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.
SummaryProblems of sexual function and fertility in long-term survivors (≥5 years) of haematological malignancy are often neglected in clinic. Our centre carried out a questionnaire study in this population addressing patientperceived fertility and sexual function. 718 patients responded (56% of those invited; 39% Hodgkin, 45% non-Hodgkin lymphoma, 16% acute leukaemia). Respondent women were more likely to remain childless than a normal control population. Self-reported infertility was more likely in men than women [odds ratio (OR) 1Á77, P = 0Á001]. Myeloablative therapy increased the likelihood of childlessness (OR 2Á48, P = 0Á004). Few attended fertility support services (12%). 24% of men banked sperm and 29% of these used the sample, of which 46% resulted in successful pregnancy. Fertility clinic attendance and sperm storage was more likely post-1990 (OR 4Á05, P < 0Á001; OR 5Á05, P < 0Á001 respectively). Reporting a negative impact of cancer on sexual function was more common in women than men (OR 2Á20, P < 0Á001), and increased with current age and age at diagnosis (by 3-4% per year, P ≤ 0Á001) but decreased with longer followup (by 2%/year, P = 0Á005). Patients on anti-depressants and those reporting cancer-related body change/appearance concerns more frequently reported a negative impact (P < 0Á04 and P < 0Á03 respectively). These self-reported outcomes confirm literature findings, suggest improvement over time, but highlight a need for involvement of support services.
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SummaryTo assess the impact of cancer (IOC) on subsequent quality of life (QOL), 718 long-term haematological cancer survivors completed validated psychosocial, functional and QOL scales, including IOC. Fifteen percent reported significant psychological distress, 18% high levels of fatigue and 10% moderate to severe functional impairment. These groups of participants also showed poorer QOL. There were no significant differences in psychological distress (P = 0Á76), fatigue (P = 0Á23) or functional impairment (P = 0Á74) across different cancer subtypes. Two separate hierarchical regression analyses examined the combined association of disease-type, psychosocial and other factors on negative and positive IOC scores respectively. Higher negative IOC scores were significantly associated (P ≤ 0Á001) with medical comorbidity, psychological distress, lower social support, high fatigue levels and functional impairment. Paediatric patients (diagnosed at <17 years) had significantly higher negative IOC scores than adult patients (P = 0Á001); greater years since diagnosis was significantly (P < 0Á001) associated with less negative IOC. Higher positive IOC was associated with acute leukaemia (P = 0Á01); lower positive IOC with paediatric patients (P < 0Á001), white ethnicity (P < 0Á001), higher education (P = 0Á003), no partner (P = 0Á01) and lower social support (P = 0Á01). Screening for medical comorbidity, psychological distress and fatigue identifies those needing most support and should allow earlier interventions to address negative and positive IOC to improve the well-being of cancer survivors.Keywords: psychosocial factors, depression, haematological cancer, quality of life, long-term survivors.As survival rates for cancer continue to improve, the number of cancer survivors, i.e. people previously diagnosed with cancer, in the UK (currently 2 million) is projected to rise to 3 million by 2040, when 23Á3% of men and 24Á9% of women over 65 years will be cancer survivors (Maddams et al, 2012). It is thus of great importance that the healthcare needs of long-term cancer survivors (alive ≥5 years since initial diagnosis) are properly identified so that they can be adequately met.Haematological cancers represent the fifth most common type of cancer in the UK, accounting for 7% of all cancers (http://www.cancerresearchuk.org/cancer-info/cancerstats/types/) and comprise leukaemias, Non-Hodgkin Lymphomas (NHL) and Hodgkin Lymphoma (HL). Currently, the 5-year survival rates for these range from 50% (NHL) to 75% (HL), depending on type and stage of tumour, treatment and age of patient (http://www.cancerresearchuk.org/cancer-info/cancerstats/types/). The 5-year survival rate for acute leukaemia (AL) is much more variable depending on the age and molecular risk factors of the disease. The illness course and treatments for these different disorders vary widely depending on subtypes, and long-term haematological cancer survivors can experience a variety of adverse physical effects following treatment, including cardiovascular and ...
These exploratory findings will contribute to the design of future trials to confirm the extent of motor and non-motor symptom effects of exenatide in larger cohorts of patients.
Background: B cell depletion with rituximab is commonly used for patients with systemic lupus erythematosus (SLE) refractory to conventional therapy but yields variable responses. We hypothesised that high B cell activating factor (BAFF) levels after rituximab can cause disease flares thereby limiting its effectiveness.
IntroductionFew treatment options exist for patients with systemic lupus erythematosus (SLE) who fail conventional therapy. Although widely used to treat lupus, the efficacy of B cell depletion therapy using rituximab has not been demonstrated in randomised clinical trials. Following rituximab, elevated levels of serum B cell activating factor (BAFF) have been associated with failure to remit or subsequent lupus relapse. The administration of belimumab, a monoclonal antibody specific for BAFF and approved for lupus therapy, could potentiate the efficacy of rituximab and enable longer periods of disease remission. The aim of this trial is to assess the safety and efficacy of belimumab following rituximab in patients with SLE.Methods and analysisBEAT Lupus is a double-blind, randomised, placebo controlled, phase II clinical trial. Patients with SLE commencing a treatment cycle of rituximab (two 1g infusions, 2 weeks apart) as standard of care will be randomised to receive belimumab or placebo, 4 to 8 weeks following the first rituximab infusion. Belimumab or placebo infusions are administered for 52 weeks. The primary outcome measure is anti-double stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes include measures of adverse events, lupus disease activity and cumulative steroid dose. The kinetics of B cell repopulation will be assessed in a subgroup of participants. Belimumab administration after rituximab may provide a novel therapeutic pathway for patients with active lupus if safety is demonstrated in this proof of concept study, and lower anti-dsDNA antibodies levels are achieved in those patients treated with belimumab compared with placebo.Ethics and disseminationThe protocol has been reviewed and approved by the Hampstead Research Ethics Committee - London (reference 16/LO/1024). Trial information is available at https://www.isrctn.com/ISRCTN47873003, and the results of this trial will be submitted for publication in relevant peer-reviewed journals. Key findings will also be presented at national and international conferences.Trial registration number ISRCTN47873; date assigned to the registry: 28 November 2016. The stage is pre-results.
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