Placebo-controlled Randomized Clinical Trial Research Articles

Effect of perioperative COX-2 and beta-adrenergic inhibition on 5-year disease-free-survival in colorectal cancer: A pilot randomized controlled Colorectal Metastasis PreventIon Trial (COMPIT)

IntroductionBased on translational and epidemiological evidence, perioperative inhibition of beta-adrenergic and COX2 signaling can reduce the risk for post-surgical metastatic disease. Here we aimed to assess in a pilot study the impact of a perioperative combined COX-2 and beta-adrenergic blockade on long-term cancer outcomes in colorectal cancer patients undergoing curative surgery. Materials and methodsThirty-four newly diagnosed colorectal cancer patients without evidence of metastases enrolled in this double-blinded placebo-controlled randomized clinical trial (treatment, n = 16; placebo, n = 18). A 20-day oral treatment of propranolol and etodolac regimen was initiated 5 days before surgery. Beneficial effects on short-term molecular biomarkers of cancer progression were reported earlier. Here we present outcomes of five postoperative years of disease-free-survival and overall survival. ResultsAdverse event rates were equivalent between the two groups. Intent-to-treat analyses of 5-year follow-up showed that 2/16 (12.5%) vs 9/18 (50%) patients exhibited recurrence in treatment vs placebo groups, respectively (p = 0.033), and 2/16 (12.5%) vs 4/18 (22%) died (p = 0.467). In protocol compliant patients 0/11 (0%) vs. 8/17 (47%) exhibited recurrence in treatment vs. placebo groups, respectively (p = 0.007), and 0/11 (0%) and 3/17 (17.6%) died (p = 0.151). ConclusionsIn this pilot clinical trial, a combined perioperative treatment with propranolol and etodolac significantly improved 5-year disease-free-survival. The small sample size and a single center study design merits caution in interpreting these results, specifically in estimating the effect-size. Larger studies in colorectal cancer are warranted and needed.

Treatment With Dupilumab in Patients With Atopic Dermatitis: Systematic Review and Meta-Analysis.

Atopic dermatitis (AD) is a type 2 chronic skin disorder associated with systemic and psychosocial comorbidities decreasing the quality of life for many patients. Dupilumab, a human monoclonal antibody that blocks interleukins IL-4 and IL-13, is a recently added systematic treatment option with an emerging evidence base. Here, we assessed the safety and efficacy of dupilumab in patients with AD. We conducted a systematic review and meta-analysis of placebo-controlled randomized clinical trials evaluating the safety and efficacy of dupilumab on AD-related outcomes including clinical symptoms, quality of life and adverse events (AE). Subgroup analysis was further performed in adults and children/adolescents. Fourteen trials were included: twelve in adults (n = 3,817) and two in children/adolescents (n = 618). Dupilumab decreased the Eczema Area Severity Index (EASI) score [standardized mean difference (SMD) = -0.98; 95% confidence interval (95% CI) = (-1.09, -0.88)], the percent change difference in Scoring Atopic Dermatitis (SCORAD) [mean difference (MD) = -31.56, 95% CI = (-33.75, -29.36)], and in pruritus Numeric Rating Scale (pNRS) [MD = -29.24, 95% CI = (-32.11, -26.37)]. It also achieved a reduction of at least ≥75% in the EASI score [Risk Ratio (RR) = 2.89, 95% CI = (2.47, 3.38)], the Investigator's Global Assessment (IGA) score ≤1 [RR = 3.47, 95% CI = (2.96, 4.06)] and eight additional endpoints with no signs of increased AE compared to placebo. In subgroup analysis, the results were concordant for both groups. Dupilumab improved clinical symptoms and quality of life in adults and children/adolescents with a safety profile comparable to placebo.

A double-blind randomized placebo-controlled trial of albumin in outpatients with hepatic encephalopathy: HEAL study

Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life (QoL), can persist. A double-blind, placebo-controlled randomized clinical trial was performed to determine the impact of albumin vs. saline on MHE and QoL in individuals with prior HE already on standard of care. Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on treatment for HE were included. Patients on regular IV albumin infusions were excluded. Participants were randomized 1:1 to receive either weekly infusions of 25% IV albumin 1.5g/kg or saline over 5 weeks. MHE was defined using either psychometric hepatic encephalopathy score (PHES), Stroop or critical clicker frequency. MHE, QoL (based on sickness impact profile [SIP] total, physical, psychosocial domain) and serum markers (inflammation, endothelial dysfunction, and ischemia-modified albumin) were compared between baseline, the final infusion visit (end-of-drug [EOD]) and 1-week post final infusion (end-of-study [EOS]). Forty-eight (24/group) participants were randomized and balanced (including by HE medication use) at baseline. Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and ischemia-modified albumin decreased only in the albumin group at EOD and EOS vs. baseline. PHES and Stroop MHE reversal and improvement were greater in the albumin group at EOD and persisted at EOS. SIP total and psychosocial, but not physical, domain improved only in the albumin group at EOD and EOS vs. baseline. A significant reduction in IL-1β and endothelial dysfunction markers was also observed in the albumin group. In a double-blind, placebo-controlled trial of outpatients with cirrhosis, prior HE and current MHE, albumin infusions were associated with improved cognitive function and psychosocial QoL, likely due to amelioration of endothelial dysfunction. www. gov NCT03585257. Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life, can persist. We found that intravenous albumin infusions were associated with improved cognitive function and psychosocial quality of life, likely owing to amelioration of endothelial dysfunction, compared to placebo in outpatients with prior HE and current MHE. In patients who continue to demonstrate cognitive dysfunction and impaired quality of life despite standard of care therapy for HE, albumin infusions could be considered if these results are validated.

Use of Cannabidiol (CBD) oil in the treatment of PTSD: Study design and rationale for a placebo-controlled randomized clinical trial

BackgroundThe burden of illness for PTSD is staggering and confers significant interference in work, social functioning, as well as increased risk for other physical and mental health problems. Recently, there's been considerable attention paid to the potential therapeutic use of cannabidiol (CBD) products in the treatment of a variety of physical and mental health problems. The endocannabinoid system (ECS) is a logical therapeutic target for combating PTSD and other fear-based disorders given that cannabinoid receptors and other molecular mediators crucial for ECS signaling are richly expressed in a variety of brain regions that govern the regulation of learned fear and defensive behavior. MethodsThis is an 8-week single-site Phase II randomized double-blind placebo-controlled fixed dose clinical trial. Participants recruited throughout the United States (N = 150) meeting DSM-5 criteria for posttraumatic stress disorder are randomly assigned to one of three treatment arms: (a) 300 mg CBD Isolate; (b) 300 mg CBD Broad Spectrum; and (c) Placebo oil. The primary outcome is PTSD symptom severity as indexed by the PTSD Checklist for DSM-5 (PCL-5) assessed at post treatment (Week 9) and follow-up (Week 13). Secondary outcomes including patient-rated depression, overall disability, anxiety, quality of life, and alcohol use are assessed weekly throughout the trial. Safety and CBD adherence are assessed daily throughout the trial. ConclusionThis is the first placebo-controlled clinical trial investigating (a) CBD for the treatment of PTSD; and (b) the first study to test the relative efficacy of CBD Isolate vs CBD Broad Spectrum.Trial registrationClinicalTrials.gov registered (12/12/2019), trial identifier NCT04197102. Protocol version: issued 08/04/2022, protocol amendment number #2019-05-0123.

Effect of Tocilizumab on Disease Activity in Patients With Active Polymyalgia Rheumatica Receiving Glucocorticoid Therapy

Few treatments are available for patients with glucocorticoid-dependent polymyalgia rheumatica. IL-6 antagonists may reduce disease activity in patients with active glucocorticoid-dependent polymyalgia rheumatica. To compare the efficacy of tocilizumab vs placebo in patients with glucocorticoid-dependent polymyalgia rheumatica. This double-blind, parallel-group, placebo-controlled randomized clinical trial enrolled 101 patients with polymyalgia rheumatica at 17 hospitals in France from February 2017 to October 2019. Final follow-up occurred in November 2020. Inclusion criteria were persistent disease activity (polymyalgia rheumatica activity score computed using the C-reactive protein level [CRP PMR-AS] >10) and prednisone dose greater than or equal to 10 mg per day. Patients were randomly assigned to receive intravenous tocilizumab (8 mg/kg; n = 51) or placebo (n = 50) every 4 weeks for 24 weeks, combined with predefined standardized tapering of oral prednisone. The primary efficacy end point was CRP PMR-AS less than 10 (range, 0-100; higher values indicate greater activity; no minimal clinically important difference defined) combined with either prednisone dose less than or equal to 5 mg per day or a decrease in prednisone dose greater than or equal to 10 mg from baseline at week 24. There were 11 secondary outcomes assessed at week 24 included in this report, including disease activity (measured by CRP PMR-AS) and the proportion of patients no longer taking prednisone. Of the 101 randomized patients (mean age, 67.2 years; 68 [67.3%] women), 100 (99%) received at least 1 infusion and 100 completed the trial. The primary end point was achieved in 67.3% of patients in the tocilizumab group and 31.4% of patients in the placebo group (adjusted difference, 36.0% [95% CI, 19.4%-52.6%]; adjusted relative risk, 2.3 [95% CI, 1.5-3.6]; P < .001). Of 11 reported secondary end points at 24 weeks, 7 showed significant differences favoring tocilizumab, including mean CRP PMR-AS score (7.5 [95% CI, 5.4-9.6] vs 14.9 [95% CI, 11.4-18.4]; adjusted difference, -7.5 [95% CI, -11.2 to -3.8]; P < .001) and the percentage of patients no longer receiving prednisone (49.0% vs 19.6%; adjusted difference, 29.3% [95% CI, 18.9%-39.7%]; adjusted relative risk, 2.5 [95% CI, 1.8-3.5]; P < .001). The most frequent adverse events were infections, experienced by 23 patients (46.9%) in the tocilizumab group and 20 (39.2%) in the placebo group. Among patients with active polymyalgia rheumatica despite prednisone therapy, tocilizumab, compared with placebo, resulted in a significantly greater percentage of patients with a CRP PMR-AS less than 10 with reduced prednisone requirements at week 24. Further research is needed to confirm efficacy and to determine the balance of potential benefits and harms. ClinicalTrials.gov Identifier: NCT02908217.

Efficacy and safety of nitazoxanide in treating SARS-CoV-2 infection: a systematic review and meta-analysis of blinded, placebo-controlled, randomized clinical trials

PurposeNitazoxanide is a broad-spectrum antiparasitic that has been tested for COVID-19 due to its anti-inflammatory effects and in vitro antiviral activity. This study synthesized the best evidence on the efficacy and safety of nitazoxanide in COVID-19.MethodsSearches for studies were performed in peer-reviewed and grey-literature from January 1, 2020 to May 23, 2022. The following elements were used to define eligibility criteria: (1) Population: individuals with COVID-19; (2) Intervention: nitazoxanide; (3) Comparison: placebo; (4) Outcomes: primary outcome was death, and secondary outcomes were viral load, positive RT-PCR status, serum biomarkers of inflammation, composite measure of disease progression (ICU admission or invasive mechanical ventilation), and any adverse events; (5) Study type: blinded, placebo-controlled, randomized clinical trials (RCTs). Treatment effects were reported as relative risk (RR) for dichotomous variables and standardized mean difference (SMD) for continuous variables with 95% confidence intervals (CI).ResultsFive blinded, placebo-controlled RCTs were included and enrolled individuals with mild or moderate SARS-CoV-2 infection. We found no difference between nitazoxanide and placebo in reducing viral load (SMD =  − 0.16; 95% CI − 0.38 to 0.05) and the frequency of positive RTP-PCR results (RR = 0.92; 95% CI 0.81 to 1.06). In addition, there was no decreased risk for disease progression (RR = 0.63; 95% CI 0.38 to 1.04) and death (RR = 0.81; 95% CI 0.36 to 1.78) among patients receiving nitazoxanide. Patients with COVID-19 treated with nitazoxanide had decreased levels of white blood cells (SMD =  − 0.15; 95% − 0.29 to − 0.02), lactate dehydrogenase (LDH) (SMD − 0.32; 95% − 0.52 to − 0.13), and D-dimer (SMD − 0.49; 95% CI − 0.68 to − 0.31) compared to placebo, but the magnitude of effect was considered small to moderate.ConclusionThis systematic review showed no evidence of clinical benefits of the use of nitazoxanide to treat patients with mild or moderate COVID-19. In addition, we found a reduction in WBC, LDH, and D-dimer levels among nitazoxanide-treated patients, but the effect size was considered small to moderate.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00228-022-03380-5.

1294TiP Olanzapine for anorexia in cancer cachexia patients: A placebo-controlled randomized trial

Cancer-associated cachexia (CAC) is a complex multifactorial syndrome. Various antipsychotics have been associated with weight gain, especially olanzapine (OLZ) which is suggested to have a role in the management of CAC. It remains unclear whether OLZ has an ameliorating effect on cancer patients’ anorexia, even when those patients exhibit no nausea or vomiting. Given the potential effect of OLZ on CAC and the mixed findings regarding this subject, the current trial aims at evaluating the efficacy of OLZ as a monotherapy in incurable cancer patients with cancer cachexia-associated anorexia. This is a single institution double-blind placebo-controlled randomized clinical trial. One hundred and sixty-four patients are being recruited from December 2021. The trial includes adult patients with incurable solid tumor, CAC, loss of appetite (≥4 score on the 0 to 10 loss of appetite scale of the Edmonton Symptom Assessment System [ESAS]), Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and a predicted survival >3 months. Causes for exclusion are: highly emetogenic chemotherapy, antipsychotic or appetite stimulant administration, nausea or vomiting score >3 on the 0 to 10 scale of the ESAS, weight gain for a known cause (e.g., oedema) or central nervous system disease. Participants will be 1:1 randomized to the intervention arm (OLZ 5 mg tablet once a night for 28 days) or the control arm (placebo tablet once at night for 28 days). The primary endpoint is the change in the loss of appetite score on the 0 to 10 scale of the ESAS from day 0 to day 7 of treatment. The secondary endpoints include the change in loss of appetite score from day 0 to days 14, 21 and 28 and the change in quality of life, handgrip strength, body mass index, body weight, lean body mass, fatigue and c-reactive protein level from day 0 to day 28. NCT05243251. Cairo University.

The effect of Abelmoschus esculentus L. (Okra) extract supplementation on dietary intake, appetite, anthropometric measures, and body composition in patients with diabetic nephropathy.

Background: Diabetes is a risk factor for chronic kidney disease because it induces nephropathy. Okra is a rich source of antioxidants, vitamins, minerals, and fibers, of which favorable effects in diabetes have been reported in many animal studies. The present trial aimed to investigate the effect of dried okra extract (DOE) supplementation on anthropometric measures, body composition, appetite, and dietary intake in diabetic nephropathy (DN) patients. Methods: In this triple-blind placebo-controlled randomized clinical trial, 64 DN patients were randomly allocated to receive a 125-mg capsule of DOE (n=32) or placebo (n=32) for 10 weeks. At baseline and endpoint of the trial, anthropometric variables, body composition indices, dietary intake, and appetite scores were evaluated. Results: The results showed that energy (P=0.047, CI: -425.87, -3.25, ES: 0.539) and carbohydrate (P=0.038, CI: -85.64, -2.53, ES: 0.555) intake as well as desire to eat salty food (P=0.023) were reduced in DOE group at the endpoint, compared to the baseline values. However, anthropometric measures, body composition, and appetite score were not significantly different between the two study groups. Conclusion: In conclusion, the present clinical trial showed that DOE could significantly decrease energy intake and carbohydrate consumption in the DN patients. Further clinical trials are needed to determine the effects of this supplement.

Effects of daily functional acorn cake consumption on insulin resistance in individuals with obesity or overweight and the metabolic syndrome: a placebo-controlled randomised clinical trial

AbstractThe metabolic syndrome is a multi-factorial condition and functional foods need more investigation as novel adjunct treatments for this group. This study aimed to determine the effects of daily consumption of a functional acorn cake in conjunction with energy restriction (119.50 kJ) on individuals with overweight or obesity and the metabolic syndrome. In this randomised double-blinded study, eighty-four participants were randomly allocated to either an energy-restricted diet plus two servings (2 × 30 g)/d of functional acorn cake (a cake made of acorn for the intervention group) (FC) (n 42) or an energy-restricted diet plus placebo cake (PC) (n 42). Body composition and biochemical parameters were measured before and after 10 weeks of intervention. Seventy-three participants completed this trial. No differences in loss of body weight, waist circumference, fat mass, fasting blood glucose and blood pressure were shown between two groups. Body weight decreased by 4·2 (sd 1·9) kg and 5·1 (sd 2·8) kg in PC and FC groups, respectively. Compared with PC, the consumption of FC resulted in a significant reduction in serum insulin (P = 0·02), homoeostasis model assessment for insulin resistance (P = 0·02), high-sensitivity C-reactive protein (P = 0·04) and a significant increase in adiponectin concentration (P = 0·04). Although lipid metabolism did not differ among groups, total cholesterol and HDL-cholesterol improved non-significantly in the FC group. Functional acorn cake as an adjunct to energy restriction could possibly improve insulin resistance in individuals with obesity. Further research is needed to elucidate whether functional acorn cake can be used as a preventive strategy for the metabolic syndrome in individuals with obesity.

Glucocorticosteroid and Silicone Gel During Patch Application Without Clinical Scar Improvement After Central Venous Catheter Removal: A Randomized Trial.

We studied whether glucocorticosteroid during patch occlusion has a beneficial effect on scar outcome in children and adolescents treated for cancer. A double-blinded placebo-controlled randomized clinical trial was performed. The main outcome was the Vancouver Scar Scale. Secondary outcomes were scar width and scar quality measured using the Patient and Observer Scar Assessment Scale. The patients were divided into an intervention groups and a control group. The intervention group was randomized into active and placebo group. The active treatment consisted of cream with glucocorticosteroid and fusidic acid. The placebo treatment consisted of cream with fusidic acid. Both groups received silicone gel patch after central venous catheter removal. The control group received no specific skin care. Assessment at 12 months showed that the intervention group had a significantly lower Vancouver Scar Scale and a smaller scar (0,1cm) compared with the control group ( P =0.00, P =0.02) but no benefit of glucocorticosteroid. The Patient and Observer Scar Assessment Scale showed no significant difference between the intervention and control groups ( P =0.84, P =0.36). Silicone gel sheet alone or in combination with application of glucocorticosteroid during sheet occlusion does not clinically improve scar outcome after removal of central venous catheter in children treated for neoplastic diseases.

The Effects of Vitamin K2 (Menaquinone-7) on the Leptin and Adiponectin Levels in Overweight/Obese Type 2 Diabetes Patients: A Randomized Clinical Trial

Background: Type 2 diabetes mellitus (T2DM) is a prevalent disease with metabolic consequences. Lower levels of adiponectin and higher levels of leptin were reported in T2DM. This study aimed to evaluate the effect of menaquinone-7 (MK-7) supplementation on adiponectin and leptin in overweight/obese T2DM patients. Methods: Sixty men and women with T2DM and 27 ≤ body mass index &lt; 35 kg/m2 , participated in this double-blind placebo-controlled randomized clinical trial for 12 weeks. The subjects were allocated into intervention (200 µg/day MK-7) or placebo groups. Three-day food records, anthropometrics and physical activity were assessed and fasting blood samples were collected at the pre- and post-intervention. Serum adiponectin, leptin, fasting blood sugar (FBS) and fasting insulin (FI) were measured and adiponectin to leptin ratio (A/L ratio) was calculated. Results: MK-7 decreased fasting blood sugar (P: 0.018) and fasting insulin (P: 0.012), according to a within group analysis of the 45 patients who finished the research. Fasting blood sugar (P: 0.024) and leptin levels (P: 0.032) were lower in the MK-7 group, but there were no significant changes between the groups in terms of adiponectin or the adiponectin to leptin (A/L) ratio. Conclusion: Current study showed that MK-7 supplementation could lead to significant reduction in leptin and FBS, but it has no effect on the adiponectin and A/L ratio in overweight/ obese T2DM patients.

High-Dose Dexamethasone and Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure

The benefit of high-dose dexamethasone and oxygenation strategies vs standard of care for patients with severe acute hypoxemic respiratory failure (AHRF) caused by COVID-19 pneumonia is debated. To assess the benefit of high-dose dexamethasone compared with standard of care dexamethasone, and to assess the benefit of high-flow nasal oxygen (HFNo2) or continuous positive airway pressure (CPAP) compared with oxygen support standard of care (o2SC). This multicenter, placebo-controlled randomized clinical trial was conducted in 19 intensive care units (ICUs) in France from April 2020 to January 2021. Eligible patients were consecutive ICU-admitted adults with COVID-19 AHRF. Randomization used a 2 × 3 factorial design for dexamethasone and oxygenation strategies; patients not eligible for at least 1 oxygenation strategy and/or already receiving invasive mechanical ventilation (IMV) were only randomized for dexamethasone. All patients were followed-up for 60 days. Data were analyzed from May 26 to July 31, 2021. Patients received standard dexamethasone (dexamethasone-phosphate 6 mg/d for 10 days [or placebo prior to RECOVERY trial results communication]) or high-dose dexamethasone (dexamethasone-phosphate 20 mg/d on days 1-5 then 10 mg/d on days 6-10). Those not requiring IMV were additionally randomized to o2SC, CPAP, or HFNo2. The main outcomes were time to all-cause mortality, assessed at day 60, for the dexamethasone interventions, and time to IMV requirement, assessed at day 28, for the oxygenation interventions. Differences between intervention groups were calculated using proportional Cox models and expressed as hazard ratios (HRs). Among 841 screened patients, 546 patients (median [IQR] age, 67.4 [59.3-73.1] years; 414 [75.8%] men) were randomized between standard dexamethasone (276 patients, including 37 patients who received placebo) or high-dose dexamethasone (270 patients). Of these, 333 patients were randomized among o2SC (109 patients, including 56 receiving standard dexamethasone), CPAP (109 patients, including 57 receiving standard dexamethasone), and HFNo2 (115 patients, including 56 receiving standard dexamethasone). There was no difference in 60-day mortality between standard and high-dose dexamethasone groups (HR, 0.96 [95% CI, 0.69-1.33]; P = .79). There was no significant difference for the cumulative incidence of IMV criteria at day 28 among o2 support groups (o2SC vs CPAP: HR, 1.08 [95% CI, 0.71-1.63]; o2SC vs HFNo2: HR, 1.04 [95% CI, 0.69-1.55]) or 60-day mortality (o2SC vs CPAP: HR, 0.97 [95% CI, 0.58-1.61; o2SC vs HFNo2: HR, 0.89 [95% CI, 0.53-1.47]). Interactions between interventions were not significant. In this randomized clinical trial among ICU patients with COVID-19-related AHRF, high-dose dexamethasone did not significantly improve 60-day survival. The oxygenation strategies in patients who were not initially receiving IMV did not significantly modify 28-day risk of IMV requirement. ClinicalTrials.gov Identifier: NCT04344730; EudraCT: 2020-001457-43.

A Complex Case: Patient with Elevated Lp(a) and Debilitating Stroke

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis DES, 43-year-old male, is referred for elevated lipoprotein(a) (Lp(a)), status-post ischemic left hemispheric stroke. There are potential interventions but insufficient evidence to make strong recommendations. Objective/Purpose To determine an appropriate treatment plan tailored to DES' situation. Methods This is a review of treatment options, barriers to care, and ethical considerations rendering this scenario complex. Results DES' medical history includes obesity, smoker, type 2 diabetes mellitus, hypertension, legal blindness, and subsequent ischemic left hemispheric stroke with residual global aphasia and right-sided hemiparesis. DES will remain a long-term care facility resident. He was referred by neurology after identifying an Lp(a) level greater than three times the upper limit of normal. Prior to initiating atorvastatin 80mg daily, DES' lipid levels are identified in Table 1. The 2018 AHA/ACC/Multisociety Guideline on the Management of Blood Cholesterol (1) supports using Lp(a) as a risk-enhancing factor to inform clinical decision-making, preventing atherosclerotic cardiovascular disease (ASCVD) in adults with at least 5% 10-year ASCVD risk, per the Pooled Cohort Equation. The National Lipid Association (NLA) Statement: Use of Lipoprotein(a) in Clinical Practice (2), supports testing Lp(a) in younger patients with prior cardiovascular events (CVE) and intensive low-density lipoprotein cholesterol (LDL-C) lowering, especially with proprotein convertase subtilisin-kexin 9 (PCSK9) monoclonal antibodies. The NLA mentions FDA criteria for lipoprotein-apheresis. Ongoing investigations of Lp(a)-lowering pharmacotherapy involve our program's HORIZON study of pelacarsen (3), testing whether it is superior to placebo in reducing CVE's in adults with prior myocardial infarction, stroke, symptomatic peripheral arterial disease, plus elevated Lp(a). Conclusions We considered whether additional preventive strategies directed at DES' Lp(a) is worthwhile after a debilitating stroke. Guidelines do not recommend care beyond closely monitoring lipid levels. Apheresis becomes available when LDL-C is greater than 110mg/dL, per FDA criteria. Participation in clinical decision-making and randomized placebo controlled clinical trials (RCT) is problematic. The team recommended closely monitoring lipid levels, but did not recommend additional pharmacotherapy, apheresis or RCTs. DES' diminished functional capacity, incomplete social support as a long-term care facility resident, and unclear indications for additional therapy guided our decision-making. DES' scenario enabled a discussion regarding clinical decision-making, clinician-patient discussions, patient engagement, socioeconomic/racial disparities, and limitations of guidelines within caring for complex patients. Nothing to disclose.

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial

BackgroundConvalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy.Research QuestionIs rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19?Study Design and MethodsThis was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (illness severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies (“serostatus”) at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality.ResultsAmong 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh SI [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58).InterpretationAmong adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes.Clinical Trial RegistrationClinicalTrials.gov; No.: NCT04362176; URL: www.clinicaltrials.gov

Novel Invisible Spectral Flicker Induces 40 Hz Neural Entrainment with Similar Spatial Distribution as 40 Hz Stroboscopic Light.

Background:Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer’s disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted.Objective:A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous light (CON) and 40 Hz stroboscopic light (STROBE).Methods:The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next.Results:Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95% CI 7.16 to 12.14).Conclusion:This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker.

The effects of a combination oral spray (Mucosamin®) for the prevention of oral mucositis in pediatric patients undergoing hematopoietic stem cell transplantation: a double blind randomized clinical trial.

Oral mucositis (OM) is a frequent complication of conditioning regimens for hematopoietic stem cell transplantation (HSCT). Damage to the nuclear and non-nuclear materials of the mucosal cells by the production of Reactive Oxygen Species (ROS) and proinflammatory cytokines could result to development and progression of OM. Previous studies have shown the effectiveness of Mucosamin® oral spray in the management of pain and acceleration of OM healing. The aims of the current study were to evaluate prophylactic effects of Mucosamin® oral spray in reducing the incidence and severity of OM in pediatric patients undergoing allogeneic HSCT. The current study was designed as a double-blind, placebo-controlled randomized clinical trial. Sixty patients were enrolled in the study and received placebo or Mucosamin® spray. Patients in both groups used sprays 4 times daily. Product application was begun at the time of initiation of conditioning regimen and was continued for 14days. Mucosamin® significantly reduced incidence and severity of OM compared to the placebo (P values: 0.027 and 0.035, respectively). This product could also decrease OM duration and delay OM onset (P values: 0.007 and 0.006, respectively). Mucosamin® could effectively reduce incidence, severity, and duration of OM and delay OM onset in pediatric patients undergoing allogeneic HSCT. The study protocol was registered in the Iranian Registry of Clinical Trials under the registry number IRCT20190917044805N1.

Efficacy and Safety of Varenicline for Smoking Cessation in Patients With Type 2 Diabetes

Evidence of effective smoking cessation interventions in patients with diabetes is limited. The unique behavioral and metabolic characteristics of smokers with type 2 diabetes warrants a randomized clinical trial of the smoking cessation drug varenicline. To evaluate the efficacy and safety of varenicline in patients with type 2 diabetes with an intention to quit smoking. This multicenter, double-blind, placebo-controlled randomized clinical trial recruited patients from 6 outpatient clinics in 5 hospitals in Catania, Italy. Patients with type 2 diabetes, who were smoking at least 10 cigarettes a day, and who intended to quit smoking were screened for eligibility. Eligible patients were randomized to either varenicline or placebo treatment. The trial consisted of a 12-week treatment phase followed by a 40-week follow-up, nontreatment phase. Intention-to-treat data analysis was performed from December 2020 to April 2021. Varenicline, 1 mg, twice daily or matched placebo administered for 12 weeks. Patients in both treatment groups also received smoking cessation counseling. The primary efficacy end point of the study was the continuous abstinence rate (CAR) at weeks 9 to 24. Secondary efficacy end points were the CAR at weeks 9 to 12 and weeks 9 to 52 as well as 7-day point prevalence of abstinence at weeks 12, 24, and 52. A total of 300 patients (mean [SD] age, 57.4 [0.8] years; 117 men [78.0%] in varenicline group and 119 men [79.3%] in placebo group) were randomized to receive varenicline (n = 150) or placebo (n = 150). The CAR at weeks 9 to 24 was significantly higher for the varenicline than placebo group (24.0% vs 6.0%; odds ratio [OR], 4.95; 95% CI, 2.29-10.70; P < .001). The CARs at weeks 9 to 12 (31.3% vs 7.3%; OR, 5.77; 95% CI, 2.85-11.66; P < .001) and weeks 9 to 52 (18.7% vs 5.3%; OR, 4.07; 95% CI, 1.79-9.27; P < .001) as well as the 7-day point prevalence of abstinence at weeks 12, 24, and 52 were also significantly higher for the varenicline vs placebo group. The most frequent adverse events occurring in the varenicline group compared with the placebo group were nausea (41 [27.3%] vs 17 [11.4%]), insomnia (29 [19.4%] vs 19 [12.7%]), abnormal dreams (19 [12.7%] vs 5 [3.4%]), anxiety (17 [11.4%] vs 11 [7.3%]), and irritability (14 [9.4%] vs 8 [5.4%]). Serious adverse events were infrequent in both groups and not treatment-related. Results of this trial showed that inclusion of varenicline in a smoking cessation program is efficacious in achieving long-term abstinence without serious adverse events. Varenicline should be routinely used in diabetes education programs to help patients with type 2 diabetes stop smoking. ClinicalTrials.gov Identifier: NCT01387425.

Effect of Perioperative Dexmedetomidine on Delayed Graft Function Following a Donation-After-Cardiac-Death Kidney Transplant

Delayed graft function (DGF) is a risk factor for acute rejection and graft failure after kidney transplant. Previous studies have suggested that dexmedetomidine may be renoprotective, but whether the use of dexmedetomidine would improve kidney allograft function is unknown. To investigate the effects of perioperative dexmedetomidine on DGF following a donation-after-cardiac-death (DCD) kidney transplant. This single-center, double-blind, placebo-controlled randomized clinical trial was conducted at The First Affiliated Hospital of Soochow University in Suzhou, China. Adults (18 years or older) who were scheduled for DCD kidney transplant were enrolled between September 1, 2019, and January 28, 2021, and then randomized to receive either dexmedetomidine or normal saline (placebo). One-year postoperative outcomes were recorded. All analyses were based on the modified intention-to-treat population. Patients who were randomized to the dexmedetomidine group received a 24-hour perioperative dexmedetomidine intravenous infusion (0.4 μg/kg/h intraoperatively and 0.1 μg/kg/h postoperatively). Patients who were randomized to the normal saline group received an intravenous infusion of the placebo with the same dose regimen as the dexmedetomidine. The primary outcome was the incidence of DGF, defined as the need for dialysis in the first posttransplant week. The prespecified secondary outcomes were in-hospital repeated dialysis in the first posttransplant week, in-hospital acute rejection, and serum creatinine, serum cystatin C, estimated glomerular filtration rate, need for dialysis, and patient survival on posttransplant day 30. Of the 114 patients enrolled, 111 completed the study (mean [SD] age, 43.4 [10.8] years; 64 male patients [57.7%]), of whom 56 were randomized to the dexmedetomidine group and 55 to the normal saline group. Dexmedetomidine infusion compared with normal saline reduced the incidence of DGF (17.9% vs 34.5%; odds ratio [OR], 0.41; 95% CI, 0.17-0.98; P = .04) and repeated dialysis (12.5% vs 30.9%; OR, 0.32; 95% CI, 0.13-0.88; P = .02, which was not statistically significant after multiple testing corrections), without significant effect on other secondary outcomes. Dexmedetomidine vs normal saline infusion led to a higher median (IQR) creatinine clearance rate on postoperative days 1 (9.9 [4.9-21.2] mL/min vs 7.9 [2.0-10.4] mL/min) and 2 (29.6 [9.7-67.4] mL/min vs 14.6 [3.8-45.1] mL/min) as well as increased median (IQR) urine output on postoperative days 2 (106.5 [66.3-175.6] mL/h vs 82.9 [27.1-141.9] mL/h) and 7 (126.1 [98.0-151.3] mL/h vs 107.0 [82.5-137.5] mL/h) and at hospital discharge discharge (110.4 [92.8-121.9] mL/h vs 97.1 [77.5-113.8] mL/h). Three patients (5.5%) from the normal saline group developed allograft failure by the post hoc 1-year follow-up visit. This randomized clinical trial found that 24-hour perioperative dexmedetomidine decreased the incidence of DGF after DCD kidney transplant. The findings support the use of dexmedetomidine in kidney transplants. Chinese Clinical Trial Registry Identifier: ChiCTR1900025493.

Secondary hypertension and its treatment in cats

Secondary hypertension caused by an underlying disease is common in older cats, especially in those with chronic kidney disease and/or hyperthyroidism. Systolic blood pressure should be measured whenever an associated disease is diagnosed and persistent systolic blood pressure &gt;160mmHg should prompt treatment to prevent or reverse target organ damage. Amlodipine and telmisartan are licensed in the UK to treat feline hypertension and both drugs have been evaluated in prospective randomised placebo-controlled clinical trials in hypertensive cats with systolic blood pressure of 160–200mmHg that did not have evidence of target organ damage. Initial reductions of 20–30mmHg can be expected with either medication, and cats should be re-evaluated after 14 days and dose adjustments made as required. No studies have compared the performance of one drug against the other and either medication should be selected as the first-line treatment for feline hypertension. At present, there are more data in the literature to support the use of amlodipine in cats with severe hypertension (systolic blood pressure &gt;200mmHg), or with evidence of ocular or neurological target organ damage.

GP.2 Deep learning prediction of response to disease modifying therapy in primary progressive multiple sclerosis

Background: Only one disease modifying therapy (DMT), ocrelizumab, was found to slow disability progression in primary progressive multiple sclerosis (PPMS). Modeling the conditional average treatment effect (CATE) using deep learning could identify individuals more responsive to DMTs, allowing for predictive enrichment to increase the power of future clinical trials. Methods: Baseline clinical and MRI data were acquired as part of three placebo-controlled randomized clinical trials: ORATORIO (ocrelizumab), OLYMPUS (rituximab) and ARPEGGIO (laquinimod). Data from ORATORIO and OLYMPUS was separated into a training (70%) and testing (30%) set, while ARPEGGIO served as additional validation. An ensemble of multitask multilayer perceptrons was trained to predict the rate of disability progression on both treatment and placebo to estimate CATE. Results: The model could separate individuals based on their predicted treatment effect. The top 25% of individuals predicted to respond most have a larger effect size (HR 0.442, p=0.0497) than the entire group (HR 0.787, p=0.292). The model could also identify responders to laquinimod. A simulated study where the 50% most responsive individuals are randomized would require 6-times less participants to detect a significant effect. Conclusions: Individuals with PPMS who respond favourably to DMTs can be identified using deep learning based on their baseline clinical and imaging characteristics.