High Placebo Response Research Articles

Meta-Analysis: Evaluating Placebo Rates Across Outcomes in Eosinophilic Oesophagitis Randomised Controlled Trials.

High placebo responses have limited drug development in eosinophilic oesophagitis. The optimal configuration of trial outcomes is uncertain. To inform more efficient future trial designs, to characterise clinical, endoscopic and histologic placebo responses in eosinophilic oesophagitis randomised controlled trials (RCTs). We updated a Cochrane systematic review and meta-analysis, searching multiple databases to January 1, 2024, to identify placebo-controlled RCTs evaluating medical therapies for patients with eosinophilic oesophagitis. The primary outcome was the pooled proportion of study-defined clinical, endoscopic and histologic responders and remitters randomised to placebo, using an intention-to-treat approach and random-effects model. Sources of heterogeneity were explored using meta-regression. We included 25 RCTs. The pooled proportion of clinical response was 41.0% [95% CI: 29.7%-52.8%] with substantial heterogeneity (I2 = 74.9%). On meta-regression, older age and a higher probability of being randomised to placebo reduced the likelihood of clinical response to placebo. The pooled proportion of histologic remission defined as a peak eosinophil count [PEC] ≤ 6 eosinophils per high power field [HPF] or ≤ 1 eosinophil/HPF was 4.3% [95% CI: 2.6%-6.2%] (I2 = 23.6%) and 1.3% [95% CI: 0.5%-2.5%] (I2 = 0%), respectively. The standardised mean difference in the Eosinophilic Oesophagitis Endoscopic Reference Score to placebo was -0.25 [95% CI: -0.41, -0.10]. Over 40% of patients in eosinophilic oesophagitis trials respond clinically to placebo, and this is associated with trial design factors such as randomisation ratio and trial population. Objective endoscopic and histologic measures are associated with very low placebo responses.

Citrus supplementation in subjective cognitive decline: results of a 36-week, randomized, placebo-controlled trial

BackgroundDeveloping interventions for older adults with subjective cognitive decline (SCD) has the potential to prevent dementia in this at-risk group. Preclinical models indicate that Citrus-derived phytochemicals could benefit cognition and inflammatory processes, but results from clinical trials are still preliminary. The aim of this study is to determine the effects of long-term supplementation with Citrus peel extract on cognitive performance and inflammation in individuals with SCD.MethodsEighty participants were randomly assigned to active treatment (400 mg of Citrus peel extract containing 3.0 mg of naringenin and 0.1 mg of auraptene) or placebo at 1:1 ratio for 36 weeks. The primary endpoint was the change in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score across the 36-week trial period. Other cognitive outcomes included tests and scales evaluating verbal memory, attention, executive and visuospatial functions, and memory concerns. The secondary endpoint was the change of interleukin-8 (IL-8) levels over the 36-week trial period in a subsample of 60 consecutive participants. An Intention-to-treat approach with generalized linear mixed models was used for data analysis.ResultsThe RBANS total score showed significant improvement in both Citrus peel extract and placebo groups at 36 weeks (p for time < .001, d = 0.36, p time x treatment = .910). Significant time effects were also found in cognitive domains of short- and long-term verbal memory (p < .001) and scales of subjective memory (p < .01), with no significant time x treatment interaction. The largest effect sizes were observed in verbal memory in the placebo group (d = 0.69 in short-term, and d = 0.78 in long-term verbal memory). Increased IL-8 levels were found at 36-week follow-up in both Citrus peel extract and placebo groups (p for time = .010, d = 0.21, p time x treatment = .772). Adverse events were balanced between groups.ConclusionsIn this randomized clinical trial, long-term Citrus peel extract supplementation did not show cognitive benefits over placebo in participants with SCD, possibly due to high placebo response. These findings might have specific implications for designing future nutraceutical trials in individuals experiencing SCD.Trial registrationThe trial has been registered at the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 (https://www.clinicaltrials.gov/ct2/show/NCT04744922).

Demonstration of Group-Level and Individual-Level Efficacy Using Time-to-Event Designs for Clinical Trials of Antiseizure Medications.

Participants with treatment-resistant epilepsy who are randomized to add-on placebo and remain in a trial for the typical 3 to 5-month maintenance period may be at increased risk of adverse outcomes. A novel trial design has been suggested, time to prerandomization monthly seizure count (T-PSC), which would limit participants' time on ineffective therapy. We reanalyzed 11 completed trials to determine whether the primary efficacy conclusions at T-PSC matched each of the original, longer trials. A total of 11 double-blind, placebo-controlled trials of levetiracetam, brivaracetam, lacosamide, topiramate, and lamotrigine for either focal-onset or generalized-onset epilepsy were selected. We evaluated the group-level and individual-level efficacy of treatments including the median percent reduction (MPR) in seizure frequency and 50% responder rate (50RR) at T-PSC, time to second seizure, and time to first seizure compared with the full-length trial. The primary efficacy conclusions of 10 of the 11 trials would have been the same with a T-PSC design compared with the traditional design (the exception of lamotrigine had a very high initial placebo response). As a proportion of the full-length effect size, 90% of the MPR and 85% of the 50RR were seen at T-PSC (95% CI 73%-113% and 65%-110%, respectively). Using the T-PSC design, the time on blinded treatment was at least 312 participant-years shorter (40% of total duration) and 142,000 seizures occurred during this time (60% of total seizures). By contrast, the time to first or second seizure designs reproduced group-level effect size, but the primary efficacy conclusions of each trial and individual-level efficacy correspondence were fair to poor. These results support the use of this trial design for new epilepsy medication trials because this reanalysis of 11 randomized controlled trials demonstrated that observation until T-PSC was sufficient to demonstrate efficacy while potentially improving participant safety by reducing the time of exposure to placebo and inadequate treatment. Despite analysis of 11 trials including 3,619 participants, we did not observe a significant reduction in the group-level effect size, which is directly related to statistical power. The next step is to evaluate whether T-PSC is sufficient to evaluate safety as measured by adverse events.

Sample size calculation for the sequential parallel comparison design with binary endpoint using exact methods

High placebo responses in clinical trial could reduce the treatment effect leading to the failure of a promising drug. Several strategies have been developed to minimize high placebo responses, including the sequential parallel comparison design (SPCD). For a study with binary outcome, the existing statistical methods to test the drug effectiveness always rely on the asymptotic limiting distribution. When a study's sample size is small to medium, the asymptotic approaches do not have satisfactory performance with regard to type I error rate and statistical power. For that reason, we propose utilizing exact conditional approach to calculate sample size based on the existing test statistics to order the sample space. The proposed method controls the type I error rate under the unconditional framework. We compare the proposed exact sample sizes using different test statistics and the sample size for a randomized parallel study. We would recommend using exact sample sizes for the SPCD with small- to medium sample sizes and the SPCD with extreme response rates.

Antidepressants in the acute treatment of post-traumatic stress disorder in adults: a systematic review and meta-analysis.

Currently, there are few pharmacotherapy options for clinicians treating post-traumatic stress disorder (PTSD), and antidepressants are usually the medication of choice. This meta-analysis aimed to review the efficacy of antidepressants in the acute treatment of PTSD in adults while investigating the contribution of study design and placebo response to the findings of these studies. Randomized, double-blind, placebo-controlled clinical trials that compared antidepressants with placebo for acute treatment of PTSD were selected. Standardized mean difference (SMD) in change in Clinician-Administered PTSD Scale scores were pooled after examining for heterogeneity. A random-effects meta-analysis was performed. Twenty-nine antidepressant-placebo comparisons, involving 4575 subjects, were analyzed. The SMD among all studies was 0.25, a small to medium effect size, lower than that in studies of antidepressants in adult major depressive disorder. The SMDs for low and high mean placebo responses, were 0.27 and 0.22, respectively. The overall SMD for paroxetine studies was in the moderate range (0.43) and that for sertraline studies was in the small range (0.12). Our findings suggest that antidepressants have modest efficacy in alleviating PTSD symptoms. Patient-level meta-analyses are required to further explore the potential clinical relevance of sertraline for PTSD.

Safety and Efficacy of Levomilnacipran Extended Release in Pediatric Patients Aged 7-17 Years with Major Depressive Disorder: Results of Two Phase 3, Randomized, Double-Blind Studies.

Objective: Major depressive disorder (MDD) presents a significant psychosocial burden, and there is an unmet need for additional treatment options in pediatric patients. Here, we report the results of two phase 3 multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group studies evaluating the efficacy and safety of levomilnacipran extended release in children and adolescents with MDD. Methods: In the first study, LVM-MD-11, patients aged 12-17 years received daily doses of levomilnacipran 40 mg (n = 134), levomilnacipran 80 mg (n = 138), fluoxetine 20 mg (n = 134), or placebo (n = 141). In the second study, LVM-MD-14, patients aged 7-17 years received levomilnacipran 40 to 80 mg (n = 166), fluoxetine 20 mg (n = 166), or placebo (n = 160) daily. Primary and secondary efficacy endpoints were changes in Children's Depression Rating Scale-Revised (CDRS-R) total score and Clinical Global Impressions-Severity (CGI-S) score, respectively. Results: In LVM-MD-11, there were no significant differences in change in CDRS-R total score between patients treated daily with placebo (least squares mean [LSM] change in CDRS-R total score -22.9) versus levomilnacipran 40 mg (-23.3; p = 0.8035) or 80 mg (-22.6; p = 0.8681). Similarly, in LVM-MD-14, there were no significant differences in LSM change in CDRS-R total score with placebo (-21.3) versus levomilnacipran 40 to 80 mg daily (-23.0; p = 0.2215). There were also no significant differences between the fluoxetine and placebo groups in either study for changes in CDRS-R total score. Changes in CGI-S score were not significant between placebo and levomilnacipran 40 to 80 mg daily or between placebo and fluoxetine. Levomilnacipran was generally well tolerated. Conclusions: The high placebo response in this study prevented the detection of an effect of levomilnacipran in children and adolescents. Clinical Trial Registration numbers: NCT02431806 and NCT03569475.

Discrepancies in hidradenitis suppurativa lesion characterization by providers and patients.

The hidradenitis suppurativa (HS) clinical response (HiSCR) has come under scrutiny as several HS clinical trials failed to meet primary endpoints with high placebo responses. This may be due to limitations of the tool and raters' ability to accurately characterize and count lesions, rather than lack of efficacy of the studied drug. Due to HS lesion complexity and potential differences in rater training, it was hypothesized that there would be discrepancies in how providers characterize and count lesions for HS clinical trials. To evaluate how HS providers and patients name and count HS lesions and to identify discrepancies among providers to initiate the development of consensus-driven guidance for HS rater training. An online survey was distributed to the members of HIdradenitis SuppuraTiva cORe outcomes set International Collaboration (HISTORIC). Respondents were asked to classify lesion images composed of multiple and different morphology types and answer questions regarding inclusion of associated dermatological conditions. Forty-seven HISTORIC members responded (29 providers; 18 patients). There was variability in how respondents classified HS lesions. Of 12 questions containing images, four had ≥50% of respondents choosing the same answer. With an image of a lesion composed of different morphologies, 45% of providers counted it as a single lesion and 45% counted it as multiple distinct lesions. With an image of multiple interconnected draining tunnels, 7% of providers classified it as a single draining tunnel while 79% categorized it as multiple draining tunnels with the number estimated by visual inspection. There was also variability in deciding whether lesions occurring in associated conditions should be considered separately or included in HS lesion counts. Patient responses were also variable. The result of the current study reaffirms the gap in how providers characterize and count HS lesions for clinical trials and the need to develop consensus-driven rater training related to HS outcome measures.

Triptans in the Acute Migraine Management of Children and Adolescents: An Update.

To summarize recent findings regarding triptan use in the acute treatment of pediatric migraine. Prevalence of pediatric migraine is rising. The American Headache Society and American Academy of Neurology updated guidelines to provide evidence-based recommendations for the treatment of acute migraine in youth. In the setting of a dearth of new randomized controlled trials (RCTs), we review current guidelines, triptan use in the emergency department, and an era of secondary analyses. Measuring the efficacy of triptans in pediatric migraine has been challenged by high placebo response rates. Secondary analyses, combining data from multiple RCTs, support that triptans are safe and effective in the treatment of migraine. Triptans are a vital tool and the only FDA-approved migraine-specific treatment available in pediatrics. There is a need for further studies and funding support in pediatric headache medicine.

A Conversation with Professor Ted Kaptchuk, a Key Architect of Modern TCM in the West

Abstract The interview was conducted on November 20th, 2022 by Ioannis Solos and Charles Buck. Ted Kaptchuk (泰开阳) is a Professor of Medicine and a Professor of Global Health &amp; Social Medicine at Harvard Medical School. In 1975, he graduated from the Macau Institute of Chinese Medicine, Macau, China. After returning to the West, Ted taught Chinese medicine throughout the States, Europe, Latin America, and Australia. Ted’s book, The Web that Has No Weaver: Understanding Chinese Medicine is a groundbreaking explanation of East Asian medicine that continues to shape the discourse of the Chinese medicine profession in the West and has been translated into 13 languages. In 1990, Ted was recruited in Harvard Medical School to help research Chinese medicine. After encountering high placebo responses in multiple acupuncture clinical trials, Ted decided to switch his career to primarily studying placebo. He has published over 300 peer-reviewed articles. He has been awarded the Lifetime Achievement Award from the Society of Acupuncture Research (2015), the Lifetime Achievement Award from the Society for Interdisciplinary Placebo Studies (2021), and the William Silen Lifetime Achievement Award in Mentoring from Harvard Medical School (2022).

Irritable bowel syndrome in children: the placebo response rate and influencing factors a meta-analysis.

Irritable bowel syndrome is common in children and exhibits a high placebo response. This study was to explore the placebo response rate and its influencing factors in children with irritable bowel syndrome. A systematic search was performed on Pubmed, Embase, MEDLINE, Cochrane Library, CNKI, Wanfang, and CBM from database inception to March 2022. Randomized controlled trials of irritable bowel syndrome in children were included in the study. The primary outcome was the placebo response rate of improvement. Thirteen studies were included, with 445 patients in the placebo group. The rate of improvement and abdominal pain disappearance were 28.2% (95% CI, 16.6-39.9%) and 5% (95% CI, 0-18.4%). The placebo response based on the abdominal pain score was 0.675 (95% CI, 0.203-1.147). The mode of administration (P < 0.01), dosing schedule (P < 0.01), and clinical outcome assessor (P = 0.04) have a significant impact on the magnitude of placebo effect. The placebo response rate for pediatric irritable bowel syndrome was 28.2%. In clinical trials, reducing dosing frequency, selecting appropriate dosage forms, and using patient-reported outcomes can help mitigate the placebo effect. This is the first meta-analysis to assess the placebo response rates for improvement and disappearance in children with IBS. The finding suggested that the mode of administration, dosing schedule, and clinical outcome assessor could potentially influence the magnitude of the placebo effect in children with IBS. This study would provide a basis for estimating sample size in clinical trial design with a placebo control.

Efficacy and safety of intermittent theta burst stimulation on adolescents and young adults with major depressive disorder: A randomized, double blinded, controlled trial

BackgroundIntermittent theta burst stimulation (iTBS) is a newer form of Repetitive Transcranial Magnetic Stimulation (rTMS) for depression. However, its efficacy and safety in adolescents and young adults with major depressive disorder (AYA-MDD) have not been well studied, especially when applied with a strategy that combines neuronavigation targeting and accelerated iTBS. MethodsIn this study, ninety patients were randomly assigned to twice-daily (two 600-pulse sessions spaced out by 10 min, n = 31), once-daily (one 600-pulse session, n = 29) or sham iTBS (no pulses, n = 30) groups for 10 treatment days. The primary outcome measure was the change in depression scores on the Hamilton Rating Scale for Depression (HAMD-17). Other clinical symptoms, such as anxiety, were also evaluated. ResultsLinear mixed model analysis found that scores on the HAMD-17 and its factors improved in all three groups, but these improvements did not significantly differ among groups. Other clinical symptoms such as anxiety also improved. Response and remission rates were relatively low and did not differ among groups at any time point. The most common adverse event was headache, and the proportion of participants who reported headache in the twice-daily and once-daily groups was significantly higher than that in the sham group. ConclusionsThe current results indicated that twice-daily and once-daily iTBS under neuronavigation are safe and well tolerated in AYA-MDD, but the overall efficacy was not superior to that of sham treatment. We speculated several possible reasons such as the high placebo response of the young population, inadequate iTBS pulses and so on.

Addressing high placebo response rates in randomized clinical trials for hidradenitis suppurativa.

Addressing high placebo response rates in randomized clinical trials for hidradenitis suppurativa.

Clinical and biomarker responses to BI 655064, an antagonistic anti-CD40 antibody, in patients with active lupus nephritis: a randomized, double-blind, placebo-controlled, phase II trial.

To characterize its dose-response relationship, BI 655064 (an anti-CD40 monoclonal antibody) was tested as add-on to mycophenolate and glucocorticoids in patients with active lupus nephritis (LN). 121 patients were randomized (2:1:1:2) to placebo or BI 655064 120mg, 180mg or 240mg and received a weekly loading dose for 3 weeks followed by dosing every 2 weeks for the 120mg and 180mg groups, and 120mg weekly for the 240mg group. complete renal response (CRR) at Week 52. Secondary endpoints included CRR at Week 26. A dose-response relationship with CRR at Week 52 was not shown (BI 655064 120mg, 38.3%; 180mg, 45.0%; 240mg, 44.6%; placebo, 48.3%). At Week 26, 28.6% (120mg), 50.0% (180mg), 35.0% (240mg), and 37.5% (placebo) achieved CRR. The unexpected high placebo response prompted a post-hoc analysis evaluating confirmed CRR (cCRR, at Weeks 46 and 52). cCRR was achieved in 22.5% (120mg), 44.3% (180mg), 38.2% (240mg), and 29.1% (placebo) of patients. Most patients reported ≥1 adverse event (BI 655064, 85.7-95.0%; placebo, 97.5%), most frequently infections and infestations (BI 655064 61.9-75.0%; placebo 60%). Compared with other groups, higher rates of serious (20% vs. 7.5-10%) and severe infections (10% vs. 4.8-5.0%) were reported with 240mg BI 655064. The trial failed to demonstrate a dose-response relationship for the primary CRR endpoint. Post-hoc analyses suggest a potential benefit of BI 655064 180mg in patients with active LN. This article is protected by copyright. All rights reserved.

Difelikefalin (Korsuva)

&#x0D; CADTH recommends that difelikefalin should not be reimbursed by public drug plans for the treatment of moderate to severe pruritus associated with chronic kidney disease (CKD-aP) in adult patients on hemodialysis (HD).&#x0D; The CADTH Canadian Drug Expert Committee could not conclude whether treatment with difelikefalin resulted in clinically meaningful improvements. Evidence from 2 randomized controlled trials (KALM-1 and KALM-2) demonstrated that treatment with difelikefalin was associated with statistically significant improvements in itch; however, whether the improvement is clinically meaningful to patients is unclear due to a high placebo response and the trials measuring itch in a way that is inconsistent with clinical practice. As such, it is difficult to determine the actual treatment effect of difelikefalin.&#x0D; Patients living with moderate to severe CKD-aP on HD expressed a need for treatments that improve quality of life (QoL). Based on the available evidence, it is unclear if difelikefalin is associated with an improvement in QoL.&#x0D; There is a lack of evidence to show that difelikefalin would meet the needs identified by patients, such as reducing hospital visits and the amount of overall medication required, improving sleep quality and reducing sleep disturbance, and reducing side effects.&#x0D;

Efficacy and Safety of Vibegron for the Treatment of Overactive Bladder in Women: A Subgroup Analysis From the Double-Blind, Randomized, Controlled EMPOWUR Trial

ABSTRACT The sudden, intense urge to urinate, with or without urge urinary incontinence (UUI), is the predominant characterization of overactive bladder (OAB). Despite a similar prevalence of OAB between both women and men (respectively 17% and 16%), the disproportionate effects of the most bothersome symptoms of UUI fall to women. In addition, OAB’s prevalence in women increases with age when compared with men, leading to decreased scores in quality of life (QoL) measures, sexual function, depression, and sleep quality. Although behavioral therapies such as bladder training and pelvic floor muscle exercises are recommended as the first-line treatment of OAB symptom management, other treatments do exist. These second-line treatments, such as anticholinergics, are commonly prescribed as treatment for these conditions, but their use also entails persistence-limiting adverse effects. Such adverse effects include risk of dementia and cognitive impairment. The American Urogynecologic Society recommends alternative medication consideration for all patients and outright avoidance of anticholinergics for OAB treatment in women older than 70 years. Vibegron, a selective b3-adrenergic receptor agonist, was approved in 2020 for adult OAB treatment. The EMPOWUR trial, the international, placebo- and active-controlled, randomized, double-blind, phase 3 trial, demonstrated over the course of 12 weeks both the efficacy and safety of both vibegron and tolterodine for adults with OAB. Based on the disproportionate nature and bother of OAB symptoms in women, this study intended to analyze subgroups of the EMPOWUR trial to compare the QoL outcomes, 12-week treatment safety, and efficacy of vibegron treatment in women. End points for coprimary efficacy were altered from baseline at week 12 in mean daily number of UUI episodes and micturitions. Secondary efficacy end points included daily number of urgency episodes (also week 12). Exploratory outcomes included change from baseline at weeks 2, 4, and 8 for the same factors. The full set analysis for this study included all women (randomized) receiving greater than 1 dose of vibegron or placebo who experienced greater than 1 measured change using baseline valuations of urgency episodes, micturitions, and QoL outcomes unrelated to incontinence. A total of 1515 patients were included in the safety set, 1289 (84.9%) of which were women (placebo, n = 459; vibegron, n = 463; tolterodine, n = 364), with the mean age being 59.5 years. The study determined that vibegron was associated with a statistically significant greater reduction among women from baseline at week 12 in comparison to placebo. QoL also improved significantly across the board, including total, concern, sleep, coping, and symptom bother subscale scores compared with placebo. Treatment emergent adverse effects incidence was 39.3% with vibegron, 34.9% with placebo, and 39.6% with tolterodine, leading to 1.5%, 1.1%, and 3.8% of women, respectively, discontinuing treatment. The most common treatment emergent adverse effects reported was headache. An analytical limitation was the relatively brief study period of 12 weeks. The double-blind 40-week extension of the EMPOWUR trial (52 total treatment weeks) substantiated long-term safety and efficacy of vibegron (J Urol. 2021;205:1421–1429). Although a relatively high placebo response rate was observed (consistent with other analyses), vibegron was still associated with statistically significant improvements when compared with placebo in OAB symptoms in women. This subgroup analysis of OAB-diagnosed women yielded results consistent with those of the EMPOWUR 12-week trial, which indicated statistically significant reductions versus placebo in efficacy end points with once-daily vibegron 75 mg. The results also showed favorable safety and tolerability profiles. Vibegron treatment among women with OAB also significantly improved measures of QoL versus placebo. All results therefore indicate the efficacy and safety of treatment of women’s OAB with vibegron.

Methodology considerations for 'Safety and effectiveness of cannabinoids to Danish patients with treatment-refractory chronic pain' by Horsted et al.

The recently published exploratory, non-controlled, study by Horsted et al. (2023) reports on the potential safety and pain-relieving effects of cannabinoids (THC, CBD), or mixed in a non-randomized order. The authors conclude that ‘oral cannabinoid therapy in general appears to be safe and effective for relief of chronic pain in some patients, including a subset of patients with cancer-related pain (9%), not responding adequately to conventional treatment regimens or experiencing intolerable adverse events’. The author's conclusion is in direct contrast to the conclusion and recommendations from the International Associations for the Study of Pain (IASP) Cannabis Task Force. Based on a thorough evaluation of current evidence, Rice et al. (2021) concluded ‘That the available clinical evidence neither supports nor refutes claims of analgesic efficacy or safety for cannabinoids, cannabis, or cannabis-based medicines’ and suggested future studies and recommendations should follow rigid rules of conclusive randomized, placebo-controlled randomized controlled trials (RCTs) to provide evidence (Haroutounian et al., 2021). The study by Horsted et al. is a retrospective study and hence is not monitored by the Danish medical agency and executed as a good clinical practice (GCP) study although investigating the effect of a new treatment modality. Furthermore, the study was not registered at ClinicalTrials.gov as this is not normally mandatory for retrospective studies submitted to the European Journal of Pain. Many RCTs have been published demonstrating no effect of cannabinoids on clinical pain or potential underlying pain mechanisms when compared to placebo (e.g. Zubcevic et al., 2022). None of such studies and only one of the 14 IASP statement's current state-of-the-art papers are referenced in the manuscript by Horsted et al. and hence not discussed in the light of the current best evidence. The study found an average decrease in clinical pain intensity of 1.8 (baseline pain approx. 7 on a 0–10 numerical rating scale), which corresponds to an effect of approx. 25%. This is in the low end of placebo effects reported in previous high-quality pain studies and what is reported in other well-controlled placebo-controlled pain studies (McQuay et al., 1996). The expectancy and placebo effects are largely (and often exclusively) found responsible for the therapeutic effects of non-pharmacological treatments such as, e.g. cannabis. The Horsted et al. study was conducted in Denmark and here cannabis has attracted much attention in the media. The positive media promotion of cannabis products will increase the placebo effects and as the study was conducted without any control or placebo groups the effect size and the placebo responses can obviously not be separated. Most recent meta-analysis likewise concluded that ‘placebo responses contribute significantly to pain reduction in cannabinoid clinical trials’ and ‘the unusually high media attention surrounding cannabinoid trials, with positive reports irrespective of scientific results, may uphold high expectations and shape placebo responses in future’. The authors state that ‘with the relatively long follow-up it is likely that the placebo effect is of less importance’. This is not empirically validated as studies have shown long-lasting (up to 5 years) placebo effects in trials. The Horsted et al. study enrolled 826 patients, yet only 214 patients were follow-up for the last visit, 243 patients were registered as ‘lost to follow-up’ and an additional 122 patients were discontinued. In addition, among the included patients, data of interest were missing (e.g. 39 (18%) of the 214 included patients with the last visit recorded had missing values regarding pain intensity measured as numeric rating scale). Only 25.9% (214/826) of the included eligible patients were included in the analysis. All these excluded patients are likely to not benefit from the study drug (no effect or severe side effects), which is not addressed in details. Thus, the excluded patients (constituting +40% of the original sample) are a likely source of a major selection bias, compromising the study's validity and conclusions. The authors do refer to the supplementary material for a description of the excluded patients, but this material is not presented in a way that allows for further analyses. The exploratory nature of this non-placebo controlled cannabis study does not provide new evidence for the use of cannabinoids for the treatment of pain. The pain alleviation reported is at its best similar to placebo responses reported in multiple randomized pain cannabis trials. The concerningly high number of patients excluded from the analysis further compromises the integrity and validity of the study. Center for Neuroplasticity and Pain (CNAP) is supported by the Danish National Research Foundation (DNRF121). The Center for Mathematical Modeling of Knee Osteoarthritis (MathKOA) is funded by the Novo Nordisk Foundation (NNF21OC0065373). The authors declare no conflict of interest.

Dynamic Feedback Between Antidepressant Placebo Expectancies and Mood

Despite high antidepressant placebo response rates, the mechanisms underlying the persistence of antidepressant placebo effects are still poorly understood. To investigate the neurobehavioral mechanisms underlying the evolution of antidepressant placebo effects using a reinforcement learning (RL) framework. In this acute within-patient cross-sectional study of antidepressant placebos, patients aged 18 to 55 years not receiving medication for major depressive disorder (MDD) were recruited at the University of Pittsburgh between February 21, 2017, to March 1, 2021. The antidepressant placebo functional magnetic resonance imaging task manipulates placebo-associated expectancies using visually cued fast-acting antidepressant infusions and controls their reinforcement with sham visual neurofeedback while assessing expected and experienced mood improvement. The trial-by-trial evolution of expectancies and mood was examined using multilevel modeling and RL, relating model-predicted signals to spatiotemporal dynamics of blood oxygenation level-dependent (BOLD) response. A bayesian RL model comparison in 60 individuals (mean [SE] age, 24.5 [0.8] years; 51 females [85%]) with MDD revealed that antidepressant placebo trial-wise expectancies were updated by composite learning signals multiplexing sensory evidence (neurofeedback) and trial-wise mood (bayesian omnibus risk <0.001; exceedance probability = 97%). Placebo expectancy, neurofeedback manipulations, and composite learning signals modulated the visual cortex and dorsal attention network (threshold-free cluster enhancement [TFCE] = 1 - P >.95). As participants anticipated antidepressant infusions, learned placebo expectancies modulated the salience network (SN, TFCE = 1 - P >.95), positively scaling with depression severity. Results of this cross-sectional study suggest that on a timescale of minutes, antidepressant placebo effects were maintained by positive feedback loops between expectancies and mood improvement. During learning, representations of placebos and their perceived effects were enhanced in primary and secondary sensory cortices. Latent learned placebo expectancies were encoded in the SN.

Placebo response in trials with patients with anxiety, obsessive-compulsive and stress disorders across the lifespan: a three-level meta-analysis

QuestionRandomised controlled trials assessing treatments for anxiety, obsessive-compulsive and stress-related disorders often present high placebo response rates in placebo groups. Understanding the placebo response is essential in accurately estimating the...

Objective response rate of placebo in randomized controlled trials of anticancer medicines.

Spontaneous regression of advanced solid tumors is infrequent but may occur. Quantifying response rates from placebo in cancer drug trials may provide important information for physicians, patients, and regulators. We aimed to provide a pooled placebo response rate from drug trials in advanced solid tumors. We pooled the overall response rate (ORR), complete response rate (CR) and partial response rates (PR) in the placebo arm of placebo-controlled randomized controlled trials (RCTs) of cancer drugs for advanced solid tumors published during 2015-2021 using random-effects model. 45 phase 3 RCTs including 5684 patients on placebo met our inclusion criteria and formed the study cohort. The pooled overall ORR, CR and PR rates in the placebo arm were 1% (95% CI, 0%-2%), 0% (95% CI, 0%-0%), and 1% (95% CI, 0%-2%) respectively. Higher placebo responses were observed in prostate cancer and sarcoma trials. Overall, 1% patients with advanced solid tumors can expect to achieve some response even in absence of treatment. However, complete regression without treatment is extremely rare, almost zero percent. This information will be helpful to patients in their decisions, as well as regulators in evaluating cancer drugs' efficacy based on response rates alone. None.

Acupuncture for the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome

Acupuncture is a promising therapy for irritable bowel syndrome (IBS), but the use of subjective scales as an assessment is accompanied by high placebo response rates. To preliminarily test the feasibility of using US Food and Drug Administration (FDA)-recommended end points to evaluate the efficacy of acupuncture in the treatment of IBS. This pilot, multicenter randomized clinical trial was conducted in 4 tertiary hospitals in China from July 1, 2020, to March 31, 2021, and 14-week data collection was completed in March 2021. Individuals with a diagnosis of IBS with diarrhea (IBS-D) were randomized to 1 of 3 groups, including 2 acupuncture groups (specific acupoints [SA] and nonspecific acupoints [NSA]) and a sham acupuncture group (non-acupoints [NA]) with a 1:1:1 ratio. Patients in all groups received twelve 30-minute sessions over 4 consecutive weeks at 3 sessions per week (ideally every other day). The primary outcome was the response rate at week 4, which was defined as the proportion of patients whose worst abdominal pain score (score range, 0-10, with 0 indicating no pain and 10 indicating unbearable severe pain) decreased by at least 30% and the number of type 6 or 7 stool days decreased by 50% or greater. Ninety patients (54 male [60.0%]; mean [SD] age, 34.5 [11.3] years) were enrolled, with 30 patients in each group. There were substantial improvements in the primary outcomes for all groups (composite response rates of 46.7% [95% CI, 28.8%-65.4%] in the SA group, 46.7% [95% CI, 28.8%-65.4%] in the NSA group, and 26.7% [95% CI, 13.0%-46.2%] in the NA group), although the difference between them was not statistically significant (P = .18). The response rates of adequate relief at week 4 were 64.3% (95% CI, 44.1%-80.7%) in the SA group, 62.1% (95% CI, 42.4%-78.7%) in the NSA group, and 55.2% (95% CI, 36.0%-73.0%) in the NA group (P = .76). Adverse events were reported in 2 patients (6.7%) in the SA group and 3 patients (10%) in NSA or NA group. In this pilot randomized clinical trial, acupuncture in both the SA and NSA groups showed clinically meaningful improvement in IBS-D symptoms, although there were no significant differences among the 3 groups. These findings suggest that acupuncture is feasible and safe; a larger, sufficiently powered trial is needed to accurately assess efficacy. Chinese Clinical Trial Registry: ChiCTR2000030670.