Placebo Control Arm Research Articles

Predicting Tumor Volume Doubling Time and Progression-Free Survival in Untreated Patients from Patient-Derived-Xenograft (PDX) Models: A Translational Model-Based Approach

Tumor volume doubling time (TVDT) has been shown to be a potential surrogate marker of biological tumor activity. However, its availability in clinics is strongly limited due to ethical and practical reasons, as its assessment requires at least two subsequent tumor volume measurements in untreated patients. Here, a translational modeling framework to predict TVDT distributions in untreated cancer patient populations from tumor growth data in patient-derived xenograft (PDX) mice is proposed. Eleven solid cancer types were considered. For each of them, a set of tumor growth studies in PDX mice was selected and analyzed through a mathematical model to characterize the distribution of the exponential tumor growth rate in mice. Then, assuming an exponential growth of the tumor mass in humans, the growth rates were scaled from PDX mice to humans through an allometric scaling approach and used to predict TVDTs in untreated patients. A very good agreement was found between model predicted and clinically observed TVDTs, with 91% of the predicted TVDT medians fell within 1.5-fold of observations. Further, exploiting the intrinsic relationship between tumor growth dynamics and progression free survival (PFS), the exponential growth rates in humans were used to generate the expected PFS curves in absence of anticancer treatment. Predicted curves were extremely close to published PFS data from studies involving patient cohorts treated with supportive care or low effective therapies. The proposed approach shows promise as a potential tool to increase knowledge about TVDT in humans without the need of directly measuring tumor dimensions in untreated patients, and to predict PFS curves in untreated patients, that could fill the absence of placebo-controlled arms against which to compare treaded arms during clinical trials. However, further validation and refinement are needed to fully assess its effectiveness in this regard.

Placebo Effect in the Treatment of Patellar Tendinopathy and Its Influencing Factors: Systematic Review With Meta-analysis and Meta Regression of Randomized Controlled Trials.

The effectiveness of nonsurgical treatment of patellar tendinopathy is questioned due to the conflicting results of placebo-controlled randomized controlled trials (RCTs) in which placebo arms often show impressive results. To quantify the magnitude of placebo effect of the different nonsurgical treatments of patellar tendinopathy. We also evaluated the influence of patients and treatments characteristics on the response to the placebo. Systematic review; Level of evidence, 1. We searched PubMed, Web of Science, Embase, Scopus, Cochrane Library, and gray literature databases on May 10, 2023, with no time limitation. RCTs on nonoperative treatment of patellar tendinopathy, including a placebo control arm reporting the evolution of symptoms after placebo administration, were included. A single-arm meta-analysis was performed with the Victorian Institute of Sport Assessment-Patella (VISA-P) at mid-term follow-up (3-6 months) as the primary outcome. The VISA-P score at short-term (1-3 months) and long-term (6-12 months) follow-ups, as well as visual analog scale (VAS) for pain at all 3 time points were also analyzed. A subanalysis based on the type of placebo and a meta-regression were conducted to look for potential determinants of the placebo effect. Risk of bias and level of evidence were also analyzed using the revised tool for risk of bias in randomized trials and Grading of Recommendations Assessment, Development and Evaluation. In total, 14 studies (251 patients) were included. VISA-P score at mid-term follow-up (3-6 months) showed statistically significant improvements of 13 of 100 points (P = .001). The change at short-term follow-up (1-3 months) was not statistically significant, whereas at long-term follow-up (6-12 months) it was 27 of 100 points (P < .001). Regarding VAS, results were statistically significant only at mid-term (MD = -1.5/10; P = .02) and long-term (MD = -3.2/10; P < .001) follow-ups. The meta-regression showed positive correlations between the response to placebo and the follow-up length (P < .001) and the effect size in the experimental group (P = .006). The level of evidence was moderate for mid- and long-term results and low for short-term results. The placebo effect for nonsurgical treatments of patellar tendinopathy is long-lasting (up to 12 months) and statistically and clinically significant. It has a perceived and true component and differs among treatments. The duration of follow-up and the effect size of experimental groups correlate with the magnitude of the placebo component, underlining the importance of RCTs to determine the effectiveness of new treatments of patellar tendinopathy.

Mosquito Shield™, a transfluthrin passive emanator, protects against pyrethroid-resistant Anopheles gambiae sensu lato in central Benin

BackgroundSpatial repellents can provide personal and household protection against biting vector mosquitoes by volatizing repellents into the air within a given area. Mosquito Shield™ is a transfluthrin passive emanator undergoing evaluation for malaria control. Studies evaluating its entomological impact against different local malaria vector populations would help guide its deployment in endemic countries.MethodsA two-arm single-blinded small-scale household randomised entomological trial was conducted to assess the impact of Mosquito Shield™ on the human landing rate of wild pyrethroid-resistant Anopheles gambiae sensu lato (s.l.) vector mosquitoes in houses in the Ganhoua village of the Zakpota District of central Benin. From a total of 30 houses, 15 were randomly allocated to receive Mosquito Shield™, while the remainder received a placebo product. The trial lasted through the life of the Mosquito Shield™ product (32 days). Mosquito sampling was performed by human landing catches at baseline and at 6 timepoints post-intervention (days 0–1, 7–8, 14–15, 21–22, 28–29 and 31–32). Collections were performed for 2 nights at each sampling time point. WHO cylinder bioassays were conducted during the trial with F1 An. gambiae s.l. mosquitoes that emerged from larvae from the study area to assess the intensity of resistance to pyrethroids in the wild vector population.ResultsThe vector population in the study area showed a high intensity of resistance to pyrethroids. Baseline An. gambiae s.l. human landing rates were similar in houses in both study arms before product application (11.53/person/night vs 11.67/person/night, p > 0.05). A total of 5736 mosquitoes were collected in the placebo control arm and 3862 in the Mosquito Shield™ arm post-intervention. Overall An. gambiae s.l. post-intervention human landing rates were significantly lower in houses in the Mosquito Shield™ arm (18.13/person/night) compared to the houses in the placebo control arm (26.84/person/night, IRR = 0.658, p < 0.001). Over the lifespan of the product, Mosquito Shield™ provided a significant protective efficacy of 34.2% (22.1–44.4%, p < 0.001) against wild pyrethroid-resistant An. gambiae s.l. vectors compared to the placebo. Human landing rates of other nuisance vector mosquito species (Culex and Mansonia) were also reduced in houses treated with Mosquito Shield™ compared to the placebo.ConclusionMosquito Shield™, a transfluthrin passive emanator, provided significant protection against pyrethroid-resistant malaria vectors to households in Benin. The spatial repellent shows potential to reduce malaria transmission by pyrethroid-resistant An. gambiae s.l. vector mosquitoes and cover gaps in malaria control when deployed to complement existing vector control interventions.

Efficacy and safety of low-dose celecoxib with chemoradiation in locally advanced head-and-neck squamous cell carcinoma

Background: Head-and-neck squamous cell carcinoma (HNSCC) is a major cancer in India with a poor prognosis. Novel antineoplastic agents, such as selective cyclooxygenase-2 inhibitors such as celecoxib, have shown antitumor, anti-angiogenesis, and radiosensitizing effects, improving radiotherapy response in many cancers. Aims and Objectives: This study aimed to determine the efficacy and safety of low-dose celecoxib combined with concurrent chemoradiation in Locally Advanced HNSCC. Materials and Methods: A double-arm prospective randomized control study was conducted, in which 103 eligible locally advanced HNSCC patients were randomized to concurrent chemoradiotherapy 66 Gy/2 Gy/33 fractions/61/2 weeks along with Inj Cisplatin 40 mg/m2 weekly either with celecoxib 100 mg twice daily (Study Arm – 62) or placebo (Control Arm – 41). Tumor response was evaluated using response evaluation criteria in solid tumors criteria 1.1 and acute toxicities based on the radiation therapy oncology group and common terminology criteria for adverse events criteria 5.0. Results: On analysis using the Chi-square test, the complete response rate was 65.6% in the study arm compared to 44.7% in the control arm, with P=0.0441 (significant at P&lt;0.05). The incidence of acute dermatitis and mucositis (grade ≥3) in the study and control arms was 29.3% versus 23.6%, with P=0.544 and 40% versus 37% with a P=0.782 (insignificant at P&lt;0.05), respectively. The patients in both arms were followed up to assess late toxicities, locoregional control rate, disease-free survival, and overall survival. Conclusion: Adding low-dose daily celecoxib to concurrent chemoradiation with weekly cisplatin in locally advanced HNSCC significantly improved the clinical response rates with acceptable treatment-related toxicities.

Prognostic factors of patients (pts) with salvage-line metastatic colorectal cancer (mCRC).

115 Background: Randomized clinical trials provide the best evidence for the effects of a new treatment. However, the use of a placebo control arm may present practical and ethical concerns for enrolled patients and treating providers. The CRC ARCAD global database includes a total of 1,673 individual patient data (IPD) treated with placebo plus best supportive care in a salvage-line setting for refractory mCRC. By using placebo IPD, we have proposed to construct a synthetic control arm for clinical trials (Yoshino T. et al., Nature Medicine 2023). Methods: From 40,889 IPD from 59 studies in ARCAD mCRC database, 723 placebo pts were selected from 4 placebo-controlled randomized studies in a salvage-line setting (CORRECT, RECOURSE, CONCUR and TERRA). We analyzed the impact of baseline patient characteristics and various prognostic factors on outcome in the placebo control. Results: The adjusted hazard ratios (HRs) (95% confidence interval [CI]) were 0.52 (0.40-0.67) for the number of metastatic sites (1 vs 2+), 0.71 (0.59-0.84) for ECOG performance status (PS) (0 vs 1), 0.54 (0.45-0.66) for liver metastases (No vs Yes), 0.54 (0.40-0.71) for peritoneal metastases (No vs Yes), and 0.51 (0.38-0.70) for Royal Marsden Hospital (RMH) Score (consisting of albumin level, number of metastatic sites, and LDH level) (0-1 vs 2-3). Conclusions: Number of metastatic sites, ECOG PS, liver metastasis, peritoneal metastasis and RMH Score were significant prognostic factors in patients with mCRC receiving placebo in a salvage-line setting. Further prognostic factors should be investigated to increase the accuracy of the proposed synthetic control arm. [Table: see text]

A Multicentre, Randomized, Double-Blinded, Phase 2b Study Evaluating the Efficacy and Safety of MaaT033, an Oral, Pooled Microbiome Ecosystem Therapy in Patients Undergoing Allogenic Hematopoietic Cell Transplantation to Improve Overall Survival: The Phoebus Trial

Background and significance: Allogenic hematopoietic cell transplantation (alloHCT) is a well-established therapy for various life-threatening hematologic malignancies. The use of alloHCT is constantly increasing, with nearly 20 000 transplantations reported to the European Society for Blood and Marrow Transplantation (EBMT) per year. However, this treatment is limited by high morbidity and mortality, mainly related to relapse, infection, graft-versus-host disease (GvHD), and conditioning-related toxicity. Several pioneering studies have shown that the diversity of the gut microbiota of patients not only correlates with the occurrence of medical complications after alloHCT, including GvHD (Jenq et al. 2012, Stein-Thoeringer et al. 2019) and bloodstream infections (Taur et al. 2012), but also with relapse of the underlying disease (Peled et al. 2017). Gut microbiota diversity restoration with fecal microbiotherapy could be an effective treatment to improve patients' clinical outcomes including overall survival (OS) after alloHCT, through the prevention and resolution of gut microbiota dysbiosis. MaaT033 is a freeze-dried, full-ecosystem, high-diversity, fecal microbiota medicinal product, formulated as delayed-release capsules and derived from pooled allogenic human fecal material. The PHOEBUS trial is a phase 2b study to evaluate the efficacy of MaaT033 in improving survival of adult alloHCT patients (Clinicaltrials.gov identifier: NCT05762211) Study design and Methods: 387 subjects aged ≥ 50 years with hematologic malignancies for which an alloHCT is indicated will be randomized 1:1 to receive either MaaT033 (experimental arm) or placebo (control arm) before initiation of the conditioning regimen and after hematopoietic recovery following alloHCT. Stratification of patients will be performed based on disease risk index (low-intermediate versus high-very high) and donor-host compatibility (HLA-identical versus HLA-mismatch). Inclusion criteria include age ≥ 50 years, alloHCT with a reduced-toxicity or reduced-intensity conditioning regimen, neutrophils &amp;gt; 0.5 G/L, and administration of broad-spectrum antibiotics within the last 90 days prior to inclusion. Exclusion criteria comprise non-myeloablative conditioning regimen, conventional myeloablative conditioning regimen, in-vitro T-cell depletion, alloHCT with cord blood cells, alloHCT from an unrelated donor with ≥ 3/10 HLA-mismatches, use of alemtuzumab, vedolizumab or abatacept for GvHD prophylaxis, history of chronic digestive disease. The primary endpoint is to evaluate OS at 12 months after randomization. Secondary endpoints will include evaluation of the safety of MaaT033, GvHD-free survival, cumulative incidence of acute GvHD and chronic GvHD, non-relapse mortality, relapse-free survival, GvHD-free, relapse-free survival, the proportion of patients with severe infections, gut microbiota composition, and quality of life. Exploratory endpoints will describe the impact of MaaT013 on immune recovery, the nutritional status of the patients, and resource utilization. Patients will receive MaaT033 or placebo (3 capsules per day) for 1 week before the start of the conditioning regimen. Experimental treatment (3 capsules per day) will be resumed at neutrophil recovery and pursued up to 90 days after alloHCT. Patients will be followed monthly up to 6 months post alloHCT and then every 3 months up to 12 months. The study is approved in France and Germany; expansion to other countries is planned for 2024. Study start is expected in September 2023.

Fecal microbial transplantation as a novel therapeutic for autism spectrum disorders: a review of the current literature

BackgroundAutism spectrum disorders (ASDs) are complex neurobiological conditions with poor long-term outcomes and limited treatment options. The microbiota–gut–brain axis indicates a pathway by which the gut microbiota links to ASDs. Fecal microbial transplantation (FMT), whereby the gut microbiota is replaced with that of a healthy individual, shows promise for the treatment of neurobiological conditions. This review examines the current evidence for the use of FMT as a therapeutic for ASD.DiscussionASDs and their associated gastrointestinal symptoms are improved with FMT, potentially due to the engraftment of features of a healthy gut. Longer treatment regimens that include daily maintenance doses appear to be the most effective long-term therapeutic option, with benefits persisting 2 years post-intervention. Evidence is mixed regarding the use of preparatory treatments. Considering the sex bias in ASD research, small sample sizes and the lack of placebo control arms, randomized controlled trials would be of benefit to the evidence base regarding the use of FMT as a therapeutic option for ASD.ConclusionFMT is a promising new therapeutic for ASD, but the evidence base is in its infancy.

Prospective, randomized, double-blind phase 2B trial of the TLPO and TLPLDC vaccines to prevent recurrence of resected stage III/IV melanoma: a prespecified 36-month analysis

BackgroundThe tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate...

Intraarticular management of chronic haemophilic arthropathy (Review).

Hemophilia is an inherited X-linked bleeding condition with predominant joint involvement due to intra-articular bleeding, hemosiderin deposition and the synovial hypertrophy that is responsible for cartilage destruction, joint deformity and malalignment, pain and functional restriction. Management of chronic arthropathy includes conservative and surgical approaches. Conservative therapies consist of pain modulation, oral drugs, physiotherapy and intra-articular agents. For the present review, the literature was searched for intra-articular agents and 20 papers on the use of corticosteroids (CS), hyaluronic acid (HA) and platelet-rich plasma (PRP), with different regimes of administration, were included. CS had a longer record of injection, with statistically significant pain reduction and functional improvement in the short-term and moderate persistence in the long-term. HA was able to improve the clinical and functional status of joints with moderate or severe hemophilia. PRP was relatively recently introduced to joint management and the results remain controversial. Different associations between the above-mentioned agents were proposed by studies including a small number of patients, producing comparable results. It was concluded that there is a need for extensive research on intra-articular agents, with stratification according to the severity of joint involvement. The lack of a blinded or placebo-controlled arm due to ethical aspects makes the task challenging.

Placebo Effects and Neuromodulation: Ethical Considerations and Recommendations.

Placebo-controlled trials are the gold standard of evaluating treatment efficacy in clinical research. Neuromodulation is emerging as an important treatment pathway for many neuropsychiatric conditions, and placebo control arms of these trials require careful design with unique considerations (e.g., sham devices that mimic active stimulation, blinding effectiveness). Inherent to placebo-controlled trials are ethical concerns, such as deception, and potential harm of not receiving the active treatment. In this article, we outline important ethical considerations of placebo-controlled trials across neuromodulation approaches and provide recommendations on how ethical principles can be adhered to going forward. We specifically address issues of autonomy and respect for persons, beneficence, and justice. Within the context of this ethical framework, we also discuss factors influencing placebo effects in neuromodulation, the importance of adequate blinding, and alternative trial designs that could be considered.

Meta-analysis: Placebo rates in microscopic colitis randomised trials and applications for future drug development using a historical control arm.

Effective medical therapies for patients with microscopic colitis (MC) who fail budesonide are lacking. However, conducting randomised controlled trials (RCTs) in MC has been challenging due to small sample sizes. Understanding placebo responses can help inform more efficient future trials. The aim of this study is to estimate clinical and histologic placebo response rates and to determine factors associated with placebo response in MC. EMBASE, MEDLINE, and CENTRAL were searched until 7 January 2022, to identify placebo-controlled RCTs in adult patients with MC. Clinical and histologic response in the placebo arms were pooled using random-effects models. Stratified analyses based on disease- and trial-level characteristics, leave-one-out meta-analysis, and cumulative meta-analysis were performed. Twelve RCTs enrolling a total of 391 patients (placebo n= 163) with MC were included. Pooled clinical and histologic placebo response rates were 24.4% (95% CI: 12.4%-38.4%), I2 = 60.8%, p < 0.01, and 19.9% (95% CI: 5.3%-39.0%), I2 = 66.4%, p= 0.01 (tests for heterogeneity), respectively. Clinical response to placebo was numerically higher in patients with lymphocytic compared to collagenous colitis (39.9% vs. 19.8%, p=0.08). Heterogeneity in clinical response to placebo was significantly reduced when the Miehlke 2014 RCT was excluded in the leave-one-out meta-analysis or when a more stringent secondary definition of response based on the Hjortswang criteria was applied. Approximately one-quarter of patients in MC trials respond to placebo, although with substantial heterogeneity, reflecting the need for standardised outcome definitions and study designs for MC. This analysis also serves to inform future MC trials that may consider incorporating an external, historical placebo control arm, rather than directly randomising patients to placebo.

Concentration QTc analysis of giredestrant: Overcoming QT/heart rate confounding in the presence of drug-induced heart rate changes.

Concentration-QTc (C-QTc) analysis has become a common approach for evaluating proarrhythmic risk and delayed cardiac repolarization of oncology drug candidates. Significant heart rate (HR) change has been associated with certain classes of oncology drugs and can result in over- or underestimation of the true QT prolongation risk. Because oncology early clinical trials typically lack a placebo control arm or time-matched, treatment-free baseline electrocardiogram collection, significant HR change brings additional challenges to C-QTc analysis in the oncology setting. In this work, a spline-based correction method (QTcSPL) was explored to mitigate the impact of HR changes in giredestrant C-QTc analysis. Giredestrant is a selective estrogen receptor degrader being developed for the treatment of patients with estrogen receptor-positive (ER+) breast cancer. A dose-related HR decrease has been observed in patients under giredestrant treatment, with significant reductions (>10bpm) observed at supratherapeutic doses. The QTcSPL method demonstrated superior functionality to reduce the correlation between QTc and HR as compared with the Fridericia correction (QTcF). The effect of giredestrant exposure on QTc was evaluated at the clinical dose of 30 mg and supratherapeutic dose of 100 mg based on a prespecified linear mixed effect model. The upper 90% confidence interval of ΔQTcSPL and ΔQTcF were below the 10ms at both clinical and supratherapeutic exposures, suggesting giredestrant has a low risk of QT prolongation at clinically relevant concentrations. This work demonstrated the use case of QTcSPL to address HR confounding challenges in the context of oncology drug development for the first time.

Comparison of the efficacy and safety of leflunomide versus placebo combined with basic prednisone therapy in patients with active disease phase of Takayasu arteritis: study protocol for a randomized, double-blinded controlled trial (Takayasu arteritis clinical trial in China: TACTIC).

Takayasu arteritis (TAK) is an immune-induced granulomatous vasculitis that occurs primarily in young Asian women. Our previous cohort studies have indicated that leflunomide (LEF), which can lead to rapid induction and might be a promising alternative treatment for TAK. To compare the efficacy and safety of LEF versus placebo combined with prednisone for active TAK in a Chinese population. This will be a multicenter, randomized, double-blinded controlled trial aiming to recruit 116 TAK patients with active disease. This study will last 52 weeks. Participants will be assigned randomly to the LEF intervention arm or placebo control arm at a 1:1 ratio. Initially, LEF combined with prednisone will be given to the intervention arm and a placebo tablet combined with prednisone will be given to the placebo arm. At the end of week 24, subjects who achieved clinical remission or partial clinical remission will proceed to maintenance therapy with LEF to the end of week 52; those who did not achieve clinical remission or partial clinical remission in the LEF intervention arm will drop out from the study, and those in the placebo control arm will switch to LEF treatment to week 52. The primary endpoint will be the clinical remission rate of LEF versus placebo at the end of week 24. The secondary endpoints will be the time to clinical remission, mean dose of prednisone, disease recurrence, time to recurrence, adverse events, as well as clinical remission in subjects who switched from the placebo control arm to LEF therapy after week 24. Intention to treat will be the primary analysis. This is the first randomized double-blinded placebo-controlled trial to clarify the efficacy and safety of LEF in treating active TAK. The results will provide more evidence for TAK management. ClinicalTrials.gov identifier: NCT02981979.

Human monkeypox outbreak: Epidemiological data and therapeutic potential of topical cidofovir in a prospective cohort study

Human monkeypox has become increasingly frequent worldwide since the outbreak was first reported in May 2022. As cidofovir is effective against vaccinia and other Orthopoxvirus diseases, we hypothesize that its topical use could be an effective treatment for monkeypox skin lesions, avoiding the adverse effects of systemic administration. We conducted a prospective study to collect data on the clinical and virologic course of patients with monkeypox. All patients were offered symptomatic treatment. They were also offered treatment with topical cidofovir on a compassionate use basis. Twelve patients received treatment with topical cidofovir 1%, while the others received only symptomatic treatment. Prospective visits were scheduled for the collection of clinical and virological data. Lesions cleared quicker in the cidofovir-treated group (hazard ratio, 4.572; P=.0039). The median time to resolution was 12 (11.5-15) and 18 (16-21) days, respectively. On day 14, polymerase chain reaction-positive skin lesions were detected in 10% of the cidofovir sample, compared with 62.5% of the non-treated group (P= .019). Local adverse effects were frequent (50%), especially in the anogenital region. No systemic adverse effects were reported. The study is not a clinical trial and lacks a placebo-controlled arm. Topical cidofovir is a potentially relevant therapy in patients with skin lesions but mild systemic involvement. Reducing time to resolution could shorten isolation time and improve the cosmetic impact in areas such as the face.

Afatinib maintenance therapy following post-operative radiochemotherapy in head and neck squamous cell carcinoma: Results from the phase III randomised double-blind placebo-controlled study BIB2992ORL (GORTEC 2010–02)

ObjectiveWe investigated the efficacy and safety of afatinib maintenance therapy in patients with head and neck squamous cell carcinoma (HNSCC) with macroscopically complete resection and adjuvant radiochemotherapy (RCT). MethodsThis French multicentric randomised phase III double-blind placebo-controlled study included adult patients with ECOG-PS≤2, normal haematological, hepatic and renal functions, and non-metastatic, histologically confirmed HNSCC of the oral cavity, oropharynx, larynx or hypopharynx, with macroscopically complete resection and adjuvant RCT (≥2 cycles of cisplatin 100 mg/m2 J1, J22, J43 and 66Gy (2Gy/fraction, 5 fractions/week, conventional or intensity modulated radiotherapy ≥60Gy). Randomised patients were planned to receive either afatinib (afa arm) or placebo (control arm (C)) as maintenance therapy for one year. Primary endpoint was disease free survival (DFS). A 15% improvement in DFS was expected at 2 years with afatinib (from 55 to 70%). ResultsAmong the 167 patients with resected HNSCC included in 19 cancer centres and hospitals from Dec 2011, 134 patients were randomised to receive one-year maintenance afatinib or placebo (afa:67; C:67). Benefit/risk ratio was below assumptions and independent advisory committee recommended to stop the study in Feb 2017, the sponsor decided premature study discontinuation, with a 2-year follow-up for the last randomised patient. 2y-DFS was 61% (95% CI 0.48–0.72) in the afatinib group and 64% (95% CI 0.51–0.74) in the placebo group (HR 1.12, 95% CI 0.70–1.80). ConclusionMaintenance therapy with afatinib compared with placebo following post-operative RCT in patients with HNSCC did not significantly improve 2y-DFS and should not be recommended in this setting outside clinical trials.ClinicalTrials.gov identifier NCT01427478.

Outcomes of dual antiplatelet therapy in combination with direct oral anticoagulants in patients with acute coronary syndrome: a meta-analysis

Abstract Background Recent data showed that the use of direct oral anticoagulants (DOAC) in addition to dual antiplatelet therapy (DAPT) is associated with reduced risk of adverse cardiovascular (CV) outcomes in patients with acute coronary syndrome (ACS) with or without percutaneous coronary intervention (PCI), but It has also been associated with increased risk of bleeding. The data differs among different studies, thus, the CV outcomes associated with use of DOAC therapy plus DAPT are not fully understood. We conducted a meta-analysis to explore the CV and bleeding outcomes of DOAC therapy plus DAPT vs DAPT with or without placebo in patients with ACS Methods We conducted a literature search of studies exploring the use of DAPT plus DOAC therapy with focusing on bleeding and CV outcomes including myocardial infarction (MI), stroke, stent thrombosis, limb thrombosis and VTE using Ovid, Scopus, PubMed, Medline, and EBSCO databases from January 2010 to March 2020. We used the following terms for the literature search: (Aspirin AND Clopidogrel OR Prasugrel OR Ticagrelor) AND (Apixaban OR Rivaroxaban OR Edoxaban OR Dabigatran OR Betrixaban). The efficacy outcome was a composite of CV death, MI and stroke, and the safety outcome was major bleeding. Results 4857 articles were included. Only RCTs and RCTs post-hoc analysis, were included (N=3). We found no significant heterogeneity and lower odds of the efficacy outcome in DOAC plus DAPT (experimental arm) compared to DAPT plus placebo (Control arm), which were unchanged in both the fixed and random effect models (Odds Ratio [OR] 0.87, 95% Confidence Interval [CI]: 0.78–0.97, I2=0%). We found no significant heterogeneity and higher odds of the safety outcome in DOAC plus DAPT (experimental arm) compared to DAPT plus placebo (Control arm) (OR fixed model 3.27, 95% CI: 2.28–4.70; OR random model 3.18, 95% CI: 2.21–4.57; I2=0%). Conclusion DOAC therapy plus DAPT in patients with ACS with or without PCI was associated with a lower rate of CV death, MI and stroke when compared to DAPT alone or with placebo and also associated with significant increase in major bleeding Funding Acknowledgement Type of funding sources: None.

A randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as an adjunctive anti-inflammatory treatment for major depressive disorder

BackgroundMajor depressive disorder (MDD) is a leading cause of disability worldwide. The current treatments are ineffective in approximately one-third of patients, resulting in a large economic burden and reduced quality of life for a significant proportion of the global population. There is considerable evidence that increased inflammation may distinguish a sub-type of MDD, and there are no validated diagnostic tools or treatments for neuroinflammation in MDD patients. The current study aims to explore the potential role of low-dose naltrexone (LDN), a drug with purported anti-inflammatory properties in the central nervous system, as an adjunctive treatment in patients with MDD.Methods/designThis double-blind placebo-controlled hybrid parallel arm study enables the exploration of peripheral and central inflammatory markers with LDN as an approach to investigate inflammation as a pathophysiological contributor to MDD. Eligible participants with MDD (n = 48) will be stratified into the high and low inflammatory groups according to the levels of high-sensitivity C-reactive protein (hs-CRP) and then randomized to receive LDN or placebo for an initial 12 weeks, followed by a further 12 weeks during which all participants will receive LDN. The primary outcome measure will be the Montgomery-Åsberg Depression Rating Scale (MADRS) administered at baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks, 20 weeks, and 24 weeks, to assess the effectiveness of the anti-depressant response. The secondary outcomes include the use of MRI techniques including quantitative magnetization transfer (qMT), echo-planar spectroscopic imaging (EPSI), and diffusion-weighted imaging (DWI) to help to elucidate the neurobiological mechanism of LDN, and the inflammatory mechanisms in action in MDD. Electroencephalography, blood samples, cognitive tasks, and additional questionnaires will also be used to determine if there is a specific profile of symptoms in individuals with inflammatory MDD. Healthy participants (n = 24) will be recruited for baseline outcome measures only, to enable comparison with patients with MDD.DiscussionThis trial contributes to the literature on inflammation in MDD, including the understanding of the pathophysiology and efficacy of anti-inflammatory treatments. The investigation of inflammatory mechanisms in MDD is an important first step in the development of biomarkers to classify patient sub-groups, increase the accuracy of diagnosis, and tailor the approach to patients in clinical practice. This study may provide evidence of the benefit of LDN for the groups in whom conventional anti-depressants are ineffective and lead the way for translation into clinical practice.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12622000881730. Registered on 21 June 2022

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.

Meta-analysis of the Placebo and Nocebo effects associated with Placebo treatment in randomized trials of lipid-lowering therapies.

Randomized controlled trials (RCTs) of lipid-lowering therapy (LLT) in which the control groups received placebo without background LLT offer unique insights into the placebo and nocebo effects of lipid-lowering RCTs. Embase and Medline were searched for hyperlipidaemia RCTs with placebo-controlled arms. Placebo arms with background LLT were excluded. A single arm meta-analysis of proportions was used to estimate major adverse cardiovascular events (MACE) and adverse events (AE). A meta-analysis of means was used to estimate the pooled mean differences of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoproteins (HDL) and triglycerides (TG).A total of 40 RCTs and 37668 placebo-treated participants were included. The pooled mean changes for TC, LDL, HDL, and TG were -0.019mmol/L, -0.028mmol/L, 0.013mmol/L, and 0.062mmol/L respectively among placebo-treated participants, indicating a modest placebo effect. The pooled average nocebo effect among placebo-treated participants was 42.62% for all AEs and 3.38% for musculoskeletal-related AEs, 11.36% for gastrointestinal-related AEs, and 6.62% for headaches. Placebo-treated participants in secondary prevention RCTs had a far higher incidence of these nocebo effects than primary prevention RCTs: any AEs (OR 6.76, 95% CI: 5.56-8.24, P<0.001), and gastrointestinal-related AE (OR 1.23, 95% CI: 1.00-1.51, P=0.049). No differences in nocebo effects were found between the placebo arms of statin and non-statin trials. Our meta-analysis of placebo-treated participants in RCTs with no background LLT indicate a modest placebo effect but prominent nocebo effect of musculoskeletal, headache, and gastrointestinal symptoms that was greatest among secondary prevention RCTs. These findings may inform the design of future LLT RCTs.

Effectiveness of a concise malaria training program on knowledge, attitudes and practices among patent medicine vendors: A study protocol

Despite several regional and global containment efforts by various government and non-governmental agencies, malaria still continues to ravage populations. Most notable is Africa, which accounts for 90% of the global cases and corresponding estimated total deaths. High mortality and morbidity have been associated with a shortage of health manpower, with the disease having overburdened the health systems. Patent Medicine Vendors (PMVs) are common sources of over-the-counter medicines and services throughout sub-Saharan Africa, thanks to their already established close-to-client infrastructure. Many people patronize PMVs as an alternative to formal health institutions. However, various literature has shown evidence that the knowledge, attitudes, and practices (KAP) of PMVs are grossly poor and insufficient to qualify them to fill the manpower gaps. The aim of this paper is to outline the study protocol of a trial to test the efficacy of malaria knowledge, attitude, and practice training among PMVs. A single blinded, randomized, controlled community trial was conducted at Yobe South Senatorial District among 292 respondent PMVs by comparing an intervention to a placebo-controlled arm. Four assessments were performed using self-administered questionnaires. The primary outcome measured was an expected increase in KAP at follow-up assessments compared to baseline assessments. Analysis of the data was conducted using SPSS version 26. The study tested the efficacy of a randomized controlled trial on malaria KAP involving various health promotion methods. It is hoped that the developed module will offer effective training that could serve as a model to reduce the scourge of malaria in all of sub-Saharan Africa.