Daily Placebo Research Articles

Novel antibody cocktail targeting Bet v 1 rapidly and sustainably treats birch allergy symptoms in a phase 1 study

The efficacy of an allergen-specific IgG cocktail to treat cat allergy suggests that allergen-specific IgG may be a major protective mechanism elicited by allergen immunotherapy. Extending these findings, we tested a Bet v 1-specific antibody cocktail in birch-allergic subjects. This was a phase 1, randomized, double-blind, study with 2 parts. Part Aadministered ascending doses of the Bet v 1-specific antibody cocktail REGN5713/14/15 (150-900 mg) in 32 healthy adults. Part B administered a single subcutaneous 900-mg dose or placebo in 64 birch-allergic subjects. Total nasal symptom score response to titrated birch extract nasal allergen challenge and skin prick test (SPT) with birch and alder allergen were assessed at screening and days 8, 29, 57, and 113 (SPT only); basophil activation tests (n= 26) were conducted. Single-dose REGN5713/14/15 significantly reduced total nasal symptom score following birch nasal allergen challenge relative to baseline. Differences in total nasal symptom score areas under the curve (0-1 hour) for subjects treated with REGN5713/14/15 versus those given placebo (day 8: -1.17, P= .001; day 29: -1.18, P= .001; day 57: -0.85, P=.024) and titration SPT with birch difference in area under the curve of mean wheal diameters for subjects treated with REGN5713/14/15 versus placebo (all P< .001) were sustained for ≥2 months; similar results were observed with alder SPT. REGN5713/14/15 was well tolerated. Basophil responsiveness to birch-related allergens was significantly decreased in subjects treated with REGN5713/14/15 versus those given placebo on days 8, 57, and 113 (all P< .01). Single-dose REGN5713/14/15 was well tolerated and provided a rapid (1 week) and durable (2 months) reduction in allergic symptoms after birch allergen nasal allergen challenge, potentially offering a new paradigm for the treatment of birch allergy symptoms.

107-OR: Six-Day Subcutaneous GIP Infusion Increases Circulating Free Fatty Acids without Altering the Adipose Tissue Transcriptome, Adipocyte GIP Receptor Levels, or Circulating Inflammation Markers in Patients with Type 1 Diabetes

Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to increase adipose tissue lipolysis (at low insulin levels), adipokine secretion and circulating levels of inflammation markers via the GIP receptor (GIPR) in adipose tissue. We investigated the effect of a 6-day subcutaneous (sc) GIP infusion on circulating lipids and inflammation markers, the adipose tissue transcriptome and the presence of GIPR mRNA (ISH) in adipose tissue in patients with type 1 diabetes (T1D). In a randomized, placebo-controlled, double-blind, crossover study, 20 men with T1D (age [mean± SD] 26±8 years, BMI 23.8±1.8 kg/m2, HbA1c 51±10 mmol/mol (6.8±3.1%) underwent 2 × 6 days of continuous sc GIP (6 pmol/kg/min) infusion and placebo (saline) infusion, with an interposed 7-day washout period. Fasting blood samples were drawn frequently within the initial 3 hours and after 1 and 6 days of infusion. Adipose tissue biopsies were collected before and after 6 days of infusion. During the initial 3 hours of infusion, but not at day 1 and 6, GIP increased baseline-subtracted area under the curve of plasma free fatty acids (FFA) compared to placebo (16.8±10.4 vs. 4.4±9.2 min × mmol/L, P &amp;lt;0.001) without affecting plasma glycerol and triglycerides. A panel of 23 circulating inflammation markers were unaffected by the GIP infusion. Adipose tissue transcriptomics did not show differentially expressed genes after 6 days of GIP infusion compared to placebo. In situ hybridization (ISH) localized the GIPR mRNA in the adipocyte and not in connective tissue. ISH verified GIPR mRNA levels were not altered by 6 days of GIP infusion. In patients with T1D, a 6-day sc GIP infusion temporarily increases circulating levels of FFA without altering the adipose tissue transcriptome, GIPR mRNA levels in adipocytes or circulating inflammation markers. Disclosure S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. T. F. Dejgaard: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Boehringer Ingelheim International GmbH, Research Support; Self; AstraZeneca, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. C. Pyke: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. M. B. Christensen: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. B. Hoe: None. C. N. Nielsen: None. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. F. Dela: None. A. Overgaard: Stock/Shareholder; Self; Novo Nordisk A/S. J. Størling: None. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D037)

1234-P: Impact of Treatment Adherence to Observed Weight Loss in the GLOW Study

Adherence to weight management treatments is suboptimal. The Gelesis Loss Of Weight (GLOW; NCT02307279) pivotal trial data were used to assess treatment adherence impact on weight loss. The primary objectives of the GLOW study were to assess the effects of an oral superabsorbent hydrogel (OSH) on weight loss (targeted difference of ≥ 3%) and ≥ 5% weight loss responder status in subjects with a body mass index of 27-40 kg/m2. A total of 436 subjects were randomized to 3 capsules twice per day of OSH or placebo taken with 500 mL (16 oz) of water before lunch and dinner while on a hypocaloric diet (-300 kcal/day) for 24 weeks. There were 172 OSH- and 152 placebo-treated subjects who completed the study. Capsules counted at each study visit every 2-4 weeks were used to calculate overall percent treatment adherence (PTA) after the final visit. The PTA impact on weight loss was assessed using ANCOVA models with baseline BMI, fasting glucose and sex as covariates. A logit model with the same covariates was also used to assess the impact of PTA ≥ 95% or &amp;lt; 95% in subjects who achieved ≥ 10% or &amp;lt; 10% weight loss at 24 weeks. In the OSH group, mean PTA for was 97.61% ± 4.68% (SD) ranging from 70% to 111%, and all but 1 subject had PTA ≥ 80%. A significant interaction of ≥ 5% weight loss responder status and PTA was found (P=0.039); therefore, separate ANCOVA models were fit. PTA predicted weight loss at week 24 among the OSH group ≥ 5% responders, but not the ≥ 5% non-responders. Also, a PTA increase of 1 day/week predicted an additional 3.5% weight loss (β = 0.-25 ± 0.11 SE, P=0.024). PTA did not predict weight loss in the placebo group. OSH-treated subjects with ≥ 95% PTA were 4 times more likely to achieve ≥ 10% weight loss compared to those with &amp;lt; 95% PTA (P=0.027, odds ratio=4.27, 95%CI=1.18 to 15.41). These findings suggest that OSH has a binary impact on the treated subjects rather than a uniform effect. Increased PTA during OSH treatment predicted increased weight loss in patients responding to therapy with ≥ 5% weight loss, and not in non-responders or the placebo group. Disclosure L. E. Urban: Employee; Self; Gelesis. C. Apovian: Board Member; Self; Abbott, Allergan plc, Gelesis, Novo Nordisk, Nutrisystem, Tivity Health, Xeno Bioscience, Zafgen, Inc. L. Aronne: Other Relationship; Self; Allurion, Eisai &amp; Janssen Pharmaceuticals, ERX Pharmaceuticals, Gelesis, Jamieson Wellness, Myos Corp, Intellihealth Corp, Novo Nordisk, Pfizer Foundation, Real Appeal, Research Support; Self; Astrazeneca, Aspire Bariatrics. H. Leider: Employee; Self; Gelesis.

PCN83 Healthcare Resource Utilization (HCRU) of Patients with Resected Esophageal Cancer or Gastroesophageal Junction Cancer (EC/GEJC) Receiving Adjuvant Nivolumab Treatment Versus Placebo:

from CheckMate-577 (CM-577) Trial In the global, double-blind, randomized Phase 3 CM-577 trial involving patients with resected EC/GEJC previously treated with neoadjuvant chemoradiotherapy, adjuvant nivolumab therapy was associated with improvement in disease-free survival, similar quality of life relative to placebo, and was well tolerated. This study examined the HCRU of patients during adjuvant treatment with nivolumab versus placebo in CM-577. Data on hospital admissions and non-protocol-specified visits (NPSVs)—the latter defined as hospital outpatient, emergency room, physician office, home healthcare, or other visits—were collected from all 794 randomized CM-577 participants during treatment (patients treated for one year or until disease progression). Frequency and duration of hospital admissions and NPSVs were summarized and exposure-adjusted analysis of hospitalizations, including calculation of exposure-adjusted incidence rate ratio (IRRs) for reduction of incidence with nivolumab versus placebo, was completed by modelling events using negative binomial regression accounting for treatment duration as an offset variable. During treatment, 25% of patients on nivolumab and 28% of patients on placebo experienced at least one hospitalization, with 18% (nivolumab) and 22% (placebo) experiencing a single hospitalization. Median length of hospitalization was 8 and 6 days for nivolumab and placebo, respectively. Average treatment exposure was similar in each arm; adjusting for treatment exposure, the incidence of hospital admission was similar for patients treated with nivolumab versus placebo (0.78 versus 0.69 admissions/patient/year; IRR=1.12 [95% CI 0.78, 1.62]). Frequency of NPSV was similar between treatment arms (nivolumab 33%; placebo 32%), with <20% of patients in each arm requiring >1 NPSV. The most common types of NPSVs in both arms were hospital outpatient and physician office visits. In CM-577, patients with EC/GEJC receiving adjuvant nivolumab treatment did not have significantly higher HCRU than patients receiving placebo. These findings further support clinical data to demonstrate treatment benefit and tolerability for adjuvant nivolumab in patients with resected EC/GEJC.

Effects of chronic dietary grape seed extract supplementation on aortic stiffness and hemodynamic responses in obese/overweight males during submaximal exercise

ABSTRACT We investigated the effect of chronic grape seed extract (GSE) on blood pressure and aortic stiffness (AoS) among overweight and obese males. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (Q), total vascular conductance (TVC), and AoS were measured during two submaximal cycling exercises (40% and 60% VO2max), after 7 consecutive days of GSE or placebo (PL) ingestion with one week washout period. Compared with PL, GSE supplementation significantly decreased MAP at rest (85 ± 3 mmHg vs. 82 ± 3 mmHg), 40% (102 ± 3 mmHg vs. 99 ± 3 mmHg), and 60% workloads (109 ± 3 mmHg vs. 107 ± 3 mmHg) (P = 0.001, ES = 0.2). AoS was significantly reduced (13.0 ± 1.9 AU vs. 10.2 ± 1.0 AU) at rest (P = 0.002, ES = 0.6). Q was decreased at rest and across all workloads, but there were no significant differences (7.5 ± 0.4 L/min vs. 7.1 ± 0.4 L/min; 20.4 ± 1.2 L/min vs. 19.6 ± 0.9 L/min; 26.3 ± 1.1 L/min vs. 25.5 ± 1.6 L/min, respectively). GSE had no effect on HR, TVC, and SV. Our study indicates that chronic supplementation with GSE reduces arterial pressure at rest and during exercise primarily via the substantial reduction in AoS. Thus, GSE can be a dietary supplement to treat augmented blood pressure responses in obese and overweight males at rest and during exercise. Trial registration: ClinicalTrials.gov identifier: NCT04465110.

Trial of Psilocybin versus Escitalopram for Depression

BackgroundPsilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking.MethodsIn a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6.ResultsA total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (P=0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups.ConclusionsOn the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants. (Funded by the Alexander Mosley Charitable Trust and Imperial College London’s Centre for Psychedelic Research; ClinicalTrials.gov number, NCT03429075.)

Olive leaf extract effect on cardiometabolic profile among adults with prehypertension and hypertension: a systematic review and meta-analysis.

BackgroundThis systematic review and meta-analysis aimed to determine the effectiveness of olive leaf extract on cardiometabolic profiles among prehypertensive and hypertensive groups. MethodologyThe Cochrane central register of controlled trials, Medline (1966 to April week 1, 2020), Embase (1966 to April week 1, 2020) and trial registries for relevant randomized clinical trials were used. Published and unpublished randomized clinical trials were reviewed and evaluated. Random effects models were used to estimate the continuous outcomes and mean differences (MDs); both with 95% confidence intervals (CIs). The primary outcomes were changes in systolic and diastolic BP. The secondary outcomes were changes in lipid profile, glucose metabolism, inflammatory markers for CVD, kidney and liver functions safety parameters. We assessed the data for risk of bias, heterogeneity, sensitivity, reporting bias and quality of evidence.ResultsFive trials were included involving 325 patients aged 18–80 years. Two trials involved high-income countries and three trials involved moderate-income countries. The analysis performed was based on three comparisons. No significant changes were found between systolic or diastolic blood pressure (BP) for the first comparison, 1,000 mg per day for a combined formulation of olive leaf extract versus a placebo. The second comparison, 500 mg per day of olive leaf extract versus placebo or no treatment, showed a significant reduction in systolic BP over a period of at least 8 weeks of follow up (MD −5.78 mmHg, 95% CI [−10.27 to −1.30]) and no significant changes on diastolic BP. The third comparison, 1,000 mg per day of olive leaf extract versus placebo shows no significant difference but an almost similar reduction in systolic BP (−11.5 mmHg in olive leaf extract and −13.7 mmHg in placebo, MD 2.2 mmHg, 95% CI [−0.43–4.83]) and diastolic BP (−4.8 mmHg in olive leaf extract and −6.4 mmHg in placebo, MD 1.60 mmHg, 95% CI [−0.13–3.33]). For secondary outcomes, 1,000 mg per day of olive leaf extract versus captopril showed a reduction in LDL (MD −6.00 mg/dl, 95% CI [−11.5 to −0.50]). The 500 mg per day olive leaf extract versus placebo showed a reduction in inflammatory markers for CVD IL-6 (MD −6.83 ng/L, 95% CI [−13.15 to −0.51]), IL-8 (MD −8.24 ng/L, 95% CI [−16.00 to −0.48) and TNF-alpha (MD −7.40 ng/L, 95% CI [−13.23 to −1.57]).ConclusionsThe results from this review suggest the reduction of systolic BP, LDL and inflammatory biomarkers, but it may not provide a robust conclusion regarding the effects of olive leaf extract on cardiometabolic profile due to the limited number of participants in the included trials.Review registrationsPROSPERO CDR 42020181212.

A Placebo-Controlled, Pseudo-Randomized, Crossover Trial of Botanical Agents for Gulf War Illness: Reishi Mushroom (Ganoderma lucidum), Stinging Nettle (Urtica dioica), and Epimedium (Epimedium sagittatum)

This report is third in a three-part clinical trial series screening potential treatments for Gulf War Illness (GWI). The goal of the project was to rapidly identify agents to prioritize for further efficacy research. We used a placebo-controlled, pseudo-randomized, crossover design to test the effects of reishi mushroom (Ganoderma lucidum), stinging nettle (Uritca dioica), and epimedium (Epimedium sagittatum) in 29 men with GWI. Participants completed 30 days of symptom reports for baseline, then a botanical line consisting of 30 days of placebo, followed by 30 days each of lower-dose and higher-dose botanical. After completing a botanical line, participants were randomized to complete the protocol with another botanical, until they completed three botanical trials. GWI symptom severity, pain, and fatigue were contrasted between the four conditions (baseline, placebo, lower-dose, higher dose) using linear mixed models. GWI symptom severity was unchanged from placebo in the reishi lower-dose condition (p = 0.603), and was higher in the higher-dose condition (p = 0.012). Symptom severity was not decreased from placebo with lower-dose stinging nettle (p = 0.604), but was significantly decreased with higher-dose stinging nettle (p = 0.048). Epimedium showed no significant decreases of GWI symptoms in the lower (p = 0.936) or higher (p = 0.183) dose conditions. Stinging nettle, especially at higher daily dosages, may help reduce the symptoms of GWI. Epimedium does not appear to beneficially affect GWI symptom severity, and reishi may exaggerate symptoms in some GWI sufferers. These results are in a small sample and are preliminary. Further research is required to determine if stinging nettle is indeed helpful for the treatment of GWI, and what dosage is optimal. This trial was registered on ClinicalTrials.gov (NCT02909686).

Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial

Type III interferons have been touted as promising therapeutics in outpatients with coronavirus disease 2019 (COVID-19). We conducted a randomized, single-blind, placebo-controlled trial (NCT04331899) in 120 outpatients with mild to moderate COVID-19 to determine whether a single, 180 mcg subcutaneous dose of Peginterferon Lambda-1a (Lambda) within 72 hours of diagnosis could shorten the duration of viral shedding (primary endpoint) or symptoms (secondary endpoint). In both the 60 patients receiving Lambda and 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively, and symptom duration did not differ significantly between groups (HR 0.94; 95% CI 0.64 to 1.39). Both Lambda and placebo were well-tolerated, though liver transaminase elevations were more common in the Lambda vs. placebo arm (15/60 vs 5/60; p = 0.027). In this study, a single dose of subcutaneous Peginterferon Lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in outpatients with uncomplicated COVID-19.

Effect of prazosin on feline recurrent urethral obstruction.

The aim of this study was to determine if male cats treated with 7 days of prazosin following relief of urethral obstruction (UO) experienced decreased rates of recurrent urethral obstruction (rUO) within 30 days vs those treated with 7 days of placebo. All castrated male cats presenting for the first time with UO from May 2014 to August 2017 were eligible for enrollment. Exclusion criteria included the administration of medications or passage of a urinary catheter prior to referral, the presence of heart disease or hypertension requiring medication, prior treatment with glucocorticoids, non-steroidal anti-inflammatory medications, prazosin or phenoxybenzamine, or radiographic identification of cystoliths. Cats were treated with standardized anesthetic and analgesic protocols, standardized indwelling urinary catheter management, and were hospitalized for care. A random numbers table was generated prior to study initiation and cats were randomized to receive either prazosin (0.5 mg PO q12h for 7 days) or placebo in a blinded fashion. A 30-day follow-up with owners via telephone was performed to identify the rate of rUO. Cats that did not receive the full course of study medication were removed from the analysis. The study was unblinded at the end of data collection. Eighty cats were enrolled and 65 cats completed the study; 12 were excluded because they did not receive the study medication. Sixteen of 65 cats experienced rUO (25%). Of the 16 cats experiencing rUO, five received placebo (n = 5/28 [18%]) and 11 received prazosin (n = 11/37 [30%]). Ten of the cats that experienced rUO reblocked while still hospitalized. There was no significant difference in frequency of rUO in cats treated with prazosin vs placebo (P = 0.27). Prazosin administered at 0.5 mg PO q12h did not decrease the rate of rUO in this population of obstructed male cats vs placebo. These results further support evidence suggesting that prazosin may not be beneficial in prevention of feline rUO.

Inhaled JAK inhibitor GDC-0214 reduces exhaled nitric oxide in patients with mild asthma: A randomized, controlled, proof-of-activity trial

The Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma. We sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (Feno), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma. We conducted a double-blind, randomized, placebo-controlled, phase 1 proof-of-activity study in adults with mild asthma and Feno higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in Feno from baseline to day 14. Baseline was defined as the average Feno during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed. Thirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean Feno at baseline across all subjects was 93± 43 ppb. At day 14, placebo-corrected difference in Feno was -23% (95% CI, -37.3 to -9) for 15 mg QD and -42% (95% CI, -57 to -27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater Feno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition. GDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in Feno in mild asthma and was well tolerated without evidence of systemic toxicity.

Short-Course Antimicrobial Therapy for Pediatric Community-Acquired Pneumonia

Community-acquired pneumonia (CAP) is a common occurrence in childhood; consequently, evidence-based recommendations for its treatment are required. To determine whether 5 days of high-dose amoxicillin for CAP was associated with noninferior rates of clinical cure compared with 10 days of high-dose amoxicillin. The SAFER (Short-Course Antimicrobial Therapy for Pediatric Respiratory Infections) study was a 2-center, parallel-group, noninferiority randomized clinical trial consisting of a single-center pilot study from December 1, 2012, to March 31, 2014, and the follow-up main study from August 1, 2016, to December 31, 2019 at the emergency departments of McMaster Children's Hospital and the Children's Hospital of Eastern Ontario. Research staff, participants, and outcome assessors were blinded to treatment allocation. Eligible children were aged 6 months to 10 years and had fever within 48 hours, respiratory symptoms, chest radiography findings consistent with pneumonia as per the emergency department physician, and a primary diagnosis of pneumonia. Children were excluded if they required hospitalization, had comorbidities that would predispose them to severe disease and/or pneumonia of unusual origin, or had previous β-lactam antibiotic therapy. Data were analyzed from March 1 to July 8, 2020. Five days of high-dose amoxicillin therapy followed by 5 days of placebo (intervention group) vs 5 days of high-dose amoxicillin followed by a different formulation of 5 days of high-dose amoxicillin (control group). Clinical cure at 14 to 21 days. Among the 281 participants, the median age was 2.6 (interquartile range, 1.6-4.9) years (160 boys [57.7%] of 279 with sex listed). Clinical cure was observed in 101 of 114 children (88.6%) in the intervention group and in 99 of 109 (90.8%) in the control group in per-protocol analysis (risk difference, -0.016; 97.5% confidence limit, -0.087). Clinical cure at 14 to 21 days was observed in 108 of 126 (85.7%) in the intervention group and in 106 of 126 (84.1%) in the control group in the intention-to-treat analysis (risk difference, 0.023; 97.5% confidence limit, -0.061). Short-course antibiotic therapy appeared to be comparable to standard care for the treatment of previously healthy children with CAP not requiring hospitalization. Clinical practice guidelines should consider recommending 5 days of amoxicillin for pediatric pneumonia management in accordance with antimicrobial stewardship principles. ClinicalTrials.gov Identifier: NCT02380352.

Network analysis of nitrate-sensitive oral microbiome reveals interactions with cognitive function and cardiovascular health across dietary interventions

Many oral bacteria reduce inorganic nitrate, a natural part of a vegetable-rich diet, into nitrite that acts as a precursor to nitric oxide, a regulator of vascular tone and neurotransmission. Aging is hallmarked by reduced nitric oxide production with associated detriments to cardiovascular and cognitive function. This study applied a systems-level bacterial co-occurrence network analysis across 10-day dietary nitrate and placebo interventions to test the stability of relationships between physiological and cognitive traits and clusters of co-occurring oral bacteria in older people. Relative abundances of Proteobacteria increased, while Bacteroidetes, Firmicutes and Fusobacteria decreased after nitrate supplementation. Two distinct microbiome modules of co-occurring bacteria, that were sensitive to nitrate supplementation, showed stable relationships with cardiovascular (Rothia-Streptococcus) and cognitive (Neisseria-Haemophilus) indices of health across both dietary conditions. A microbiome module (Prevotella-Veillonella) that has been associated with pro-inflammatory metabolism was diminished after nitrate supplementation, including a decrease in relative abundance of pathogenic Clostridium difficile. These nitrate-sensitive oral microbiome modules are proposed as potential pre- and probiotic targets to ameliorate age-induced impairments in cardiovascular and cognitive health.

A Placebo-Controlled, Pseudo-Randomized, Crossover Trial of Botanical Agents for Gulf War Illness: Curcumin (Curcuma longa), Boswellia (Boswellia serrata), and French Maritime Pine Bark (Pinus pinaster).

This report is part of a larger study designed to rapidly and efficiently screen potential treatments for Gulf War Illness (GWI) by testing nine different botanicals. In this placebo-controlled, pseudo-randomized, crossover clinical trial of 20 men with GWI, we tested three botanical agents with putative peripheral and central anti-inflammatory actions: curcumin (Curcuma longa), boswellia (Boswellia serrata), and French maritime pine bark extract (Pinus pinaster). Participants completed 30 +/− 3 days of baseline symptom reports, followed by 30 +/− 3 days of placebo, 30 +/− 3 days of lower-dose botanical, and 30 +/− 3 days of higher-dose botanical. Participants then repeated the process with a new botanical until completing up to three botanical cycles. Data were analyzed using linear mixed models. Curcumin reduced GWI symptom severity significantly more than placebo at both the lower (p < 0.0001) and higher (p = 0.0003) dosages. Boswellia was not more effective than placebo at reducing GWI symptoms at either the lower (p = 0.726) or higher (p = 0.869) dosages. Maritime pine was not more effective than placebo at the lower dosage (p = 0.954) but was more effective than placebo at the higher dosage (p = 0.006). This study provides preliminary evidence that curcumin and maritime pine may help alleviate symptoms of GWI. As a screening study, a final determination of the efficacy of these compounds for all individuals with GWI cannot be made, and further studies will need to be conducted to determine strength and durability of effects, as well as optimal dosage. These results suggest that GWI may, at least in part, involve systemic inflammatory processes. This trial was registered on ClinicalTrials.gov (NCT02909686) on 13 September 2016.

A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism

PurposeTo evaluate effectiveness of elamipretide in Barth syndrome (BTHS), a genetic condition of defects in TAZ, which causes abnormal cardiolipin on the inner mitochondrial membrane.MethodsWe performed a randomized, double-blind, placebo-controlled crossover trial followed by an open-label extension in BTHS to test the effect of elamipretide, a mitochondrial tetrapeptide that interacts with cardiolipin. In part 1, 12 subjects were randomized to 40 mg per day of elamipretide or placebo for 12 weeks, followed by a 4-week washout and then 12 weeks on the opposite arm. Ten subjects continued on the open-label extension (part 2) of 40 mg per day of elamipretide, with eight subjects reaching 36 weeks. Primary endpoints were improvement on the 6-minute walk test (6MWT) and improvement on a BTHS Symptom Assessment (BTHS-SA) scale.ResultsIn part 1 neither primary endpoint was met. At 36 weeks in part 2, there were significant improvements in 6MWT (+95.9 m, p = 0.024) and BTHS-SA (-2.1 points, p = 0.031). There were also significant improvements in secondary endpoints including knee extensor strength, patient global impression of symptoms, and some cardiac parameters.ConclusionIn this interventional clinical trial in BTHS, daily administration of elamipretide led to improvement in BTHS symptoms.

Daily Caffeine Intake Induces Concentration-Dependent Medial Temporal Plasticity in Humans: A Multimodal Double-Blind Randomized Controlled Trial.

Caffeine is commonly used to combat high sleep pressure on a daily basis. However, interference with sleep-wake regulation could disturb neural homeostasis and insufficient sleep could lead to alterations in human gray matter. Hence, in this double-blind, randomized, cross-over study, we examined the impact of 10-day caffeine (3 × 150mg/day) on human gray matter volumes (GMVs) and cerebral blood flow (CBF) by fMRI MP-RAGE and arterial spin-labeling sequences in 20 habitual caffeine consumers, compared with 10-day placebo (3 × 150mg/day). Sleep pressure was quantified by electroencephalographic slow-wave activity (SWA) in the previous nighttime sleep. Nonparametric voxel-based analyses revealed a significant reduction in GMV in the medial temporal lobe (mTL) after 10days of caffeine intake compared with 10days of placebo, voxel-wisely adjusted for CBF considering the decreased perfusion after caffeine intake compared with placebo. Larger GMV reductions were associated with higher individual concentrations of caffeine and paraxanthine. Sleep SWA was, however, neither different between conditions nor associated with caffeine-induced GMV reductions. Therefore, the data do not suggest a link between sleep depth during daily caffeine intake and changes in brain morphology. In conclusion, daily caffeine intake might induce neural plasticity in the mTL depending on individual metabolic processes.

Abstract PD1-11: Mature survival update of the double-blind placebo-controlled randomised phase II PAKT trial of first-line capivasertib plus paclitaxel for metastatic triple-negative breast cancer

Abstract Background: In the PAKT study, addition of the oral AKT inhibitor capivasertib to 1st-line paclitaxel therapy for metastatic TNBC resulted in significantly longer progression-free survival (PFS; primary endpoint; Schmid, J Clin Oncol 2020). The stratified PFS hazard ratio was 0.74 (95% CI, 0.50-1.08; one-sided P=0.06; predefined significance level of 0.10, one-sided; median PFS 5.9 vs 4.2 months with capivasertib vs placebo). Overall survival (OS) results were immature at the primary analysis with 53% of events but suggested long OS with capivasertib (HR, 0.61; 95% CI, 0.37-0.99; two-sided P=0.04). Here we report final results. Methods: This double-blind, placebo-controlled, randomised phase II trial, recruited women with untreated, metastatic TNBC. Total of 140 patients were randomly assigned (1:1) to paclitaxel 90mg/m2 (days 1, 8, 15) with either capivasertib (400mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included OS in the ITT population and in patients with and without PIK3CA/AKT1/PTEN-alterations. Results: With a median F/U of 40.0 months, median OS was longer in the capivasertib arm (19.1 vs 13.5 months, stratified HR 0.70, 95% CI 0.47-1.05, p=0.085). In contrast to the earlier analysis, no meaningful differences were seen in terms of benefit with capivasertib between patients with or without alterations of PIK3CA/AKT1/PTEN. Median OS numerically favoured capivasertib vs placebo both in the PIK3CA/AKT1/PTEN-altered (stratified HR 0.58, 95% CI 0.21-1.58, p=0.290) and PIK3CA/AKT1/PTEN non-altered subgroup (stratified HR 0.74, 95% CI 0.47-1.18, p=0.207). The safety profile of capivasertib plus paclitaxel was unchanged. Conclusions: Final OS results show a numerical trend favouring capivasertib; effects were observed regardless of PIK3CA/AKT1/PTEN alterations. Consistent with the previously observed PFS benefit, these findings support further evaluation of first-line Capivasertib plus paclitaxel for metastatic TNBC in the ongoing Capitello290 randomised phase III trial in patients with and without PIK3CA/AKT1/PTEN alterations. Citation Format: Peter Schmid, Jacinta Abraham, Stephen Chan, Adrian Murray Brunt, Gia Nemsadze, Richard D Baird, Yeon Hee Park, Peter Hall, Timothy Perren, Robert C Stein, László Mangel, Jean-Marc Ferrero, Melissa Phillips, John Conibear, Javier Cortes, Andrew Foxley, Elza de Bruin, Robert McEwen, Myria Nikolaou, Daniel Stetson, Brian Dougherty, Aaron Prendergast, Max McLaughlin-Callan, Matthew Burgess, Cheryl Lawrence, Hayley Cartwright, Kelly Mousa, Nicholas Turner, Duncan Wheatley. Mature survival update of the double-blind placebo-controlled randomised phase II PAKT trial of first-line capivasertib plus paclitaxel for metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-11.

Combined Cognitive-Behavioral Therapy and Placebo Treatment for Patients with Depression: A Follow-Up Assessment.

IntroductionA previous study revealed that patients with depression who received a combination of cognitive-behavioral therapy (CBT) and placebo treatment (CBT+placebo) showed greater symptom reduction than a CBT group without a placebo. Moreover, the CBT+placebo group practiced relaxation training more frequently. We conducted a 3-month follow-up assessment to investigate the temporal stability of the placebo effects.MethodsEighty-two outpatients with a diagnosis of major depressive disorder who had participated in a 4-week CBT course (CBT: n = 40; CBT with daily placebo treatment: n = 42) returned to a 3-month follow-up assessment. The participants of the CBT+placebo group had been debriefed directly after the course.ResultsCompared to the CBT group, the CBT+placebo group had lower scores on the Beck Depression Inventory-II (BDI-II) at follow-up and more participants were below the clinical cut-off score of the BDI-II. Additionally, the CBT+placebo group continued to practice relaxation more frequently.DiscussionThis study demonstrates that placebo effects are not short-lived and continue to be present after the debriefing.

Outcomes of Influenza with Treatment in Patients with Diabetes: Subgroup Analysis of the Phase 3 CAPSTONE-2 Trial

Background: Patients with diabetes are at increased risk of developing complications from influenza infections, suggesting prompt antiviral treatment could be beneficial. Objective: This analysis explored the potential benefits of antiviral treatment of influenza in patients with diabetes. Methods: Patients with influenza at high risk of complications received single-dose baloxavir versus five days of oseltamivir versus placebo. A subgroup analysis was performed in patients with diabetes. Results: Overall, 329 of 1163 patients (28.3%) in the ITTI population (oseltamivir n=111, baloxavir n=103, placebo n=115) had diabetes. Baseline characteristics in patients with diabetes were balanced. Overall, the frequency of AEs was low and similar between arms; no safety signals were unique to patients with diabetes. Of patients with diabetes, median TTIIS was shorter for patients treated with baloxavir (73.2 h) than those treated with oseltamivir (95.7 h, p=0.572) or placebo (100.6 h; p=0.048). For influenza A infections, median TTIIS (baloxavir vs oseltamivir vs placebo) was 75.4 h vs 76.5 h vs 125.0 h, respectively and for influenza B infections, 70.7 h vs 109.9 h vs 82.6 h, respectively. Baloxavir- treated patients had significantly shorter median time-to-viral-clearance compared with oseltamivir- and placebo-treated patients (p<0.001) (48 h vs 96 h vs 96 h; both groups). Systemic antibiotic use for secondary infections was low across all arms (baloxavir 3.9% vs oseltamivir 4.5% vs placebo 7.0%). Conclusions: Clinical and virological efficacy was observed in baloxavir-treated diabetic outpatients with influenza in CAPSTONE-2 and no unique safety signals were identified.

Blueberry supplementation reduces the blood lactate response to running in normobaric hypoxia but has no effect on performance in recreational runners

BackgroundBlueberries are concentrated with anthocyanins possessing antioxidant properties. As these properties counter fatigue, blueberry supplementation may improve performance and recovery, particularly in hypoxia, where oxidative stress is elevated.MethodsThis study examined the effects of blueberry supplementation on running performance, physiological responses, and recovery in normobaric hypoxia. Eleven experienced runners completed a 30-minute time-trial (TT) in normobaric hypoxia (%O2 = 15.5 %) on separate days after supplementation with four days of blueberries (BLU) or four days of placebo (PLA). Heart rate (HR), oxygen saturation (SaO2) and ratings of perceived exertion (RPE) were monitored during the TT. Blood lactate and fraction of exhaled nitric oxide (FENO) were assessed pre-TT, post-TT, and during recovery.ResultsNo significant differences were observed in the distance run during the TT, HR, SaO2, and RPE. The post-TT increase in blood lactate was significantly lower in BLU than PLA (p = 0.036). Pre-TT and post-TT FENO did not differ between conditions. Blood lactate recovery following the TT was similar between conditions.ConclusionsFour days of blueberry supplementation did not alter running performance or cardiovascular and perceptual responses in normobaric hypoxia. Supplementation lowered the blood lactate response to running, however, the significance of this finding is uncertain given the absence of an ergogenic effect.