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The effect of a transient immune activation on subjective health perception in two placebo controlled randomised experiments.

ABSTRACT: BACKGROUND:Patient-reported outcomes predict mortality and play increasingly important roles in care, but factors that modify central measures such as health ratings have been little investigated. Building on designated immune-to-brain pathways, we aimed to determine how a short-term induced inflammation response impacts self-reported health status. METHODS:Lipopolysaccharide injections were used to provoke acute systemic inflammatory responses in healthy men and women and were compared to placebo in two double-blind randomized experiments. In Experiment 1, 8 individuals (mean 24 years; SD = 3.7) received lipopolysaccharide 0.8 ng/kg once and placebo once in a cross-over design, and in Experiment 2, 52 individuals received either lipopolysaccharide 0.6 ng/kg or placebo once (28.6 years; SD = 7.1). Main outcomes were perceived health (general and current), sickness behaviour (like fatigue, pain and negative affect), and plasma interleukin-6, interleukin-8 and tumour necrosis factor-?, before and after injection. RESULTS:Compared to placebo, lipopolysaccharide lead to a deterioration in both self-rated general (Experiment 1, b = 1.88 for 0.8 ng/kg) and current health (Experiment 1 b = -3.00; and Experiment 2 b = -1.79) 1.5h after injection (p's<0.01), effects that remained after 4.5 to 5 hours (p's<0.05). The effect on current health in Experiment 2 was mediated by increased inflammation and sickness behaviour in response to lipopolysaccharide injection (? = -0.28, p = 0.01). CONCLUSION:Health is drastically re-evaluated during inflammatory activation. The findings are consistent with notions that inflammation forms part of health-relevant interoceptive computations of bodily state, and hint at one mechanism as to why subjective health predicts longevity.

SUBMITTER: Andreasson A

PROVIDER: S-EPMC6402640 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The effect of a transient immune activation on subjective health perception in two placebo controlled randomised experiments.

Andreasson Anna A Karshikoff Bianka B Lidberg Lisa L Åkerstedt Torbjörn T Ingvar Martin M Olgart Höglund Caroline C Axelsson John J Lekander Mats M

PloS one 20190306 3

<h4>Background</h4>Patient-reported outcomes predict mortality and play increasingly important roles in care, but factors that modify central measures such as health ratings have been little investigated. Building on designated immune-to-brain pathways, we aimed to determine how a short-term induced inflammation response impacts self-reported health status.<h4>Methods</h4>Lipopolysaccharide injections were used to provoke acute systemic inflammatory responses in healthy men and women and were co ...[more]

PMID: 30840633

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Project description:AZD9164 has demonstrated potential as an inhaled, long-acting, muscarinic antagonist (LAMA) bronchodilator. However, in patients with COPD, but not in healthy subjects, a transient initial drop in FEV1 was observed following inhalation of nebulised doses of AZD9164 in citrate buffer.Two additional studies were conducted to further assess the safety and tolerability of multiple ascending doses of AZD9164 in 27 white and 18 Japanese healthy subjects and in 4 patients with COPD. In these studies, AZD9164 was inhaled via Turbuhaler™.These were Phase I, randomised, double-blind, placebo-controlled, multiple ascending dose (MAD) studies conducted in Sweden and UK. Healthy subjects (mean age 25.9 yrs) and patients with COPD (mean age 66 yrs, mean post-bronchodilator FEV1 60.1% predicted normal value) were randomised 2:1 to active treatment (400, 1000 or 2800 ?g delivered doses of AZD9164) or placebo.No safety or tolerability concerns were identified in the healthy subjects at doses up to and including 2800 ?g and both studies confirmed the bronchodilator effect of AZD9164. However, the first 3 patients in the COPD cohort who received AZD9164 (1000 ?g) experienced a transient fall in FEV1 5 to 15 minutes after inhalation of AZD9164 while the patient receiving placebo did not. The study safety review process then resulted in cessation of further activities on AZD9164. Retrospective analysis showed that two healthy subjects had also had transient falls in FEV1 shortly after inhalation of AZD9164 400 and 2800 ?g respectively, although neither reported any related respiratory symptoms or other AEs.These results show that transient paradoxical bronchoconstriction can occur in some healthy subjects, in addition to patients with COPD, following inhalation of AZD9164 and that the citrate buffer used in the nebulised formulation cannot have been the only cause of the drop in FEV1 in previous studies. As preclinical data do not provide an explanation, the reasons for this brief post-dose drop in FEV1 remain unclear. However, these results highlight the importance of monitoring lung function immediately post-dose when investigating novel inhaled treatments, even when a rapid onset of effect is not expected.Clinicaltrials.gov NCT01016951 and NCT01096563.

Project description:BackgroundThe exact extent of and the mechanism by which trastuzumab causes cardiac side effects are not completely unravelled. We investigated the (cardiotoxic) side effects of trastuzumab in a relatively large homogeneous population.MethodsHealthy male volunteers (n = 54) with a left ventricle ejection fraction (LVEF) > 55% were administered 6 mg/kg trastuzumab (n = 46) IV in 90 min in a placebo-controlled, parallel study. Placebo consisted of 0 · 9% NaCl (n = 8). Assessments included body weight, routine and cardiac laboratory markers and serial echocardiographic examinations (8 placebo and 9 trastuzumab treated participants) up to 63 days after dosing. Statistical analysis was done using repeated measurements of variance.FindingsFollowing trastuzumab infusion, fluid retention was observed: mean body weight increased over the first 4 days post-administration with 0 · 4 kg (95%-confidence interval: - 0 · 2, 0 · 9, p = 0 · 2261) compared to placebo, mean haemoglobin concentration decreased with 0 · 3 mM (- 0 · 6, - 0 · 1; p = 0 · 0043), as did haematocrit (- 0 · 013 L/L [- 0 · 024, - 0 · 002], p = 0 · 0216), and protein (- 2 g/L [- 4, - 0], p = 0 · 0443) and albumin (- 2 g/L [- 3, - 1], p < 0 · 0001) concentrations. Elevations in NT-proBNP levels, parallel to the weight increase, were observed in individual cases, but not on a group level. Troponin-T concentrations did not increase. The only echocardiographic parameter that changed significantly at all studied dose levels was E/A-ratio, a load-dependent parameter: from 1 · 81 (SD 0 · 42) to 1 · 98 (0 · 31) 3-5 days after administration, contrast to placebo of 0 · 57 (90%-CI: 0 · 21-0 · 93, p = 0 · 0034). Ejection fraction and pulsed-wave Doppler recorded parameters remained unchanged.InterpretationSingle dose administration of trastuzumab in humans is associated with an immediate, transient extracellular volume increase, either as a primary or secondary (compensatory) response, which can be detected easily using routine clinical assessments. Echocardiographic changes, both short and long term, could not be found after single dose administration to drug-naive patients.

Project description:The influence of positive or negative expectations on clinical outcomes such as pain relief or motor performance in patients and healthy participants has been extensively investigated for years. Such research promises potential benefit for patient treatment by deliberately using expectations as means to stimulate endogenous regulation processes. Especially regarding recent interest and controversies revolving around cognitive enhancement, the question remains whether mere expectancies might also yield enhancing or impairing effects in the cognitive domain, i.e., can we improve or impair cognitive performance simply by creating a strong expectancy in participants about their performance? Moreover, previous literature suggests that especially subjective perception is highly susceptible to expectancy effects, whereas objective measures can be affected in certain domains, but not in others. Does such a dissociation of objective measures and subjective perception also apply to cognitive placebo and nocebo effects? In this study, we sought to investigate whether placebo and nocebo effects can be evoked in cognitive tasks, and whether these effects influence objective and subjective measures alike. To this end, we instructed participants about alleged effects of different tone frequencies (high, intermediate, low) on brain activity and cognitive functions. We paired each tone with specific success rates in a Flanker task paradigm as a preliminary conditioning procedure, adapted from research on placebo hypoalgesia. In a subsequent test phase, we measured reaction times and success rates in different expectancy conditions (placebo, nocebo, and control) and then asked participants how the different tone frequencies affected their performance. Interestingly, we found no effects of expectation on objective measures, but a strong effect on subjective perception, i.e., although actual performance was not affected by expectancy, participants strongly believed that the placebo tone frequency improved their performance.

Project description:IntroductionIn a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity.MethodsLUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies.ResultsThe median duration of treatment was approximately 24 weeks. Treatment with lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose-response was evident. Lung function also improved following lebrikizumab treatment, with greatest increase in FEV1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed.ConclusionsThese data are consistent with, and extend, previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment.Trial registration numbersThe LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov.

Project description:BackgroundImmune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase (CK) values, and autoantibodies recognizing 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) or the signal recognition particle (SRP). There are currently no approved therapies for IMNM and many patients experience active disease despite off-label treatment with intravenous immunoglobulin, glucocorticoids, and immunosuppressants. Detection of complement-activating anti-HMGCR and anti-SRP autoantibodies and the presence of complement deposition on the sarcolemma of non-necrotic myofibers led to the hypothesis that complement activation may be pathogenic in IMNM, therefore zilucoplan, a complement component 5 (C5) inhibitor, could be a potential therapy.MethodsIMNM01, a phase 2, multicenter, randomised, double-blind, placebo-controlled study (NCT04025632) at 15 sites (four countries) evaluated efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive IMNM. Participants were randomised 1:1 to receive daily subcutaneous zilucoplan (0·3mg/kg) or placebo for eight weeks; with optional enrolment in the study open-label extension. Primary efficacy endpoint was percent change from baseline to Week 8 in CK levels. Secondary endpoints included safety.FindingsBetween 07 November 2019 and 07 January 2021, 27 participants (13 female and 14 male) received zilucoplan (n=12) or placebo (n=15) and completed the 8-week main study. At Week 8 there were no clinically relevant or statistically significant differences, despite target engagement based on mode of action, between treatment arms in mean percent change (standard deviation) of CK levels versus baseline (-9·86% [26·06] versus -20·72% [31·22] in zilucoplan [n=10] and placebo arms [n=14], p=0·46, respectively) and no clinically relevant improvement over time within the treatment arm. There were no unexpected adverse safety or tolerability findings. Treatment emergent adverse events (TEAEs) and serious TEAEs were reported in n=9 (75·0%) vs n=13 (86·7%) and n=0 (0%) and n=3 (20·0%) participants, respectively. The most frequent TEAEs were headache (n=4 in both groups [33·3% and 26·7%, respectively]) and nausea (n=3 in both groups [25·0% and 20·0%, respectively]).InterpretationC5 inhibition does not appear to be an effective treatment modality for IMNM. Rather than driving myofiber necrosis, complement activation may be secondary to muscle injury.FundingStudy funded by Ra Pharmaceuticals (now part of UCB Pharma).

Project description:Chitosan is a dietary fibre which acts by reducing fat absorption and thus used as a means for controlling weight. Weight loss clinical trial outcomes, however, have contradictory results regarding its efficacy. The primary objective of the present study was to evaluate the efficacy and safety of a chitosan from fungal origin in treatment of excess weight in the absence of dietary restrictions.A phase IV, randomised, multicentre, single-blind, placebo-controlled, clinical study was conducted by administering chitosan capsules (500 mg, five/day) and indistinguishable placebo capsules as daily supplements to 96 overweight and obese subjects for 90 days. The study participants were divided in 2:1 ratio to receive either chitosan (n = 64) or placebo (n = 32). Efficacy was assessed by measuring body weight, body composition parameters, anthropometric measurements, HbA1C level and lipid profile at day 45 and day 90. Also, short form-36 quality of life (QoL) questionnaire was assessed to evaluate improvement in life-style and dietary habits were recorded for calorie intake. Safety was assessed by evaluating safety parameters and monitoring adverse events.The mean changes in body weight were -1.78 ± 1.37 kg and -3.10 ± 1.95 kg at day 45 and day 90 respectively in chitosan group which were significantly different (p < 0.0001) as compared to placebo. BMI was decreased by10.91 fold compared to placebo after 90 day administration. In concert with this, there was also reduction in body composition and anthropometric parameters together with improvement in QoL score. Chitosan was also able to reduce HbA1C levels (below 6 %) in subjects who had initial higher values. The mean caloric intake shows that there was no change in dietary habits of subjects in both groups. Lipid levels were unaffected and all adverse events were mild in nature and unrelated to study treatment.Chitosan from fungal origin was able to reduce the mean body weight up to 3 kg during the 90 day study period. Together with this, there was also improvement in body composition, anthropometric parameters and HbA1C, reflecting overall benefits for the overweight individuals. Additionally, there was also improvement in QoL score. It was safe and well tolerated by all subjects.CTRI/2014/08/004901.

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The effect of a transient immune activation on subjective health perception in two placebo controlled randomised experiments.

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The effect of a transient immune activation on subjective health perception in two placebo controlled randomised experiments.

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