Summary Background Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson’s disease. We investigated whether these effects would be apparent in a clinical trial. Methods In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson’s disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25–75 years, had idiopathic Parkinson’s disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed. Findings Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI −2·6 to 0·7) in the exenatide group and worsened by 2·1 points (−0·6 to 4·8) in the placebo group, an adjusted mean difference of −3·5 points (−6·7 to −0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions. Interpretation Exenatide had positive effects on practically defined off-medication motor scores in Parkinson’s disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson’s disease, and effects on everyday symptoms should be examined in longer-term trials. Funding Michael J Fox Foundation for Parkinson’s Research.

IMPORTANCE Exenatide, a glucagon-like peptide 1 agonist used in type 2 diabetes, was recently found to have beneficial effects on motor function in a randomized, placebo-controlled trial in Parkinson disease (PD). Accumulating evidence suggests that impaired brain insulin and protein kinase B (Akt) signaling play a role in PD pathogenesis; however, exploring the extent to which drugs engage with putative mechnisms in vivo remains a challenge.OBJECTIVE To assess whether participants in the Exenatide-PD trial have augmented activity in brain insulin and Akt signaling pathways. DESIGN, SETTING, AND PARTICIPANTS Serum samples were collected from 60 participants in the single-center Exenatide-PD trial (June 18, 2014, to June 16, 2016, which compared patients with moderate PD randomized to 2 mg of exenatide once weekly or placebo for 48 weeks followed by a 12-week washout period. Serum extracellular vesicles, including exosomes, were extracted, precipitated, and enriched for neuronal source by anti-L1 cell adhesion molecule antibody absorption, and proteins of interest were evaluated using electrochemiluminescence assays. Statistical analysis was performed from May 1, 2017, to August 31, 2017. MAIN OUTCOMES AND MEASURESThe main outcome was augmented brain insulin signaling that manifested as a change in tyrosine phosphorylated insulin receptor substrate 1 within neuronal extracellular vesicles at the end of 48 weeks of exenatide treatment. Additional outcome measures were changes in other insulin receptor substrate proteins and effects on protein expression in the Akt and mitogen-activated protein kinase pathways.RESULTS Sixty patients (mean [SD] age, 59.9 [8.4] years; 43 [72%] male) participated in the study: 31 in the exenatide group and 29 in the placebo group (data from 1 patient in the exenatide group were excluded). Patients treated with exenatide had augmented tyrosine phosphorylation of insulin receptor substrate 1 at 48 weeks (0.27 absorbance units [AU]; 95% CI, 0.09-0.44 AU; P = .003) and 60 weeks (0.23 AU; 95% CI, 0.05-0.41 AU; P = .01) compared with patients receiving placebo. Exenatide-treated patients had elevated expression of downstream substrates, including total Akt (0.35 U/mL; 95% CI, 0.16-0.53 U/mL; P < .001) and phosphorylated mechanistic target of rapamycin (mTOR) (0.22 AU; 95% CI, 0.04-0.40 AU; P = .02). Improvements in Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 off-medication scores were associated with levels of total mTOR (F 4,50 = 5.343, P = .001) and phosphorylated mTOR (F 4,50 = 4.384, P = .04). CONCLUSIONS AND RELEVANCEThe results of this study are consistent with target engagement of brain insulin, Akt, and mTOR signaling pathways by exenatide and provide a mechanistic context for the clinical findings of the Exenatide-PD trial. This study suggests the potential of using exosome-based biomarkers as objective measures of target engagement in clinical trials using drugs that target neuronal pathways.

Objective To evaluate effects of remote monitoring of adjuvant chemotherapy related side effects via the Advanced Symptom Management System (ASyMS) on symptom burden, quality of life, supportive care needs, anxiety, self-efficacy, and work limitations. Design Multicentre, repeated measures, parallel group, evaluator masked, stratified randomised controlled trial. Setting Twelve cancer centres in Austria, Greece, Norway, Republic of Ireland, and UK. Participants 829 patients with non-metastatic breast cancer, colorectal cancer, Hodgkin’s disease, or non-Hodgkin’s lymphoma receiving first line adjuvant chemotherapy or chemotherapy for the first time in five years. Intervention Patients were randomised to ASyMS (intervention; n=415) or standard care (control; n=414) over six cycles of chemotherapy. Main outcome measures The primary outcome was symptom burden (Memorial Symptom Assessment Scale; MSAS). Secondary outcomes were health related quality of life (Functional Assessment of Cancer Therapy—General; FACT-G), Supportive Care Needs Survey Short-Form (SCNS-SF34), State-Trait Anxiety Inventory—Revised (STAI-R), Communication and Attitudinal Self-Efficacy scale for cancer (CASE-Cancer), and work limitations questionnaire (WLQ). Results For the intervention group, symptom burden remained at pre-chemotherapy treatment levels, whereas controls reported an increase from cycle 1 onwards (least squares absolute mean difference −0.15, 95% confidence interval −0.19 to −0.12; P<0.001; Cohen’s D effect size=0.5). Analysis of MSAS sub-domains indicated significant reductions in favour of ASyMS for global distress index (−0.21, −0.27 to −0.16; P<0.001), psychological symptoms (−0.16, −0.23 to −0.10; P<0.001), and physical symptoms (−0.21, −0.26 to −0.17; P<0.001). FACT-G scores were higher in the intervention group across all cycles (mean difference 4.06, 95% confidence interval 2.65 to 5.46; P<0.001), whereas mean scores for STAI-R trait (−1.15, −1.90 to −0.41; P=0.003) and STAI-R state anxiety (−1.13, −2.06 to −0.20; P=0.02) were lower. CASE-Cancer scores were higher in the intervention group (mean difference 0.81, 0.19 to 1.43; P=0.01), and most SCNS-SF34 domains were lower, including sexuality needs (−1.56, −3.11 to −0.01; P<0.05), patient care and support needs (−1.74, −3.31 to −0.16; P=0.03), and physical and daily living needs (−2.8, −5.0 to −0.6; P=0.01). Other SCNS-SF34 domains and WLQ were not significantly different. Safety of ASyMS was satisfactory. Neutropenic events were higher in the intervention group. Conclusions Significant reduction in symptom burden supports the use of ASyMS for remote symptom monitoring in cancer care. A “medium” Cohen’s effect size of 0.5 showed a sizable, positive clinical effect of ASyMS on patients’ symptom experiences. Remote monitoring systems will be vital for future services, particularly with blended models of care delivery arising from the covid-19 pandemic. Trial registration Clinicaltrials.gov NCT02356081 .

BackgroundFlavanols are an important class of food bioactives that can improve vascular function even in healthy subjects. Cocoa flavanols (CFs) are composed principally of the monomer (−)-epicatechin (∼20%), with a degree of polymerisation (DP) of 1 (DP1), and oligomeric procyanidins (∼80%, DP2–10).ObjectiveOur objective was to investigate the relative contribution of procyanidins and (−)-epicatechin to CF intake–related improvements in vascular function in healthy volunteers.DesignIn a randomized, controlled, double-masked, parallel-group dietary intervention trial, 45 healthy men (aged 18–35 y) consumed the following once daily for 1 mo: 1) a DP1–10 cocoa extract containing 130 mg (−)-epicatechin and 560 mg procyanidins, 2) a DP2–10 cocoa extract containing 20 mg (−)-epicatechin and 540 mg procyanidins, or 3) a control capsule, which was flavanol-free but had identical micro- and macronutrient composition.ResultsConsumption of DP1–10, but not of either DP2–10 or the control capsule, significantly increased flow-mediated vasodilation (primary endpoint) and the concentration of structurally related (−)-epicatechin metabolites (SREMs) in the circulatory system while decreasing pulse wave velocity and blood pressure. Total cholesterol significantly decreased after daily intake of both DP1–10 and DP2–10 as compared with the control.ConclusionsCF-related improvements in vascular function are predominantly related to the intake of flavanol monomers and circulating SREMs in healthy humans but not to the more abundant procyanidins and gut microbiome–derived CF catabolites. Reduction in total cholesterol was linked to consumption of procyanidins but not necessarily to that of (−)-epicatechin. This trial was registered at clinicaltrials.gov as NCT02728466.