Placebo Treatment Research Articles

The impact of exogenous ketone body suppletion on energy and pH balance in skeletal muscle during exercise in chronic heart failure patients: a prospective randomized double-blind cross-over study

Abstract Background Heart Failure (HF) is characterized by impediments in exercise capacity. Disruptions in the energy metabolism of skeletal muscle contribute to this condition. Pre-clinical and clinical evidence showed that reductions in carbohydrate and FA metabolism in HF may be partially overcome by a compensatory increase in ketone body oxidation and suggest that suppletion of ketone bodies (KB) may improve energy metabolism in HF. Purpose We tested the effect of exogenous KB suppletion on energy and pH balance during cycling exercise using 31P Magnetic Resonance (MR) Spectroscopy of the exercising quadriceps muscle in patients with HF. Methods In a randomized, double-blind, placebo-controlled cross-over study, 14 stable HF patients with reduced ejection fraction and diminished exercise capacity underwent maximal exercise testing in a MR scanner fitted with a cycling ergometer after KB or placebo treatment. Phosphocreatine (PCr) and inorganic phosphate (Pi) resonance amplitudes and frequencies were measured continuously in the quadriceps muscle during rest, exercise and recovery using in-vivo 31P MR spectroscopy (Figure 1). Results Patients had a median age of 66 [53 – 75] years, were 14% female, had a median LVEF of 37% [27 – 40] and circulating NT-pro BNP levels of 411 [182 – 946] pg/mL. Peak oxygen uptake (VO2) was 18.2 [15.2 – 20.3] ml/kg/min, which is 68% [62 – 78%] of predicted. After treatment, exercise performance in terms of cycling duration and workload were comparable between treatment arms (Figure 2). Quadriceps acidification during exercise was larger after KB suppletion compared to placebo (ΔpH: -0.2 [-0.3 - -0.1] vs -0.1 [-0.3 - -0.1] respectively; p=0.041) while quadriceps energy depletion during exercise was not altered by treatment (ΔPi/PCr 0.77 [0.55 – 2.51] vs 0.66 [0.46 – 0.81] respectively; p=0.087). Post-exercise mitochondrial oxidative function was similar between treatment arms (KB: PCr resynthesis rate 48 sec [25 – 59] versus placebo: 42 sec [36 – 63]; p=0.767). Conclusions Ketone body suppletion increased acidification and did not improve energy balance in skeletal muscle during exercise or mitochondrial function during recovery in patients with chronic HF. These results question the value of ketone bodies as treatment to boost muscular energy metabolism during exercise in HF.31P MRS Spectrum during exercise in HFExercise and energy parameters

The Impact of Cannabidiol Treatment on Anxiety Disorders: A Systematic Review of Randomized Controlled Clinical Trials

Generalized Anxiety Disorder (GAD) is a common psychiatric condition characterized by persistent and excessive worry, often accompanied by dysautonomic symptoms that significantly impact patients’ well-being. Cannabidiol (CBD), a non-psychoactive compound derived from cannabis, has shown potential as an anxiolytic through its partial agonism of the 5HT-1A receptor and its negative allosteric modulation of CB1 receptors, which may help mitigate the anxiogenic effects of tetrahydrocannabinol (THC). This study evaluates the impact of CBD on individuals diagnosed with various anxiety disorders, comparing its effects to placebo and conventional pharmaceutical treatments through a systematic review of randomized controlled trials (RCTs). A systematic search of RCTs published between 2013 and 2023 was conducted across three databases using the terms “cannabidiol” and “anxiety”. Out of the 284 articles identified, 11 met the eligibility criteria. The studies reviewed varied widely in terms of the types of anxiety disorders and CBD dosages examined, leading to results that were often contradictory. Despite these conflicting outcomes, the data suggest that CBD may reduce anxiety with minimal adverse effects when compared to a placebo. However, further RCTs with improved methodologies, encompassing a broad range of doses and continuous CBD administration across specific anxiety disorders, are needed. Unlike previous studies and meta-analyses, this review encompasses a broader spectrum of anxiety disorders and a variety of study designs and dosages, providing a more nuanced understanding of CBD’s potential efficacy across different conditions.

The Effectiveness of Heat-Killed Pediococcus acidilactici K15 in Preventing Respiratory Tract Infections in Preterm Infants: A Pilot Double-Blind, Randomized, Placebo-Controlled Study

Background: Preterm infants discharged from the neonatal intensive care unit (NICU) have a risk of severe viral respiratory tract infections (RTIs). Researchers have recently reported the potential use of postbiotics to decrease RTIs in young children. However, the safety and efficacy of postbiotics for preventing RTIs in preterm infants is not yet established. Methods: We conducted a pilot double-blind, randomized, placebo-controlled study of the heat-killed lactic acid bacterium Pediococcus acidilactici K15 in 41 preterm infants born at <36 weeks of gestation and discharged from the NICU at Chiba University Hospital. Results: Following once-daily K15 or placebo treatment for one year, no significant differences were found in the mean number of febrile days (4.5 [1.5–7.4] days vs. 6.6 [2.6–10.5] days). The subgroup analysis showed that the effect of treatment on the number of febrile days was more prominent in the K15 group than in the placebo group, among children with older siblings. The 16S rRNA gene sequencing of fecal samples illustrated that the genus Faecalimonas was enriched in the K15 group, potentially promoting butyrate production by butyrate-producing bacteria. No adverse events were found to be associated with K15 intake. Conclusion: There were no clear data to show the effectiveness of K15 in preventing fever and RTIs in preterm babies during infancy. A larger clinical trial is warranted.

Pregabalin for Neuropathic Pain and Itch in Recessive Dystrophic Epidermolysis Bullosa

Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience neuropathic pain and itch. There is a lack of evidence on any treatment for these symptoms in patients with RDEB. To test the efficacy of pregabalin in the treatment of neuropathic pain and itch in patients with RDEB. A randomized, double-blinded, crossover trial of oral pregabalin (50-300 mg/d) vs placebo was conducted at 2 sites, Toronto (Canada) and Santiago (Chile) from January 1, 2019, to December 31, 2020. Patients eligible to participate were diagnosed with RDEB, aged 8 to 40 years, not pregnant or lactating (if female), and had evidence of probable neuropathic pain and itching defined as distal thermal sensory loss (confirmed by thermal roller), score of 4 or greater on the Douleur Neuropathique 4 questionnaire (DN4), and score greater than 4 on the 10-point visual analog scale [VAS]). Patients with a clinically important or poorly controlled medical or psychiatric condition or pregabalin intolerance or allergy were excluded. Of 41 patients screened, 3 were not eligible and 28 declined enrollment. Data analyses were performed in 2021 through 2023. Participants received both pregabalin and matched placebo (titrated to a maximum-tolerated dose of 300 mg/day) in a randomized sequence so that comparisons could be made within participants and between groups. Difference in the mean pain and itch scores between pregabalin and placebo treatment (measured using VAS) before and after intervention. In all, 10 participants were randomized to 2 groups, 6 patients (mean [SD] age, 26.7 [8.1] years; 3 females [50%]) in group 1, and 4 patients (mean [SD] age, 26.5 [7.8] years, 2 females [50%]) in group 2. Group 1 received a sequence of pregabalin-placebo while group 2 received placebo-pregabalin. Pregabalin significantly reduced mean (SD) pain scores by 1.9 (1.5) points when controlling for sequence and treatment period vs baseline, while placebo had 0.1 (2.0) points of reduction. The effect of pregabalin was a mild but significant reduction in itch compared to baseline (mean [SD] points, 0.9 [2.2]), whereas the placebo produced no reduction (0.1 [2.5]). The mean pregabalin dose was generally well tolerated. The results of this randomized crossover trial indicate that pregabalin significantly reduced pain and itch scores from baseline compared to placebo in patients with RDEB. This feasibility study provided preliminary data on the efficacy of pregabalin in managing pain and itch in RDEB and gathered essential data to inform the design of a larger cohort trial. ClinicalTrials.gov Identifier: NCT03928093.

Perioperative adjuvant therapy with short course of dupilumab with ESS for recurrent CRSwNP.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is associated with a high rate of disease recurrence following endoscopic sinus surgery (ESS). Type 2 disease is associated with a higher incidence of recurrence and is believed to impact disease resolution via interference with epithelial healing and pathogen immunity. We wished to verify if perioperative control of Type 2 inflammation with an anti-IL4/IL13 targeting monoclonal antibody and during the resolution period following surgery leads to better control of the disease long term. In this prospective, placebo-controlled, double-blinded trial. Thirty adult subjects with recurrent CRSwNP underwent ESS plus or minus 14 weeks of perioperative dupilumab, initiated 4 weeks (two injections) pre-ESS. Subjective and objective parameters of nasal patency, olfaction, quality of life (QoL), and adverse events were monitored up to 52 weeks post-ESS. Microbiological culture was performed to characterize pathogens colonization under both conditions. ESS safely improved subjective and objective measures of nasal patency, olfaction, and QoL in both groups. Olfaction was conserved longer in the dupilumab-treated group, with 33.3% of subjects presenting anosmia at 12 months after ESS in the dupilumab group compared to 50.0% with placebo. This was associated with persistent decreases in serum IgE, which were not seen with placebo treatment. No unusual safety signals were observed. Short-course adjuvant perioperative treatment with dupilumab is associated with improved long-term olfactory outcomes and persistent lowering of serum IgE.

The impact of contextual effects in exercise therapy for low back pain: a systematic review and meta-analysis

BackgroundLow back pain is the leading cause of global disability for which exercise therapy is a widely recommended treatment. Research indicates that contextual factors may also influence treatment outcomes in low back pain. Examples include the patient-therapist relationship and other treatment-related circumstances that affect patient expectations. By focusing on the specific treatment effect, clinical trials often ignore the effect of contextual factors, thereby contributing to the so-called efficacy paradox. This means that treatment effects observed in clinical practice are often greater than those reported in clinical trials.This systematic review aims to investigate the proportion of improvement in pain and disability that can be attributed to contextual effects in the outcome of exercise therapy for patients with low back pain.MethodsA meta-analysis was conducted. PubMed, Embase, and the Cochrane database were searched for eligible articles reporting randomized controlled trials that compared exercise therapy to placebo interventions. Risk of bias was assessed with the Revised Cochrane Risk of Bias Tool. Outcomes of interest were pain and disability. Meta-analysis was carried out to calculate the proportion attributable to contextual effects for both pain and disability. The body of evidence was assessed using the GRADE methodology.ResultsEight studies met the inclusion criteria and were included in the meta-analysis. Five studies were rated as having a moderate risk of bias and two studies had a low risk of bias. Proportion attributable to contextual effects was 0.60 (95% CI 0.40–0.89) for pain and 0.69 (95% CI 0.48–1.00) for disability. Certainty of the evidence as assessed with the GRADE methodology was low.ConclusionsA large extent of pain and disability improvement after exercise therapy in low back pain is attributable to contextual effects although this conclusion is based on low certainty evidence.

Effects of hyperbaric oxygen therapy on recovery after a football match in young players: a double-blind randomized controlled trial

IntroductionFootball is a physically demanding sport that requires effective recovery strategies to maintain performance level and prevent injuries. This study investigated if a single 1-h hyperbaric oxygen therapy (HBOT) session affects recovery and performance after a football match in elite youth players.MethodsTwenty elite youth football players (age 17.3 ± 0.5 years) were randomly assigned to a HBOT group or a control group (CON). They played a 90-min football game and underwent either a 60-min HBOT or placebo intervention. Before (T1), at the end of the match (T2), 1 h after HBOT or CON session (T3), and 12 h after HBOT session (T4), subjects underwent biochemical (serum samples (myoglobin (MB), creatine kinase (CK), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)) and performance measurements (linear speed at 5 m, 10 m and 20 m, squat jump (SJ), countermovement jump (CMJ) and countermovement jump with arm swing (CMJa)). The Hooper Index (HI) was collected and heart rate was measured during the game.ResultsThe football match induced significant increases in all biochemical markers, but no significant differences were found between the HBOT and control group in biochemical or performance parameters at any time point. However, there was a significant interaction effect between time and group for HI (p = 0.012, η2 = 0.124), with the HBOT group showing significantly lower HI values (8.6 ± 2.41) than the control group (11.0 ± 3.23) at 1 h post-HBOT.DiscussionA single 1-h session of HBOT did not significantly affect recovery or performance parameters in elite youth football players, though it did show a moderate positive affect on the HI at 1 h post-HBOT. Further studies should explore the impact of either longer or sequential HBOT sessions on recovery.

Fecal microbiota transplantation alters the proteomic landscape of inflammation in HIV: identifying bacterial drivers

BackgroundDespite effective antiretroviral therapy, people with HIV (PWH) experience persistent systemic inflammation and increased morbidity and mortality. Modulating the gut microbiome through fecal microbiota transplantation (FMT) represents a novel therapeutic strategy. We aimed to evaluate proteomic changes in inflammatory pathways following repeated, low-dose FMT versus placebo.MethodsThis double-masked, placebo-controlled pilot study assessed the proteomic impacts of weekly FMT versus placebo treatment over 8 weeks on systemic inflammation in 29 PWH receiving stable antiretroviral therapy (ART). Three stool donors with high Faecalibacterium and butyrate profiles were selected, and their individual stools were used for FMT capsule preparation. Proteomic changes in 345 inflammatory proteins in plasma were quantified using the proximity extension assay, with samples collected at baseline and at weeks 1, 8, and 24. Concurrently, we characterized shifts in the gut microbiota composition and annotated functions through shotgun metagenomics. We fitted generalized additive models to evaluate the dynamics of protein expression. We selected the most relevant proteins to explore their correlations with microbiome composition and functionality over time using linear mixed models.ResultsFMT significantly reduced the plasma levels of 45 inflammatory proteins, including established mortality predictors such as IL6 and TNF-α. We found notable reductions persisting up to 16 weeks after the final FMT procedure, including in the expression of proteins such as CCL20 and CD22. We identified changes in 46 proteins, including decreases in FT3LG, IL6, IL10RB, IL12B, and IL17A, which correlated with multiple bacterial species. We found that specific bacterial species within the Ruminococcaceae, Succinivibrionaceae, Prevotellaceae families, and the Clostridium genus, in addition to their associated genes and functions, were significantly correlated with changes in inflammatory markers.ConclusionsTargeting the gut microbiome through FMT effectively decreased inflammatory proteins in PWH, with sustained effects. These findings suggest the potential of the microbiome as a therapeutic target to mitigate inflammation-related complications in this population, encouraging further research and development of microbiome-based interventions.3bGeWVUV_8zBqrmtjgQWmWVideo

Placebos in Healthcare: A Behavioral Study on How Treatment Responsiveness Affects Therapy Decisions in a Simulated Patient-Physician Interaction.

Treatment choice during clinical practice is crucial to best help each patient. One of the physicians' main goals is choosing a personalized effective treatment, but it also represents a challenging issue. Here, we explored different treatment choices in a simulated patient-physician interaction. Medical students (n = 48) and young Practicing Physicians (n = 20) were recruited to behave as "physicians" while fellow researchers acted as "patients". Participants were divided equally into a Belief Group, which received positive information about placebo efficacy, and a Non-Belief Group, which received negative information. Empathy traits and psychological variables were measured in both groups. During the task, participants were asked to choose between an active (TENS treatment) or a placebo treatment, to reduce patients' pain. Patients never underwent the painful stimulation but acted as if they had, simulating high or low pain responses to the placebo treatment (placebo-responders/placebo non-responders) and low pain to the TENS treatment. Behavioral results showed that the Belief Group gave significantly more placebo treatments when faced with a patient that simulated placebo responsiveness, while the Non-Belief group showed a mirrorlike behavior, administrating more believed TENS treatments when faced with a placebo non-responder. No differences were found between Medical Students and Practicing Physicians. This study constitutes a frame of reference for medical treatment decisions, indicating that physicians' treatment choices are influenced by patients' responsiveness to the treatments, as well as by their prior beliefs and empathy traits.

The Effects of Photobiomodulation Therapy in Cubital Tunnel Syndrome, Clinical Trial.

Aim: We aimed to evaluate the effects of laser therapy together with rest splint and exercise on muscle strength, function, activities of daily living, and pain in individuals suffering from cubital tunnel syndrome (CuTS) by comparing it with placebo treatment. Materials and Methods: This prospective, single-blind, and randomized controlled study was conducted with 64 patients with CuTS in total. They were divided into two groups by randomization: Group 1 (n = 32) was provided with low-energy laser therapy + splint + exercise, and Group 2 (n = 32) was provided with low-energy sham laser therapy + splint + exercise. Patients in both groups received resting splints and nerve release exercises. Pretreatment and posttreatment (3rd week, 3rd month) evaluations were made with the Visual Analog Scale (VAS), the Quick Disability of Arm, Shoulder, and Hand Questionnaire, hand grip strength, fingertip grip strength, the Patient-Rated Ulnar Nerve Evaluation Scale (PRUNES), and Short Form-12. An electrophysiological evaluation was performed at baseline and at the 3rd month. Results: We observed significant improvements in both groups regarding pain, function, muscle strength, health profile, and quality of life in the early posttreatment (3rd week) stage and at the 3rd-month follow-up. When both groups were compared, a significant difference was determined between the VAS-Rest, VAS-Movement, PRUNES-Pain, PRUNES-Function, and PRUNES-Total parameters in the posttreatment (3rd week follow-ups), as well as PRUNES-Pain scores in the post-treatment (3rd month) stage, of the groups in favor of those in Group 1 (p < 0.05). Conclusion: The findings of our study have shown that in the treatment of CuTS, laser treatment is superior to placebo in the short term, but they have equivalent effects in the medium term. Further studies with large patient populations are needed to provide more diverse information about the therapeutic effectiveness of low-intensity laser therapy.

Pulsed Wave Mode of Fractional Radiofrequency Microneedling as a New Advance in the Treatment of Inflammatory Acne Vulgaris

Inflammatory acne vulgaris (IAV) is a common skin condition characterized by the presence of reddish, inflamed, and painful lesions on the skin. IAV can drastically affect individuals, specifically their self-esteem, psychological health, and quality of their life in general. Despite new advances in the field, traditional treatment modalities withstand many challenges. Hence, in the current study, we sought to assess the efficacy and safety of a new pulsed wave mode of the fractional microneedling radiofrequency device in the treatment of IAV. This advanced technique employs insulated microneedles to administer energy to the deep dermis without causing damage to the epidermis. Eighty patients (40 males, 40 females, age 21 ± 3, Fitzpatrick skin type III and IV), with acne severity ranging from moderate to severe, were employed in this trial. They were randomly assigned into two groups, 40 patients each. The treated group (A) underwent four sessions of fractionated microneedle RF, 1.5-month apart, whereas group B was designated as the control group that received placebo treatment. Six months following the last session, the degree of improvement assessed by the quantity of IAV lesions and the overall skin appearance in terms of facial pores, sebum excretion, scar, skin tone, and texture. The RF-treated group showed significant improvement compared to the control group after the follow-up period (p-value = 0.0071). Regarding safety, very mild adverse effects were reported, such as discomfort during the session, pinpoint hemorrhage, and erythema, with no major side effects such as burns, scarring, hyperpigmentation, or hypopigmentation were reported. Thus, our data suggest a potential role of the fractional microneedling radiofrequency device in IAV treatment that is both effective and safe.

Effectiveness of Osteopathic Treatment in Adults with Short Hamstring Syndrome: A Systematic Review.

Background/Objective: Short hamstring syndrome is common in the general population and can lead to impaired balance, function, and posture, and increased risk of injuries. Local treatments have obtained controversial results, so it is necessary to evaluate the effectiveness of other types of therapy such as osteopathic treatment. To evaluate the efficacy of osteopathic techniques in increasing the elasticity of the hamstring musculature in short hamstring syndrome. Methods: A systematic review of randomised controlled trials was conducted in PubMed, Medline, Cinhal, Scopus, WOS, SPORTDiscuss, and PEDro. The PEDro scale was used to evaluate the methodological quality and the RoB2 for the evaluation of biases. Results: A total of eight articles were selected. Most of the participants were assessed with the Active Knee Extension or Straight Leg Raise tests. The osteopathic techniques used were the muscle energy technique, suboccipital inhibition, and vertebral mobilisations. As for the control interventions, they mainly included passive stretching and placebo. Conclusions: The results suggest that osteopathic techniques are more effective than placebo or other interventions in increasing flexibility in adult patients with short hamstring syndrome. This effect can be explained by neurophysiological (Golgi apparatus, neuromuscular spindle activity, and Hoffmann reflex) and structural factors (dura mater, posture, and myofascial chains). Nevertheless, the evidence suggests that it would be beneficial to incorporate this type of treatment into flexibility improvement programmes.

Effects of acetazolamide on exercise performance in patients with COPD going to high altitude: randomised controlled trial

BackgroundIn patients with chronic obstructive pulmonary disease (COPD), preventive treatment with acetazolamide reduces adverse health effects during altitude travel. We investigated whether preventive acetazolamide treatment modifies exercise performance in COPD patients going to high altitude.MethodsIn this randomized, double-blind trial, lowlanders with COPD, FEV1 40–80%predicted, were assigned to acetazolamide (375 mg/24 h) or placebo treatment starting 24 h before ascent and while staying at 3100 m. Patients performed progressive cycling exercise to exhaustion at 760 m, before taking the study drug, and within 4 h after arrival at 3100 m. Primary outcome was the maximal power output (Wmax). ClinicalTrials.govNCT03177837.Results103 patients (32 women), mean ±sdage 57.2±8.1y, FEV1 66±11% predicted, were included in per protocol analyses. In 53 patients receiving acetazolamide, Wmax and oxygen uptake (V'O2max) at 760 m and 3100 m were 105±40 and 91±40watts, and 18.0±6.8 and 15.5±6.8 ml·min−1·kg−1(p&lt;0.001, both changes). Corresponding Wmax and V'O2max in 50 patients receiving placebo were 107±41 and 97±41watts, and 18.9±7.0 and 17.2±7.0 ml·min−1·kg−1(p&lt;0.001, both changes). Between-group differences (95%CI) in altitude-induced Wmax-changes were −3.0 watts (−8.7 to +2.7, p=0.305) and in V'O2max-changes were −0.8 ml·min−1·kg−1(−2.1 to +0.5, p=0.213). Acetazolamide mitigated the altitude-induced reduction of end-exercise PaO2by 0.7kPa (0.1 to 1.3, p=0.016). At 3100 m, maximal work rate with respiratory exchange ratio ≤1 was greater with acetazolamide than with placebo by 10.1 watts (4.0 to 16.2, p=0.022).ConclusionsIn lowlanders with COPD, preventive treatment with acetazolamide did not modify the altitude-induced reduction in maximal work rate. However, acetazolamide enhanced arterial oxygenation and submaximal, moderate-intensity work capacity compared to placebo.

8711 The Effect of Testosterone Therapy Upon Bone Remodelling in Testosterone Deficient APOE-/- Mice Fed a High Fat Diet

Abstract Disclosure: A. Williamson: None. L. Bateman: None. C. LeMaitre: None. T.H. Jones: None. N. Aberdein: None. D.M. Kelly: None. Introduction: Low testosterone can lead to bone loss in males, but the mechanisms are not fully characterised. This study investigates the effects of testosterone depletion, and subsequent testosterone treatment on parameters of bone remodeling in a murine model of cardiometabolic disease. Methods: At 8 weeks of age, high-fat diet-fed ApoE-/- mice were randomised into three groups: sham surgery + placebo treatment (control, n=9), orchidectomy + placebo treatment (n =8), and orchidectomy + testosterone treatment (n=10). 25 week old mice were sacrificed and tissues collected for analysis. Left tibiae were decalcified, paraffin embedded and sectioned prior to immunostaining of bone turnover markers including receptor activator of nuclear factor κB ligand (RANKL), Osteoprotegerin (OPG), runx2, Alkaline Phosphatase (ALP), adiponectin and marrow lipid content. Right tibiae underwent mechanical 3-point bend testing at 0.05mm/s using a CellScale Univert. Results: µCT demonstrated a significant decrease in trabecular bone volume, number, and bone mineral density (BMD) and increased trabecular thickness in orchidectomised mice compared to controls. These parameters returned to control levels in testosterone treated orchiectomised mice. No significant differences were observed in cortical bone. Lipid deposition within the bone marrow was significantly increased in testosterone deficient mice compared to testosterone replete mice. No significant differences in ALP immunopositivity were detected between groups, and runx2 was significantly decreased in orchiectomised mice treated with testosterone compared to controls. The ratio of RANKL/OPG immunopositivity was significantly increased in testosterone deficient mice compared to testosterone replete mice. 3-point bending demonstrated no significant differences in maximal force between groups despite a downward trend in orchiectomised groups compared to controls. Osteoclast number quantified from TRAP-stained sections was not different between groups. Discussion: Testosterone depletion accelerates trabecular bone loss, mediated by increased osteoclastogenesis via the RANKL/OPG pathway and increased bone marrow adiposity, an effect reversed by testosterone treatment. While this study highlights the benefits of testosterone upon trabecular bone health in male mice these changes may not alter fracture risk as 3-point-bend maximal force was not affected. Presentation: 6/2/2024

7373 CAM2029, Octreotide Subcutaneous Depot, Provides Sustained Biochemical Control of Acromegaly: Interim Results From a Phase 3 Study (ACROINNOVA 2)

Abstract Disclosure: D. Ferone: Consulting Fee; Self; Camurus AB, Recordati, Novartis-AAA, Ipsen. Grant Recipient; Self; Camurus AB, Recordati, Novartis-AAA, Ipsen. Research Investigator; Self; Camurus AB. J. Silverstein: Consulting Fee; Self; Xeris Pharmaceuticals. Research Investigator; Self; Camurus AB. P. Freda: Research Investigator; Self; Camurus AB. L. Katznelson: Advisory Board Member; Self; Camurus AB, Recordati. F. Gatto: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. P. Kadioglu: None. P. Maffei: Research Investigator; Self; Camurus AB. J. Seufert: Research Investigator; Self; Camurus AB. J.L. Spencer-Segal: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. E. Isaeva: None. A. Dreval: None. M. Harrie: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A. Svedberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A.M. Pedroncelli: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. F. Tiberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. Background: Acromegaly is characterized by excess growth hormone (GH) and insulin-like growth factor 1 (IGF-1) production. A key treatment goal is long-term biochemical control to minimize adverse effects of prolonged excess GH. CAM2029 is a novel, subcutaneous, octreotide depot, designed for convenient monthly self-administration using a pre-filled injection/pen. In a 24-week Phase 3 trial (ACROINNOVA 1, NCT04076462), CAM2029 achieved superior IGF-1 control vs placebo (IGF-1 ≤ upper limit of normal [ULN]: 72.2 vs 37.5%; P=0.0018) in acromegaly patients previously controlled with standard-of-care (SoC; octreotide long-acting repeatable/lanreotide Autogel). On trial completion, patients could roll over to a Phase 3, 52-week, open-label, long-term safety trial (ACROINNOVA 2, NCT04125836). Here, we report data from an interim analysis of roll-over patients in ACROINNOVA 2. Methods: Roll-over patients received monthly CAM2029 20 mg for 28 weeks in ACROINNOVA 2. Primary endpoint: occurrence of adverse events (AEs). Key secondary endpoints: proportion of patients with available assessments who had (i) IGF-1 ≤1x ULN (mean of weeks 50/52 measurements) and (ii) both IGF-1 ≤1x ULN (weeks 50/52 mean) and mean GH &amp;lt;2.5 µg/L (week 52). Data are reported according to prior treatment in ACROINNOVA 1. Safety data from the whole trial period are reported. Results: Fifty-four of the 64 patients completing ACROINNOVA 1 (prior CAM2029 n=36; prior placebo n=18) entered ACROINNOVA 2. At data cut-off (May 23, 2023) 28 and 15 patients in the prior CAM2029 and prior placebo groups, respectively, had completed treatment week 52; 7 and 3 were ongoing; 1 and 0 had discontinued. The medication was well tolerated with a safety profile comparable to SoC treatment; no new safety signals were observed. One treatment-related serious AE (cholelithiasis, moderate severity, resolved) occurred in the prior placebo group. Injection site treatment-emergent AEs (Grade ≤2) occurred in 50% of patients in the prior CAM2029 (18/36) and prior placebo (9/18) groups. Of evaluable patients in the prior CAM2029 and prior placebo groups, 89.3% (25/28) and 100% (15/15) had IGF ≤1x ULN at weeks 50/52; 88.5% (23/26) and 100% (14/14) had both IGF ≤1x ULN (week 50/52) and GH &amp;lt;2.5 µg/L (week 52). Mean IGF-1 levels remained &amp;lt;ULN throughout the 52-week study period for the prior CAM2029 group; in the prior placebo group, mean IGF-1 increased above 1x ULN during placebo treatment, returning to &amp;lt;ULN after switching to CAM2029 for 28 weeks. All patients previously treated with placebo regained IGF-I control upon switching to CAM2029. Conclusions: The safety profile of CAM2029 was consistent with SoC, with no new or unexpected safety signals during extended treatment. CAM2029 provided persistent control of IGF-1 and GH during 52 weeks of treatment. All patients in the prior placebo group regained biochemical control of acromegaly after switching to CAM2029. Presentation: 6/1/2024

The effect of yoga on dyspnea, sleep, and quality of life in patients with bronchiectasis: A randomized controlled trial

Background and purposeBronchiectasis is characterized by chronic cough, acute exacerbations, and excessive sputum production, along with symptoms such as shortness of breath and fatigue, which impair respiratory functions and quality of life. This study aims to investigate the effects of yoga on dyspnea, sleep quality, and overall quality of life in patients with bronchiectasis. Materials and methodsForty-eight participants with bronchiectasis were included in the study. The patients were randomly divided into two groups, the yoga group (n = 24) or control group (no placebo or sham intervention) (n = 24). The yoga group participated in a total of 24 sessions over 8 weeks, with three sessions per week. No intervention was performed on the patients in the control group. The Modified Medical Research Council (mMRC) questionnaire was used to assess patients' dyspnea level, and the Pittsburgh Sleep Quality Index (PSQI) and St. George's Respiratory Questionnaire (SGRQ) were used to assess sleep quality and health-related quality of life, respectively. ResultsIt was observed that the yoga intervention affected the intergroup change in dyspnea severity score over time (p < 0.05) (x̄yoga = 2.64-1.50 = 1.14; x̄control2.24-1.95 = 0.29). The decrease in the mean PSQI score of the yoga practice group (16.41-13.18 = 3.23) was significantly higher compared with the control group (14.90-14.57 = 0.33). Post-practice SGRQ activity scores were significantly different from pre-practice SGRQ activity scores. Similar to the change in SGRQ activity and symptom scores, the impact score also changed significantly over time (x̄yoga12.55-9.09 = 3.46; x̄control12–11.52 = 0.48). ConclusionThe results indicate that yoga may have a positive effect on dyspnea, sleep, and quality of life in patients with bronchiectasis.

Randomized Controlled Trials Studying Nonoperative Treatments of Osteoarthritis Often Use Misleading and Uninformative Control Groups: A Systematic Review.

Because there are no known treatments that alter the natural course of the pathophysiology of osteoarthritis, nonoperative treatment needs to be compared with known effective treatments that seek to mitigate symptoms or with similarly invasive inert (placebo) treatments to determine effectiveness. Comparing a treatment to an uninformative control group may inappropriately legitimize and support the use of potentially ineffective treatments. We therefore investigated the prevalence of inappropriate control groups in musculoskeletal research and asked whether these are associated with reporting a positive treatment effect. We systematically reviewed randomized trials of nonoperative treatments of osteoarthritis and asked: (1) What proportion of randomized trials use uninformative control groups (defined as a treatment less invasive than the tested treatment, or a treatment that might possibly not outperform placebo but is not acknowledged as such)? (2) Is the use of uninformative control groups independently associated with reporting a positive treatment effect (defined as p < 0.05 in favor of the intervention, or as making a recommendation favoring the intervention over the control treatment)? In a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched PubMed, Cochrane, and Embase up to September 2023 for randomized controlled trials published between 2020 to 2022 that compared one or more nonoperative treatments for the symptoms of osteoarthritis. We excluded studies that contained a surgical treatment group. We identified 103 trials that met eligibility criteria, with a total of 15,491 patients. The risk of bias was high in 60% (n = 62) of trials using the Cochrane Risk of Bias Tool, version 2. Although the high risk of bias in the included studies is concerning, it does not invalidate our design; instead, it highlights that some studies may use flawed methods to recommend treatments with unproven effectiveness beyond nonspecific effects because the kinds of bias observed would tend to increase the apparent benefit of the treatment(s) being evaluated. We used logistic regression to test the association of uninformative control groups with a positive treatment effect, accounting for potential confounders such as conflict of interest and study bias using the Cochrane Risk of Bias score. The use of uninformative control groups (treatments less invasive than the tested treatment, or treatments that might not outperform placebo but are not acknowledged as such) was found in 46% (47 of 103) of included studies. After accounting for potential confounding, there was no association between reporting positive treatment effects and the use of an uninformative control group. Studies with a low risk of bias had a lower likelihood of reporting a positive treatment effect (OR 0.2 [95% confidence interval 0.05 to 0.9]; p = 0.04, model pseudo R2 = 0.21). The finding that recent studies that mimic high-level evidence often use uninformative control groups that do not adequately account for nonspecific effects (perceived treatment benefits unrelated to a treatment's direct physiological effects) points to a high risk of legitimizing ineffective treatments. This raises the ethical imperative for patients, clinicians, journal peer reviewers, and journal editors to hold researchers to the standard of an adequate, informative control group. Awareness and risk of bias checklists might help patients and clinicians forgo new treatments based on seemingly high-level evidence that may carry only iatrogenic, financial, and psychological harm (false hope, in particular). Level I, therapeutic study.

A randomized controlled non-inferiority trial of placebo versus macrolide antibiotics for Mycoplasma pneumoniae infection in children with community-acquired pneumonia: trial protocol for the MYTHIC Study

BackgroundMycoplasma pneumoniae is a major cause of community-acquired pneumonia (CAP) in school-aged children. Macrolides are the first-line treatment for this infection. However, it is unclear whether macrolides are effective in treating M. pneumoniae CAP, mainly due to limitations in microbiological diagnosis of previous studies. The extensive global use of macrolides has led to increasing antimicrobial resistance. The overall objective of this trial is to produce efficacy data for macrolide treatment in children with M. pneumoniae CAP.MethodsThe MYTHIC Study is a randomized, double-blind, placebo-controlled, multicenter, non-inferiority trial in 13 Swiss pediatric centers. Previously healthy ambulatory and hospitalized children aged 3–17 years with clinically diagnosed CAP will be screened with a sensitive and commercially available M. pneumoniae-specific IgM lateral flow assay from capillary blood. Mycoplasma pneumoniae infection in screened patients will be verified retrospectively by respiratory PCR (reference test) and IgM antibody-secreting cell enzyme-linked immunospot (ELISpot) assay (confirmatory test for distinguishing between carriage and infection). Patients will be randomized 1:1 to receive a 5-day treatment of macrolides (azithromycin) or placebo. The co-primary endpoints are (1) time to normalization of all vital signs, including body temperature, respiratory rate, heart rate, and saturation of peripheral oxygen (efficacy), and (2) CAP-related change in patient care status (i.e., admission, re-admission, or intensive care unit transfer) within 28 days (safety). Secondary outcomes include adverse events (AEs), as well as antimicrobial and anti-inflammatory effects. For both co-primary endpoints, we aim to show non-inferiority of placebo compared to macrolide treatment. We expect no macrolide effect (hazard ratio of 1, absolute risk difference of 0) and set the corresponding non-inferiority margins to 0.7 and −7.5%. The “at least one” success criterion is used to handle multiplicity with the two co-primary endpoints. With a power of 80% to reject at least one null hypothesis at a one-sided significance level of 1.25%, 376 patients will be required.DiscussionThis trial will produce efficacy data for macrolide treatment in children with M. pneumoniae CAP that might help to reduce the prescription of antibiotics and therefore contribute to the global efforts toward reducing antimicrobial resistance.Trial registrationClinicalTrials.gov, NCT06325293. Registered on 24 April 2024

Pharmacodynamic, prognostic, and predictive biomarkers in severe and critical COVID-19 patients treated with sirukumab

We examined candidate biomarkers for efficacy outcomes in hospitalized COVID-19 patients who were treated with sirukumab, an IL-6 neutralizing antibody, in a randomized, double-blind, placebo-controlled, phase 2 trial. Between May 2020 and March 2021, 209 patients were randomized (sirukumab, n = 139; placebo, n = 70); 112 had critical COVID-19. Serum biomarkers were evaluated for the pharmacodynamic effect of sirukumab and for their potential prognostic and predictive effect on time to sustained clinical improvement up to Day 28, clinical improvement at Day 28, and mortality at Day 28. The absence of detectable IL-4 increase and smaller increases in CCL13 post-baseline were most significantly associated with better response to sirukumab (versus placebo) treatment for all clinical efficacy outcomes tested, especially in patients with critical COVID-19. These data suggest that patients with critical COVID-19 without detectable sirukumab-induced IL-4 levels are more likely to benefit from sirukumab treatment. ClinicalTrials.gov Identifier: NCT04380961.

Metronomic chemotherapy for paediatric extracranial solid tumours: a systematic review and meta-analysis of randomised clinical trials

BackgroundMetronomic chemotherapy (‘less is more, regularly’) could be an alternative to the maximum tolerated dose (‘the more, the better’) in the chemotherapeutic cancer treatment of high-risk malignant solid extracranial tumours...