnosed allergy to peanuts, or if there was an unwillingness or inability to comply with study procedures. Our primary outcome was desensitisation, defined as negative peanut challenge (1400 mg protein in DBPCFC) at 6 months (first phase). Control participants underwent OIT during the second phase, with subsequent DBPCFC. Immunological parameters and disease-specific quality-of-life scores were measured. Analysis was by intention to treat. Fishers exact test was used to compare the proportion of those with desensitisation to peanut after 6 months between the active and control group at the end of the first phase. This trial is registered with Current Controlled Trials, number ISRCTN62416244. Findings The primary outcome, desensitisation, was recorded for 62% (24 of 39 participants; 95% CI 45–78) in the active group and none of the control group after the first phase (0 of 46; 95% CI 0–9; p<0·001). 84% (95% CI 70–93) of the active group tolerated daily ingestion of 800 mg protein (equivalent to roughly five peanuts). Median increase in peanut threshold after OIT was 1345 mg (range 45–1400; p<0·001) or 25·5 times (range 1·82–280; p<0·001). After the second phase, 54% (95% CI 35–72) tolerated 1400 mg challenge (equivalent to roughly ten peanuts) and 91% (79–98) tolerated daily ingestion of 800 mg protein. Quality-of-life scores improved (decreased) after OIT (median change −1·61; p<0·001). Side-effects were mild in most participants. Gastrointestinal symptoms were, collectively, most common (31 participants with nausea, 31 with vomiting, and one with diarrhoea), then oral pruritus after 6·3% of doses (76 participants) and wheeze after 0·41% of doses (21 participants). Intramuscular adrenaline was used after 0·01% of doses (one participant). Interpretation OIT successfully induced desensitisation in most children within the study population with peanut allergy of any severity, with a clinically meaningful increase in peanut threshold. Quality of life improved after intervention and there was a good safety profile. Immunological changes corresponded with clinical desensitisation. Further studies in wider populations are recommended; peanut OIT should not be done in non-specialist settings, but it is effective and well tolerated in the studied age group. Funding MRC-NIHR partnership.

Chronic Dipeptidyl Peptidase-4 Inhibition With Sitagliptin Is Associated With Sustained Protection Against Ischemic Left Ventricular Dysfunction in a Pilot Study of Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease

Background—The incretin hormone, glucagon-like peptide-1, promotes myocardial glucose uptake and may improve myocardial tolerance to ischemia. Endogenous glucagon-like peptide-1 (7–36) is augmented by pharmacological inhibition of dipeptidyl peptidase-4. We investigated whether chronic dipeptidyl peptidase-4 inhibition by sitagliptin protected against ischemic left ventricular dysfunction during dobutamine stress in patients with type 2 diabetes mellitus and coronary artery disease. Methods and Results—A total of 19 patients with type 2 diabetes mellitus underwent dobutamine stress echocardiography with tissue Doppler imaging on 2 separate occasions: the first (control) while receiving oral hypoglycemic agents, and the second after the addition of sitagliptin (100 mg once daily) for ≈4 weeks. Sitagliptin increased plasma glucagon-like peptide-1 (7–36) levels and, at peak stress, enhanced both global (ejection fraction, 70.5±7.0 versus 65.7±8.0%; P<0.0001; mitral annular systolic velocity, 11.7±2.6 versus 10.9±2.3 cm/s; P=0.01) and regional left ventricular function, assessed by peak systolic velocity and strain rate in 12 paired, nonapical segments. This was predominantly because of a cardioprotective effect on ischemic segments (strain rate in ischemic segments, −2.27±0.65 versus −1.98±0.58 s−1; P=0.001), whereas no effect was seen in nonischemic segments (−2.19±0.48 versus −2.18±0.54 s−1; P=0.87). At 30 minutes recovery, dipeptidyl peptidase-4 inhibition mitigated the postischemic stunning seen in the control scan. Conclusions—The addition of dipeptidyl peptidase-4 inhibitor therapy with sitagliptin to the treatment regime of patients with type 2 diabetes mellitus and coronary artery disease is associated with a sustained improvement in myocardial performance during dobutamine stress and a reduction in postischemic stunning. Clinical Trial Registration—URL: http://www.isrctn.org. Unique identifier ISRCTN61646154.

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

Background Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. Methods and Findings To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = −0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015–0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%–48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%–85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. Conclusions The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2–3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%–50%, with the eventual goal of preventing T1D. Trial Registration ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735

Rationale and study design of the Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D): a non-randomised, open label, adaptive dose finding trial

Introduction CD4 T regulatory cells (Tregs) are crucial for the maintenance of self-tolerance and are deficient in many common autoimmune diseases such as type 1 diabetes (T1D). Interleukin 2 (IL-2) plays a major role in the activation and function of Tregs and treatment with ultra-low dose (ULD) IL-2 could increase Treg function to potentially halt disease progression in T1D. However, prior to embarking on large phase II/III clinical trials it is critical to develop new strategies for determining the mechanism of action of ULD IL-2 in participants with T1D. In this mechanistic study we will combine a novel trial design with a clinical grade Treg assay to identify the best doses of ULD IL-2 to induce targeted increases in Tregs. Method and analysis Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D) is a single centre non-randomised, single dose, open label, adaptive dose-finding trial. The primary objective of DILT1D is to identify the best doses of IL-2 to achieve a minimal or maximal Treg increase in participants with T1D (N=40). The design has an initial learning phase where pairs of participants are assigned to five preassigned doses followed by an interim analysis to determine the two Treg targets for the reminder of the trial. This will then be followed by an adaptive phase which is fully sequential with an interim analysis after each participant is observed to determine the choice of dose based on the optimality criterion to minimise the determinant of covariance of the estimated target doses. A dose determining committee will review all data available at the interim(s) and then provide decisions regarding the choice of dose to administer to subsequent participants. Ethics and dissemination Ethical approval for the study was granted on 18 February 2013. Results The results of this study will be reported through peer-reviewed journals, conference presentations and an internal organisational report. Trial registration numbers NCT01827735, ISRCTN27852285, DRN767.

Surgeon-specific mortality data disguise wider failings in delivery of safe surgical services.

OBJECTIVES Feedback of clinical outcome data to clinicians can promote and enhance patient safety. Surgeon-specific mortality data (SSMD) have been released to the public for a number of specialties. This implies that one individual is culpable for all deaths. Debate continues about SSMD because of risk-averse behaviour. In the USA, improved outcome measures derived from phase of care mortality analysis (POCMA) and the failure to rescue (FTR) are replacing SSMD, but they have not been tested in Europe. METHODS Using POCMA and FTR analysis, we studied hospital deaths in 1558 cardiac surgical patients between 2009 and 2013. Comorbidity and urgency status were used to calculate modified logistic EuroSCORE (MLE). The circumstances of death were critically reviewed by a panel of four experienced surgeons. Death certificate information and autopsy were taken into account. Deaths were then classified: Class 1 surgeon dependent, Class 2 FTR or Class 3 where multiple factors conspired to cause death. RESULTS There were 51 deaths providing 3.3% mortality, as predicted by MLE. In the 86% who underwent autopsy, no surgical error was identified. Most deaths in each group were related to high-risk status, age, frailty, comorbidity and urgency. FTR was the predominant factor occurring in 45%. Though difficult operations were implicated in 37%, no deaths occurred in the operating theatre. Some FTR deaths occurred in low-risk patients. Scrutiny of FTR deaths provided important information that could be used for quality improvement. CONCLUSIONS The study showed that most deaths cannot be prevented by the operating surgeon. They occurred through issues of patient comorbidity, lack of process or infrastructure. This casts doubt on SSMD publication alone as a tool for quality improvement. In contrast, POCMA and FTR highlight problems of process, and are more likely to promote advances in surgical care.

Protocol of the adaptive study of IL-2 dose frequency on regulatory T cells in type 1 diabetes (DILfrequency): a mechanistic, non-randomised, repeat dose, open-label, response-adaptive study

Introduction Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing β cells in the pancreatic islets, leading to insulinopenia and hyperglycaemia. Genetic analyses indicate that alterations of the interleukin-2 (IL-2) pathway mediating immune activation and tolerance predispose to T1D, specifically the polymorphic expression of the IL-2 receptor-α chain (CD25) on T lymphocytes. Replacement of physiological doses of IL-2 could restore self-tolerance and prevent further autoimmunity by enhancing the function of CD4+ T regulatory cells (Tregs) to limit the activation of auto reactive T effector cells (Teffs). In this experimental medicine study, we use an adaptive trial design to determine the optimal dosing regimen for IL-2 to improve Treg function while limiting activation of Teffs in participants with T1D. Methods and analysis The Adaptive study of IL-2 dose frequency on Tregs in type 1 diabetes(DILfrequency) is a mechanistic, non-randomised, repeat dose open-label, response-adaptive study of 36 participants with T1D. The objective is to establish the optimal dose and frequency of ultra-low dose IL-2: to increase Treg frequency within the physiological range, to increase CD25 expression on Tregs, without increasing CD4+ Teffs. DILfrequency has an initial learning phase where 12 participants are allocated to six different doses and frequencies followed by an interim statistical analysis. After analysis of the learning phase, the Dose and Frequency Committee will select the optimal targets for Treg frequency, Treg CD25 expression and Teff frequency. Three groups of eight participants will be treated consecutively in the confirming phase. Each dose and frequency selected will be based on statistical analysis of all data collected from the previous groups. Ethics Ethical approval for DILfrequency was granted on 12 August 2014. Results The results of this study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report. Trial registration numbers NCT02265809, ISRCTN40319192, CRN17571.

ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes

Background Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long‐term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin‐converting–enzyme (ACE) inhibitors and statins, drugs that have not been fully evaluated in adolescents. Methods We screened 4407 adolescents with type 1 diabetes between the ages of 10 and 16 years of age and identified 1287 with values in the upper third of the albumin‐to‐creatinine ratios; 443 were randomly assigned in a placebo‐controlled trial of an ACE inhibitor and a statin with the use of a 2‐by‐2 factorial design minimizing differences in baseline characteristics such as age, sex, and duration of diabetes. The primary outcome for both interventions was the change in albumin excretion, assessed according to the albumin‐to‐creatinine ratio calculated from three early‐morning urine samples obtained every 6 months over 2 to 4 years, and expressed as the area under the curve. Key secondary outcomes included the development of microalbuminuria, progression of retinopathy, changes in the glomerular filtration rate, lipid levels, and measures of cardiovascular risk (carotid intima–media thickness and levels of high‐sensitivity C‐reactive protein and asymmetric dimethylarginine). Results The primary outcome was not affected by ACE inhibitor therapy, statin therapy, or the combination of the two. The use of an ACE inhibitor was associated with a lower incidence of microalbuminuria than the use of placebo; in the context of negative findings for the primary outcome and statistical analysis plan, this lower incidence was not considered significant (hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.94). Statin use resulted in significant reductions in total, low‐density lipoprotein, and non–high‐density lipoprotein cholesterol levels, in triglyceride levels, and in the ratio of apolipoprotein B to apolipoprotein A1, whereas neither drug had significant effects on carotid intima–media thickness, other cardiovascular markers, the glomerular filtration rate, or progression of retinopathy. Overall adherence to the drug regimen was 75%, and serious adverse events were similar across the groups. Conclusions The use of an ACE inhibitor and a statin did not change the albumin‐to‐creatinine ratio over time. (Funded by the Juvenile Diabetes Research Foundation and others; AdDIT ClinicalTrials.gov number, NCT01581476.)

Random variation in rectal position during radiotherapy for prostate cancer is two to three times greater than that predicted from prostate motion

Objective: Radiotherapy for prostate cancer does not explicitly take into account daily variation in the position of the rectum. It is important to accurately assess accumulated dose (DA) to the rectum in order to understand the relationship between dose and toxicity. The primary objective of this work was to quantify systematic (Σ) and random (σ) variation in the position of the rectum during a course of prostate radiotherapy. Methods: The rectum was manually outlined on the kilo-voltage planning scan and 37 daily mega-voltage image guidance scans for 10 participants recruited to the VoxTox study. The femoral heads were used to produce a fixed point to which all rectal contours were referenced. Results: Σ [standard deviation (SD) of means] between planning and treatment was 4.2 mm in the anteroposterior (AP) direction and 1.3 mm left–right (LR). σ (root mean square of SDs) was 5.2 mm AP and 2.7 mm LR. Superior–inferior variation was less than one slice above and below the planning position. Conclusion: Our results for Σ are in line with published data for prostate motion. σ, however, was approximately twice as great as that seen for prostate motion. This suggests that DA may differ from planned dose in some patients treated with radiotherapy for prostate cancer. Advances in knowledge: This work is the first to use daily imaging to quantify Σ and σ of the rectum in prostate cancer. σ was found to be greater than published data, providing strong rationale for further investigation of individual DA.

Applying physical science techniques and CERN technology to an unsolved problem in radiation treatment for cancer: the multidisciplinary ‘VoxTox’ research programme

The VoxTox research programme has applied expertise from the physical sciences to the problem of radiotherapy toxicity, bringing together expertise from engineering, mathematics, high energy physics (including the Large Hadron Collider), medical physics and radiation oncology. In our initial cohort of 109 men treated with curative radiotherapy for prostate cancer, daily image guidance computed tomography (CT) scans have been used to calculate delivered dose to the rectum, as distinct from planned dose, using an automated approach. Clinical toxicity data have been collected, allowing us to address the hypothesis that delivered dose provides a better predictor of toxicity than planned dose.

Model selection and sample size adaptation: HYPAZ trial.

Pazopanib is a new cancer drug that works by limiting the growth of new blood vessels in tumours. About half of patients who take pazopanib develop high blood pressure (hypertension). This side effect can make patients have to reduce or stop their cancer treatment, and can cause other health problems. Understanding how pazopanib causes high blood pressure will help us to advise doctors how to treat the high blood pressure effectively, so that patients can continue to take their cancer treatment safely. A proposed explanation is that hypertension is caused by endothelial dysfunction as a consequence of reduced nitric oxide (NO) bioavailability. The aim of a study (HYPAZ) is to investigate the relationship between blood pressure and NO bioavailability in cancer patients treated with pazopanib, who develop hypertension. The predictor variable observed is the change in blood pressure from baseline. The response variable will be change in NO bioavailability measured through the change in forearm blood flow ratio (of infused versus control forearm) in response to intra-arterial acetylcholine infusion. These data will give a greater understanding to aspects of pazopanib’s mechanism and relationship to hypertension. The primary analysis for the study is to model and quantify the relationship between NO bioavailability and blood pressure. In planning the study there is little a priori evidence to suggest the shape, nor to quantify the strength, of any relationship. Hence an adaptive design is proposed to assess the evidence for any relationship and judge possible sample size revisions at an interim analysis. To perform model selection at an interim analysis is a novel feature of this adaptive design. We consider some of the operating characteristics of the proposed design.