Significant Placebo Effect Research Articles

Obesity as an influencing factor for the occurrence of caffeine-induced effects in women.

Individuals with a higher body fat percentage may have higher serum levels of caffeine and its metabolites and process caffeine more slowly than individuals with a lower body fat percentage, so the aim of this study is to compare the occurrence of positive and negative effects of caffeine in nonobese and obese women. One hundred and sixty women were included in the study. Body fat was determined using the mBCA 515 SECA analyzer. Participants were divided into 4 groups: nonobese caffeine, nonobese placebo, obese caffeine and obese placebo. Caffeine groups received 6mg/kg body weight caffeine. Placebo groups received identical starch-filled capsules. One hour after ingestion and within 24h, participants completed a caffeine-induced effect questionnaire. Caffeine intake showed statistically significant differences compared to placebo for neutral (p≤0.014; Cramér's V=0.27; 27% increase), negative (p≤0.002; Cramér's V=0.34; 34% increase), and positive effects (p≤0.015; Cramér's V=0.27; 27% increase). Further analysis revealed significant associations with increased urine output (p≤0.014; Cramér's V=0.27; 27% increase), vigor/activeness (p≤0.009; Cramér's V=0.29; 29% increase), and headache (p≤0.033; Cramér's V=0.24; 24% increase) 1h post-ingestion. No significant effects were observed in the placebo group. There was no statistically significant placebo effect. Obese and nonobese women show different responses to caffeine 60min after ingesting 6mg/kg body weight. Obese women are more likely to report adverse effects, including increased urine output, heightened vigor/activeness, and headaches, compared to nonobese women. ANZCTR12622000823774; June 10, 2022.

Davunetide sex-dependently boosts memory in prodromal Alzheimer’s disease

BackgroundThe tauopathy inhibitor, davunetide shows sex-dependent efficacy in women suffering from progressive supranuclear palsy. Extending these findings to prodromal Alzheimer’s disease, we submitted a double-blind, placebo-controlled, 12 weeks/16 weeks follow-up, davunetide clinical trial results in amnestic mild cognitive impairment (ClinicalTrials.gov ID NCT00422981), to a sex-dependent analysis.MethodsOne hundred forty-four individuals, separated into eight groups (1:2 placebo—and 2 doses, 5 mg davunetide/daily or 15 mg davunetide/twice-daily, with matching placebo intranasal volumes), were evaluated.ResultsSignificant dose-dependent cognitive increases were observed in men compared to women with a test of delayed (12 ss) visual matching to the sample. In a test of semantic working memory and attention (digit span), women showed a significant low-dose placebo effect, ensuing in a high dose significant davunetide improvement, over the matched placebo. Correlating anxiety with cognition showed sex-opposing results, with women depicting significant anxiety correlations with delayed matching to sample.DiscussionIn conclusion, sex-specific prodromal Alzheimer’s drug development is encouraged, with davunetide playing a lead initiative role.

What is the best first choice oral drug therapy for OAB?

The management of overactive bladder (OAB) involves lifestyle changes and conservative measures in the first instance with the use of liquid/dietary advice, weight loss, and bladder training. Thereafter oral pharmacotherapy is instigated in symptomatic patients. Antimuscarinics and beta 3 agonists form the main classes of drug therapy in this field. Views on what is the best first line OAB treatment is changing based on recent evidence and adverse event profiles of these medications. At the ICI-RS meeting 2023, Bristol, UKthis topic was discussed and debated as a proposal. The following article summarizes the concepts presented that day as well as the interactive discussion that took place thereafter. OAB guidelines are moving in many circumstances to an either antimuscarinic or beta 3 agonist approach based on patient factors. Several studies have raised concerns on the long-term impact of antimuscarinics, in relation to cognition, dementia, cardiovascular events, and mortality all related to antimuscarinic load. Neither antimuscarinics nor beta 3 agonists have good persistence and adherence rates in the medium to long term. Several barriers also exist to prescribing including guidelines recommending utilizing drugs with the lowest acquisition cost and "step therapy." A newer approach to managing OAB is personalized therapy in view of the many possible etiological factors and phenotypes. These concepts are highlighted in this article. Current oral pharmacotherapy in managing OAB is limited by adverse events, adherence and persistence problems. Both antimuscarinics and beta 3 agonists are efficacious but most clinical trials demonstrate significant placebo effects in this field. Personalizing treatment to the individual seems a logical approach to OAB. There is a need for better treatments and further studies are required of existing treatments with high quality longer term outcomes.

A prospective, randomized, double-blind, placebo-controlled multisite, parallel-group field study in dogs with osteoarthritis conducted in the United States of America evaluating bedinvetmab, a canine anti-nerve growth factor monoclonal antibody

ObjectiveBedinvetmab, a fully canine anti-nerve growth factor monoclonal antibody, was evaluated in dogs for control of osteoarthritis-related pain in a study conducted to support registration in the USA. Study designRandomized, double-blind, placebo-controlled, multicenter, parallel-group study. AnimalsGeneral practice client-owned dogs with osteoarthritis (n = 272). MethodsDogs were block randomized 1:1 to placebo (saline, n = 137) or bedinvetmab (n = 135; 0.5–1.0 mg kg–1) administered subcutaneously, once monthly. The primary end point, day 28 Canine Brief Pain Inventory (CBPI) treatment success (TS), required pain severity score (PSS; 0–10) decrease ≥1 and pain interference score (PIS; 0–10) decrease ≥ 2. CBPI TS rates [and number needed to treat (NNT)], change in scores [and standardized effect size (ES)], change in quality of life (QoL) and bedinvetmab half-life were calculated. ResultsSignificant (p < 0.05) improvement with bedinvetmab over placebo occurred (days 28, 42, 56, 84) for CBPI TS. Of cases evaluable for day 28 CBPI TS (placebo, n = 131; bedinvetmab, n = 128), success rates were 36.6% and 47.4%, respectively (p = 0.0410) (NNT, 9.3; PSS and PIS ES, 0.3). CBPI TS increased after the second dose in both groups, plateaued for bedinvetmab at day 42 and decreased for placebo beginning day 84. Day 84 NNT (4.3), PSS (0.4) and PIS (0.5) showed continued improvement with monthly dosing. After the first dose, mean (± standard deviation) bedinvetmab half-life was 19.1 (8.3) days. Adverse events were similar between groups and not considered treatment-related. There was a significant effect of bedinvetmab versus placebo on all CBPI components (PIS, PSS, QoL). Conclusions and clinical relevanceThese results corroborated those previously reported and provide further support of safety and effectiveness of bedinvetmab (0.5–1.0 mg kg–1) administered subcutaneously at monthly intervals to dogs for control of osteoarthritis-related pain.

Role of adenosine A2A receptors in hot and cold cognition: Effects of single-dose istradefylline in healthy volunteers

The role of the adenosine neurochemical system in human cognition is under-studied, despite such receptors being distributed throughout the brain. The aim of this study was to shed light on the role of the adenosine A2A receptors in human cognition using single-dose istradefylline. Twenty healthy male participants, aged 19–49, received 20 mg istradefylline and placebo, in a randomized, double-blind, placebo-controlled cross-over design. Cognition was assessed using computerized cognitive tests, covering both cold (non-emotional) and hot (emotion-laden) domains. Cardiovascular data were recorded serially. Cognitive effects of istradefylline were explored using repeated measures analysis of variance and paired t-tests as appropriate. On the EMOTICOM battery, there was a significant effect of istradefylline versus placebo on the Social Information Preference task (t = 2.50, p = 0.02, d=-0.59), indicating that subjects on istradefylline interpreted social situations more positively. No other significant effects were observed on other cognitive tasks, nor in terms of cardiovascular measures (pulse and blood pressure). De-briefing indicated that blinding was successful, both for participants and the research team. Further exploration of the role of adenosine A2A receptors in emotional processing may be valuable, given that abnormalities in related cognitive functions are implicated in neuropsychiatric disorders. The role of adenosine systems in human cognition requires further clarification, including with different doses of istradefylline and over different schedules of administration.

An evaluation of bremelanotide injection for the treatment of hypoactive sexual desire disorder

ABSTRACT Introduction Female sexual response implies a deep intertwining between psychosocial and neurobiological mediators. Regulation of central melanocortin signaling may enhance sexual desire. In premenopausal women with hypoactive sexual desire disorder (HSDD), melanocortin receptor agonist bremelanotide (Vyleesi) has been hypothesized to trigger excitatory brain pathways. Areas covered Hereby we summarize bremelanotide’s proposed mechanism of action, pharmacokinetics, efficacy and safety data derived from clinical trials. A literature search of peer-reviewed publications on the current evidence on the pharmacotherapy with bremelanotide was performed using the PubMed database. Expert opinion Bremelanotide appears to be moderately safe and well-tolerated; the most common adverse reaction is nausea (40%). Although data from clinical trials demonstrated a significant change in validated questionnaires, the overall clinical benefit appears to be modest. However, these results should be interpreted in the light of the dramatic challenges in conducting well-designed clinical trials for female sexual dysfunction, due to the significant placebo effect of pharmacotherapy, and the frequent use of outcome measures that are likely to be highly susceptible to expectation biases, such as long periods of recall of sexual and emotional response.

Evaluation of the benefit of rivaroxaban on VOYAGER PAD primary composite of limb, heart and brain outcomes using the global rank and win ratio methods

Abstract Background/Introduction The VOYAGER PAD trial demonstrated that rivaroxaban 2.5 mg twice daily added to background antiplatelet therapy reduced a composite of irreversible harm events of the heart limb and brain versus placebo in patients with symptomatic peripheral artery disease (PAD) after lower extremity revascularization. The primary analysis was performed as time to first event with equal weighting of components including fatal and non-fatal events. Purpose Traditional time to event analyses of composites generally assess outcomes with equal weights. Analyses evaluating outcomes using ranked or weighted methods may provide clinicians a mechanism to interpret results including different weighting and enable shared decision making with patients. Methods Exploratory analyses of the primary composite outcome were prespecified prior to trial completion/database lock. Two previously described approaches to evaluate composite outcomes by ranking or weighting were utilized. The first was the global rank method which includes ranking all components of the composite by order of clinical importance (Table 1) with a primary and alternative ranking prespecified. Each patient is assigned a rank with the worse rank for worse outcome and for patients with the same outcome, those occurring earlier assigned the worse rank. Van Elteren test for differences between groups was applied stratified by type of procedure and clopidogrel use consistent with the primary trial analysis. The second was the unmatched win ratio method according to Pocock's rule which ranked CV death higher than non-fatal events and then compared pairs of subjects, one from each treatment group for wins and losses for wins and losses as outlined in Table 1. Finkelstein and Schoenfeld statistics were utilized with confidence intervals provided from bootstrapping. Results A total of 6564 patients were randomized and all outcomes through the common study end date were counted. The global rank method using both the primary and alternative method yielded a statistically significant superior effect of rivaroxaban versus placebo (p-value for primary ranking 0.0158, p-value for alternative ranking 0.0155). When using the win-ratio approach, there were more wins for rivaroxaban (14.8%) than placebo (12.8%) with 72.4% of patients having no primary component events (Figure 1). The overall win ratio was 1.16 95% CI (1.03–1.30) in favor of rivaroxaban with p=0.0167. Conclusion(s) Rivaroxaban significantly reduces acute limb ischemia, amputation, MI, ischemic stroke or CV death in PAD after lower extremity revascularization. Exploratory analyses of this efficacy composite show consistent superiority either when considered as a ranked hierarchy of outcomes with CV death as the worst or whether considering a win-ratio approach ranking CV death as worse followed by non-fatal events. These data support the robustness of the primary trial results when considering ranking of the composite components. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Bayer

The placebo response rate and nocebo events in obesity pharmacological trials. A systematic review and meta-analysis.

SummaryBackgroundThere is a growing number of trials examining the effectiveness of pharmacotherapies for obesity, however, little is known about placebo and nocebo effect in these trials. Hence, we sought to examine the effect of placebo in obesity trials, to better understand the potential factors affecting clinical endpoints in them.MethodsMedline, Embase, and Cochrane CENTRAL were searched for articles examining weight-loss RCTs examining patients with overweight or obesity in placebo-controlled arms from inception till 25 June 2022. This paper was registered online with PROSPERO (CRD42022302482). A single arm meta-analysis of proportions was used to estimate the primary outcomes, ≥5%, ≥10%, and ≥15% total weight loss – and the adverse effects that patients experienced during the trial. A meta-analysis of means was used to estimate the pooled mean differences of the secondary outcomes including, body weight measurements, lipid levels, glycemic indices, and blood pressure over time.FindingsA total of 63 papers involving 20,454 patients and 69 trials were included. The proportion of patients that had ≥5%, ≥10%, and ≥15% weight loss was 20·4% (CI:16·1% to 25·0%), 8·3% (CI:6·1% to 10·9%), and 6·2% (CI:3·8% to 9·7%), respectively. Analysis by duration of trials showed stepwise increase in proportion of patients with ≥5% and ≥10% weight loss with increasing duration of study. Analysis of secondary outcomes found modest improvement in all analyses. The pooled average rate of overall AEs, serious AEs, and discontinuation was 73·7% (CI:68·0% to 79·0%), 3·4% (CI:2·4% to 4·5%), and 5·2% (CI:4·0% to 6·5%), respectively. In psychiatric complications, the pooled rates of anxiety and depression were 2·7% (CI:1·8% to 3·7%) and 2·5 (CI:1·7% to 3·3%).InterpretationOur meta-analysis of placebo-treated participants in weight-loss RCTs indicate a significant placebo and nocebo effect. These findings are important to quantify their effect and may inform the design of future RCTs.FundingThis research did not receive additional support from organizations beyond the authors’ academic institutions.

Efficacy of Pirfenidone vs. Placebo in Unclassifiable Interstitial Lung Disease, by Surgical Lung Biopsy Status: Data From a post-hoc Analysis

Approximately 12–13% of patients with interstitial lung disease (ILD) are diagnosed with unclassifiable ILD (uILD), often despite thorough evaluation. A recent Phase 2 study (NCT03099187) described a significant effect of pirfenidone vs. placebo on forced vital capacity (FVC) measured by site spirometry in patients with progressive fibrosing uILD (hereafter referred to as the pirfenidone in uILD study). Here, we present the results from a post-hoc analysis of this study to assess patient baseline characteristics and the efficacy of pirfenidone vs. placebo analyzed by surgical lung biopsy (SLB) status. Mean FVC (mL) change over 24 weeks was included as a post-hoc efficacy outcome. Of 253 randomized patients, 88 (34.8%) had a SLB and 165 (65.2%) did not. Baseline characteristics were generally similar between SLB subgroups; however, patients who had a SLB were slightly younger and had a higher 6-min walk distance than those without a SLB. Mean FVC change over 24 weeks for pirfenidone vs. placebo was −90.9 vs. −146.3 mL, respectively, in patients who had a SLB, and 8.2 vs. −85.3 mL, respectively, in patients without a SLB. Overall, the results from the post-hoc analysis identified that pirfenidone may be an effective treatment in progressive fibrosing uILD over 24 weeks, irrespective of SLB status; however, caution should be taken when interpreting these data due to several limitations. There are differences in the treatment effect of pirfenidone between the subgroups that require further pathological and radiological investigation. In this manuscript, we also descriptively compared baseline characteristics from the overall pirfenidone in uILD study population with other uILD populations reported in the literature, with the aim of understanding if there are any similarities or differences within these cohorts. Most baseline characteristics for patients in the pirfenidone in uILD study were within the ranges reported in the literature; however, ranges were wide, highlighting the heterogeneity of uILD populations.Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT03099187.

POS-546 EFFICACY AND SAFETY OF IPTACOPAN IN IgA NEPHROPATHY: RESULTS OF A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED PHASE 2 STUDY AT 6 MONTHS

No approved targeted therapies currently exist for IgA nephropathy (IgAN). Targeting the alternative complement pathway (AP) is an attractive therapeutic strategy given its role in the pathogenesis of IgAN. Iptacopan (LNP023) is a first-in-class, oral, potent and highly selective inhibitor of factor B of AP. This randomized, double-blind, dose-ranging, parallel-group adaptive design Phase 2 study (NCT03373461) enrolled patients with biopsy-confirmed IgAN (within the previous 3 years), urine protein-to-creatinine ratio (UPCR) ≥0.8 g/g or urine protein ≥0.75 g/24 h, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. Part 1 of the study enrolled patients for a 3-month treatment period; Part 2 of the study enrolled patients for a 6-month treatment period; both Parts comprised a 3-month treatment-free follow-up. Patients were randomized to one of the four iptacopan arms (10, 50, 100 [in Part 2 only], and 200 mg bid) or placebo. In this analysis, we report efficacy and biomarker data assessed at 6 months and treatment-emergent adverse events (AEs) assessed for the entire study duration. In addition to the pre-specified efficacy analysis of Part 2 at 6 months, Post hoc analyses combining data from Parts 1 and 2 were also performed. 46 and 66 patients were randomized in Parts 1 and 2, respectively. In Part 2, 58 patients completed 6 months of treatment. Demographic and baseline characteristics were generally well-balanced across all arms. The primary analysis yielded a statistically significant dose-response effect (1-sided p=0.038) of iptacopan versus placebo at 3 months, with maximal reduction in UPCR achieved with iptacopan 200 mg bid (23%; 80% CI: 8–34% using MCP-mod; Primary results were presented at 58thERA-EDTA Congress 2021 as late-breaking clinical trial ). UPCR continued to decrease between 3 and 6 months in the higher dosed iptacopan arms in Part 2, albeit with a wider 80% CI reflecting the smaller sample size. To allow better comparison with the primary analysis at 3 months, a Post hoc analysis of pooled data from Parts 1 and 2 was performed. The results indicated UPCR reduction from baseline up to 6 months in iptacopan 200 mg bid arm by up to 40% (80% CI: 16–53% using MCP-mod model) and at least 28% (80% CI: 3–46% using MMRM model) versus placebo (Figure 1). Sustained inhibition of AP biomarkers including plasma Bb, serum Wieslab, and urinary C5b-9 through 6 months was also observed with all doses of iptacopan above 10 mg bid (Figure 2). Iptacopan had a well-tolerated safety profile, with no deaths, no serious adverse events (SAEs) suspected to be treatment-related, and no serious infections caused by encapsulated bacteria. Iptacopan was well tolerated and led to continuous reduction in proteinuria and strong inhibition of AP activity through 6 months in patients with IgAN. These data are consistent with previous findings from the interim analysis at 3 months and support further evaluation of iptacopan in the ongoing Phase 3 APPLAUSE-IgAN trial (NCT04578834).

Effects of omega-3 fatty acids supplementation on perioperative blood loss and complications after radical prostatectomy.

Many dietary supplements, including omega-3 fatty acids (ω3), are suspected to affect blood coagulation and platelet function. Despite no clinical evidence, discontinuation is recommended before radical prostatectomy. However, long-chain ω3 (LCω3) appear beneficial against prostate cancer progression. Here, we aim to determine the effect of LCω3 supplements on perioperative bleeding, hemoglobin, platelets, and postoperative complications after radical prostatectomy. This is a planned exploratory analysis of 130 patients diagnosed with prostate cancer grade group 2 or greater enrolled in a randomized controlled trial (NCT02333435) testing the effects of LCω3, on prostate cancer biological and pathological outcomes at radical prostatectomy as main outcomes. The LCω3 intervention (MAG-EPA 3g daily) or equivalent placebo was given 4-10 weeks prior to radical prostatectomy. An intention-to-treat analysis approach was used with bi-variate statistical testing of bleeding and complications outcomes. We also estimated the difference between groups using linear regression and non-parametric quantile regression models. All models were adjusted for confounding variables selected on clinical relevance. We found no clinically significant effect of LCω3 versus placebo on perioperative bleeding, laboratory tests or postoperative complications. In contrast, as expected, we found a significant increase in perioperative bleeding in open retropubic radical prostatectomy compared to robot-assisted radical prostatectomy (adjusted difference 115.8mL, p=0.04). Our results suggest that ω3 supplements can be safely taken before radical prostatectomy without increasing surgical bleeding risk. These findings are relevant since ω3 may beneficially affect prostate cancer evolution.

Modified Mayo score versus Mayo score for evaluation of treatment efficacy in patients with ulcerative colitis: data from the tofacitinib OCTAVE program.

The subjectivity of the Physician Global Assessment (PGA) is a limitation of the Mayo score in assessing severity of ulcerative colitis (UC). We compared treatment efficacy using endpoint definitions based on modified Mayo (mMayo) score, versus those based on Mayo score, using data from the tofacitinib OCTAVE program. This post hoc analysis included data from two 8-week induction studies (OCTAVE Induction 1 and 2) and a 52-week maintenance study (OCTAVE Sustain). Remission and clinical response [with nonresponder imputation (NRI)] were assessed using mMayo (without PGA) and Mayo scores, and further stratified by prior tumor necrosis factor inhibitor (TNFi) failure status. At week 8 of OCTAVE Induction 1 and 2, remission rates with placebo and tofacitinib 10 mg twice daily (BID), respectively, were 7.7% and 24.8% (mMayo) and 6.0% and 17.6% (Mayo). At week 52 of OCTAVE Sustain, remission rates with placebo, tofacitinib 5 and 10 mg BID, respectively, were 12.1%, 35.9%, and 42.1% (mMayo) and 11.1%, 34.3%, and 40.6% (Mayo). A statistically significant (p < 0.05) treatment effect of tofacitinib versus placebo was observed for remission and clinical response at all time points, regardless of scoring definition or prior TNFi failure status. A significant effect of tofacitinib versus placebo was demonstrated across efficacy endpoints using mMayo score, consistent with previously reported data using Mayo score. Treatment effect sizes were generally similar regardless of scoring definition. This observation may help contextualize tofacitinib therapy outcomes with those of new UC therapies and support the use of Mayo score-based endpoints in UC clinical trials. ClinicalTrials.gov identifiers: NCT01465763; NCT01458951; NCT01458574.

The Placebo Effect on Symptoms, Quality of Life, and Functional Outcomes in Patients With Angina Pectoris: A Meta-analysis of Randomized Placebo-Controlled Trials.

The placebo effect is a well described phenomenon in blinded studies evaluating antianginal therapeutics, although its effect on clinical research metrics remains unknown. We conducted a systematic review and meta-analysis to quantify the effect of placebo on end points of symptoms, life quality, and functional outcomes in randomized placebo-controlled trials (RCTs) of symptomatic stable coronary artery disease. We systematically reviewed MEDLINE, EMBASE, and the Cochrane database for double-blind RCTs of antiangina therapeutics. Patients randomized to the placebo arm were the study population. Main outcomes were the changes in exercise performance (exercise treadmill test [ETT] parameters), quality of life (Seattle Angina Questionnaire domains), symptoms (Canadian Cardiovascular Society angina class) and drug usage (nitroglycerin tablets per week) between baseline and after placebo treatment. The primary outcome was ETT total duration time. Data were pooled with a random effect model. Seventy-eight RCTs (83% drug-controlled, 17% procedure-controlled) were included encompassing 4925 patients randomized to placebo. ETT total duration time was significantly improved after placebo treatment compared with baseline (mean, 29.2; 95% confidence interval, 20.6-37.8] seconds) with evidence of high heterogeneity (I2 = 98%) At subgroup analysis, crossover design was associated with a smaller placebo effect on ETT performance than parallel study design (P for interaction = 0.001). A significant placebo effect was observed for all secondary outcomes with overall high heterogeneity. A substantial placebo effect was present in angina RCTs across a variety of functional and life quality metrics. High variability in placebo effect size was present, mostly unexplained by differences in study and patient characteristics.

A Biomarker-Based Score for Risk of Hospitalization for Heart Failure in Patients With Diabetes.

OBJECTIVEHeart failure (HF) is an impactful complication of type 2 diabetes mellitus (T2DM). We aimed to develop and validate a risk score for hospitalization for HF (HHF) incorporating biomarkers and clinical factor(s) in patients with T2DM.RESEARCH DESIGN AND METHODSWe derived a risk score for HHF using clinical data, high-sensitivity troponin T (hsTnT), and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) from 6,106 placebo-treated patients with T2DM in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using Cox regression. The strongest indicators of HHF risk were included in the score using integer weights. The score was externally validated in 7,251 placebo-treated patients in DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events–Thrombolysis in Myocardial Infarction 58). The effect of dapagliflozin on HHF was assessed by risk category in DECLARE-TIMI 58.RESULTSThe strongest indicators of HHF risk were NT-proBNP, prior HF, and hsTnT (each P < 0.001). A risk score using these three variables identified a gradient of HHF risk (P-trend <0.001) in the derivation and validation cohorts, with C-indices of 0.87 (95% CI, 0.84–0.89) and 0.84 (0.81–0.86), respectively. Whereas there was no significant effect of dapagliflozin versus placebo on HHF in the low-risk group (hazard ratio [HR] 0.98 [95% CI 0.50–1.92]), dapagliflozin significantly reduced HHF in the intermediate-, high-, and very-high-risk groups (HR 0.64 [0.43–0.95], 0.63 [0.43–0.94], and 0.72 [0.54–0.96], respectively). Correspondingly, absolute risk reductions (95% CI) increased across these latter 3 groups: 1.0% (0.0–1.9), 3.0% (0.7–5.3), and 4.4% (−0.2 to 8.9) (P-trend <0.001).CONCLUSIONSWe developed and validated a risk score for HHF in T2DM that incorporated NT-proBNP, prior HF, and hsTnT. The risk score identifies patients at higher risk of HHF who derive greater absolute benefit from dapagliflozin.

Who are the placebo responders? A cross-sectional cohort study for psychological determinants.

A number of studies have demonstrated substantial individual differences in placebo effects. We aimed to identify individual psychological factors that potentially predicted the magnitude of placebo hypoalgesia and individual responsiveness. The Research Domain Criteria framework and a classical conditioning with suggestions paradigm were adopted as experimental models to study placebo phenotypes in a cohort of 397 chronic pain participants with a primary diagnosis of temporomandibular disorder (TMD) and 397 healthy control (HC) participants. The magnitude of placebo hypoalgesia was operationalized as the average difference in pain ratings between the placebo and control conditions. The individual placebo responsiveness was identified as the status of placebo responders and nonresponders based on a permutation test. We observed significant placebo effects in both TMD and HC participants. A greater level of emotional distress was a significant predictor of smaller magnitude (slope b = -0.07) and slower extinction rate (slope b = 0.51) of placebo effects in both TMD and HC participants. Greater reward seeking was linked to greater postconditioning expectations (ie, reinforced expectations) in TMD (slope b = 0.16), but there was no such a prediction in HC participants. These findings highlight that negative valence systems might play a role in impairing placebo effects, with a larger impact in chronic pain participants than in healthy participants, suggesting that individuals reporting emotional distress and maladaptive cognitive appraisals of pain may benefit less from placebo effects.

Omega-7 Mixed Fatty Acid Supplementation Fails to Reduce Serum Inflammatory Biomarkers: A Placebo-Controlled, Double-Blind Randomized Crossover Trial

We report the effects of mixed omega-7 fatty acid supplementation on changes in serum hsCRP, TNFα, and IL-6 levels and self-reported outcomes in people with non-specific chronic musculoskeletal discomfort. Design: A double-blind, placebo-controlled, 1:1 randomized single crossover trial composed of 688 mg/day palmiteolate for the verum and an equivalent amount of medium-chain triglycerides for the placebo. Method: Data were analyzed in two independent groups and as a crossover group. Results: From 211 screened participants in 2017–2019, 56 were randomized. Six participants dropped out and fifty completers contributed to the statistical analyses. At baseline, none of the investigated biomarkers were significantly correlated to subjectively assessed musculoskeletal discomfort levels. For the two-group analysis (n = 26 and n = 24), none of the serum biomarkers reached statistical significance; however, a statistically significant placebo effect was found in the subjective outcomes. Conclusion: For the crossover analysis (n = 50), three weeks of supplementation with n7FA containing 688 mg per day of palmiteolate did not reduce serum inflammatory biomarkers nor did it improve subjectively measured quality of life (QoL) compared to placebo. Future studies should explore appropriate biomarkers, sufficient power, length of dosing, inclusion criteria for volunteers with higher BMI, and the verification of cis-palmiteolate versus trans-palmiteolate.

Placebo effects in low back pain: A systematic review and meta-analysis of the literature.

Background and ObjectiveThe current treatments of primary musculoskeletal low back pain (LBP) have a low to moderate efficacy, which might be improved by looking at the contribution of placebo effects. However, the size of true placebo effects in LBP is unknown. Therefore, a systematic review and meta‐analysis were executed of randomized controlled trials investigating placebo effects in LBP.Databases and Data TreatmentThe study protocol was registered in the international prospective register of systematic reviews Prospero (CRD42019148745). A literature search (in PubMed, Embase, The Cochrane Library, CINAHL and PsycINFO) up to 2021 February 16th yielded 2,423 studies. Two independent reviewers assessed eligibility and risk of bias.ResultsEighteen studies were eligible for the systematic review and 5 for the meta‐analysis. Fourteen of the 18 studies were clinical treatment studies, and 4 were experimental studies specifically assessing placebo effects. The clinical treatment studies provided varying evidence for placebo effects in chronic LBP but insufficient evidence for acute and subacute LBP. Most experimental studies investigating chronic LBP revealed significant placebo effects. The meta‐analysis of 5 treatment studies investigating chronic LBP depicted a significant moderate effect size of placebo for pain intensity (SMD = 0.57) and disability (SMD = 0.52).ConclusionsThis review shows a significant contribution of placebo effects to chronic LBP symptom relief in clinical and experimental conditions. The meta‐analysis revealed that placebo effects can influence chronic LBP intensity and disability. However, additional studies are required for more supporting evidence and evidence for placebo effects in acute or subacute LBP.SignificanceThis systematic review and meta‐analysis provides evidence of true placebo effects in low back pain (LBP). It shows a significant contribution of placebo effects to chronic LBP symptom relief. The results highlight the importance of patient‐ and context‐related factors in fostering treatment effects in this patient group. New studies could provide insight into the potential value of actively making use of placebo effects in clinical practice.

Placebo and nocebo effects in youth: subjective thermal discomfort can be modulated by a conditioning paradigm utilizing mental states of low and high self-efficacy.

Introduction:Conditioning is a key mechanism of placebo and nocebo effects in adults, but little is known about these effects in youth. This study investigated whether personalized verbal cues evoking a sense of high or low self-efficacy can induce conditioned placebo and nocebo effects on subjective discomfort of noxious heat in youth.Methods:In a structured interview, 26 adolescents (13–18 years) described personal situations in which they experienced a sense of high, low or neutral self-efficacy. Participants were then asked to recall these memories during a conditioning paradigm, in which a high thermal stimulus applied to the forearm was repeatedly paired with a low self-efficacy cue and a low thermal stimulus with a high self-efficacy cue. In a testing phase, high, low and neutral self-efficacy cues were paired with the same moderate temperature. We hypothesized that conditioned high and low self-efficacy cues would induce conditioned placebo and nocebo responses to moderate temperatures.Results:Moderate temperatures were rated as more uncomfortable when paired with the conditioned low compared with the neutral self-efficacy cue (nocebo effect). While in the whole-group analysis, there was no significant difference between ratings of moderate thermal stimuli paired with high compared with neutral self-efficacy cues (placebo effect), a sub-group of participants with a greater range of emotional valence between high and neutral self-efficacy cues revealed a significant placebo effect. The strength of the nocebo effect was associated with higher anxiety and lower hope.Conclusion:Conditioned associations using internal self-efficacy states can change subjective discomfort of thermal sensations.

Placebo and nocebo responses in randomised, controlled trials of medications for ADHD: a systematic review and meta-analysis.

The nature and magnitude of placebo and nocebo responses to ADHD medications and the extent to which response to active medications and placebo are inter-correlated is unclear. To assess the magnitude of placebo and nocebo responses to ADHD and their association with active treatment response. We searched literature until June 26, 2019, for published/unpublished double-blind, randomised placebo-controlled trials (RCTs) of ADHD medication. Authors were contacted for additional data. We assessed placebo effects on efficacy and nocebo effects on tolerability using random effects meta-analysis. We assessed the association of study design and patient features with placebo/nocebo response. We analysed 128 RCTs (10,578 children/adolescents and 9175 adults) and found significant and heterogenous placebo effects for all efficacy outcomes, with no publication bias. The placebo effect was greatest for clinician compared with other raters. We found nocebo effects on tolerability outcomes. Efficacy outcomes from most raters showed significant positive correlations between the baseline to endpoint placebo effects and the baseline to endpoint drug effects. Placebo and nocebo effects did not differ among drugs. Baseline severity and type of rating scale influenced the findings. Shared non-specific factors influence response to both placebo and active medication. Although ADHD medications are superior to placebo, and placebo treatment in clinical practice is not feasible, clinicians should attempt to incorporate factors associated with placebo effects into clinical care. Future studies should explore how such effects influence response to medication treatment. Upon publication, data will be available in Mendeley Data: PROSPERO (CRD42019130292).

Effect of combined yoga and transcranial direct current stimulation intervention on working memory and mindfulness.

Transcranial direct stimulation, a non-invasive neurostimulation technique for modulating cortical excitability, and yoga have both respectively been shown to positively affect cognition. While preliminary research has shown that combined transcranial direct stimulation and meditation may have synergistic effects on mood and cognition, this was the first study to explore the combination of transcranial direct stimulation and yoga. Twenty-two healthy volunteers with a regular yoga practice were randomized to receive either active transcranial direct stimulation (anodal left, cathodal right dorsolateral prefrontal cortex) followed by yoga intervention or sham transcranial direct stimulation followed by yoga intervention a double-blind, cross-over design over two separate intervention days. Outcome measures included working memory performance, measured with the n-back task and mindfulness state, measured with the Toronto Mindfulness Scale, and were conducted offline, with pre-post assessments. Twenty participants completed both days of the intervention. Active transcranial direct stimulation did not have a significant effect on working memory or levels of mindfulness. There was a significant placebo effect, with better performance on day 1 of the intervention, irrespective of whether participants received active or sham transcranial direct stimulation. There was no significant difference between active versus sham transcranial direct stimulation concerning working memory performance and mindfulness, which may be accounted by the small sample size, the transient nature of the intervention, the fact that yoga and transcranial direct stimulation concerning were not conducted simultaneously, and the specific site of stimulation.