Outpatient Trial Research Articles

Glycaemic outcomes in adults with type 2 diabetes over 34 weeks with the Omnipod® 5 Automated Insulin Delivery System.

The aim was to evaluate the effect of extended use of the Omnipod® 5 Automated Insulin Delivery (AID) System in adults with type 2 diabetes and suboptimal glycaemic control. Following an 8-week single-arm, multicentre, outpatient trial of AID in adults with type 2 diabetes and baseline HbA1c ≥ 8% (≥ 64 mmol/mol), participants were given the opportunity to continue use of the AID system in a 26-week (~6 month) extension phase. The primary safety endpoints were percentage of time with sensor glucose ≥ 250 mg/dL and < 54 mg/dL. Additional glycaemic measures, including percentage of time in range (TIR) (70-180 mg/dL) and HbA1c, were evaluated. The use of non-insulin anti-hyperglycaemic medications was permitted throughout the entire study. During the initial 8-week study, participants (N = 22) achieved a decrease in percentage of time ≥ 250 mg/dL from 27.4% ± 21.0% to 10.5% ± 8.8% (p < 0.0001), which further decreased to 9.7% ± 9.2% during the extension phase (p = 0.0002 vs. standard therapy). Percentage of time < 54 mg/dL remained low from standard therapy through extension (median [interquartile range] 0.00% [0.00%, 0.06%] vs. 0.02% [0.00%, 0.05%], p > 0.05). HbA1c decreased by 1.6% ± 1.2% (15.5 ± 13.1 mmol/mol, p < 0.0001) and TIR increased by 22.4% ± 19.2% (p < 0.0001) from standard therapy through extension with no significant change in body mass index and without an observed increase in total daily insulin requirements. These longer-term findings of Omnipod 5 AID System use demonstrate the potential value of AID in helping people with type 2 diabetes reach glycaemic targets.

Time to Sustained Recovery Among Outpatients With COVID-19 Receiving Montelukast vs Placebo

The effect of montelukast in reducing symptom duration among outpatients with mild to moderate COVID-19 is uncertain. To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19. This randomized clinical trial (Accelerating COVID-19 Therapeutic Interventions and Vaccines [ACTIV]-6) was conducted from January 27 through June 23, 2023, during the circulation of Omicron subvariants. Participants aged 30 years or older with confirmed SARS-CoV-2 infection and 2 or more acute COVID-19 symptoms for less than 7 days were included across 104 US sites. Participants were randomized 1:1 to receive montelukast, 10 mg once daily, or matched placebo for 14 days. The primary outcome was time to sustained recovery (defined as ≥3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of health care utilization events (hospitalization, urgent care clinic visit, emergency department visit, or death); COVID-19 clinical progression scale score; and difference in mean time unwell. A modified intention-to-treat approach was used for the analysis. Among 1250 participants who were randomized and received the study drug or placebo, the median age was 53 years (IQR, 42-62 years), 753 (60.2%) were female, and 704 (56.3%) reported receiving 2 or more doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [AHR], 1.02; 95% credible interval [CrI], 0.92-1.12; P = .63 for efficacy). Unadjusted median time to sustained recovery was 10 days (95% CI, 10-11 days) in both groups. No deaths occurred, and hospitalizations were reported for 2 participants (0.3%) in each group; the composite of health care utilization events was reported for 18 participants (2.9%) in the montelukast group and 18 (2.9%) in the placebo group (AHR, 1.01; 95% CrI, 0.45-1.84; P = .48 for efficacy). Five participants (0.4%) experienced serious adverse events (3 [0.5%] in the montelukast group and 2 [0.3%] in the placebo group). In this randomized clinical trial of outpatients with mild to moderate COVID-19, treatment with montelukast did not reduce duration of COVID-19 symptoms. These findings do not support the use of montelukast for the treatment of mild to moderate COVID-19. ClinicalTrials.gov Identifier: NCT04885530.

Childhood Trauma Questionnaire-based child maltreatment profiles to predict efficacy of the Cognitive Behavioral Analysis System of Psychotherapy versus non-specific psychotherapy in adults with early-onset chronic depression: cluster analysis of data from a randomised controlled trial

Child maltreatment is a broadly confirmed risk factor for mental and physical illness. Some psychological treatments specifically target mental health conditions associated with child maltreatment. For example, the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) focuses on maladaptive interpersonal behaviours in chronic depression. However, how the assessment of child maltreatment could inform personalised treatment is unclear. We used data from a previously published clinical trial to investigate whether a pre-established child maltreatment clustering approach predicts differential outcomes after CBASP versus non-specific supportive psychotherapy in patients with early-onset chronic depression. We did a cluster analysis of data from a previous randomised controlled trial of unmedicated adult outpatients with early-onset chronic depression who were treated at eight university clinics and psychological institutes in Germany with 32 sessions of CBASP or non-specific supportive psychotherapy. Participants were eligible for the original trial if they were aged 18-65 years; had major depressive disorder (MDD) with an early onset and duration of at least 2 years, current MDD superimposed on a pre-existing dysthymic disorder, or recurrent MDD with incomplete remission between episodes as defined by DSM-IV; and had a score of at least 20 points on the 24-item Hamilton Rating Scale for Depression (HRSD-24). Participants were included in the current study if they had completed the short form of the Childhood Trauma Questionnaire (CTQ) at trial baseline. We used an agglomerative hierarchical clustering approach to derive child maltreatment clusters from individual patterns across the five domains of the CTQ. We used linear mixed models to investigate whether clustering could predict differential clinical outcomes (change in symptom severity on the HRSD-24) up to 2 years after treatment onset. People with lived experience were involved in the current study. 253 patients (129 [51%] treated with CBASP and 124 [49%] with supportive psychotherapy) had complete CTQ records and were included in the analysis. 169 (67%) participants were women, 84 (33%) were men, and the mean age was 45·9 years (SD 11·7). We identified seven child maltreatment clusters and found significant differences in treatment effects of CBASP and supportive psychotherapy between the clusters (F(6,948·76)=2·47; p=0·023); differences were maintained over the 2-year follow-up. CBASP was superior in distinct clusters of co-occurring child maltreatment: predominant emotional neglect (change in β -6·02 [95% CI -11·9 to -0·13]; Cohen's d=-0·98 [95% CI -1·94 to -0·02]; p=0·045), predominant emotional neglect and abuse (-6·39 [-10·22 to -2·56]; -1·04 [-1·67 to -0·42]; p=0·0011), and emotional neglect and emotional and physical abuse (-9·41 [-15·91 to -2·91]; -1·54 [-2·6 to -0·47]; p=0·0046). CTQ-based cluster analysis can facilitate identification of patients with early-onset chronic depression who would specifically benefit from CBASP. Child maltreatment clusters could be implemented in clinical assessments and serve to develop and personalise trauma-informed care in mental health. The German Research Foundation and the German Federal Ministry of Education and Research.

Convalescent Plasma and Other Antibody Therapies for Infectious Diseases-Lessons Learned from COVID-19 and Future Prospects.

Antiviral passive antibody therapy includes convalescent plasma, hyperimmune globulin, and monoclonal antibodies. Passive antibodies have proven effective in reducing morbidity and mortality for SARS-CoV-2 and other infectious diseases when given early in the disease course with sufficiently high specific total and neutralizing antibody levels. Convalescent plasma can be delivered to patients before vaccination implementation or novel drug production. Carefully designed and executed randomized controlled trials near the pandemic outset are important for regulatory bodies, healthcare workers, guideline committees, the public, and the government. Unfortunately, many otherwise well-designed antibody-based clinical trials in COVID-19 were futile, either because they intervened too late in the disease or provided plasma with insufficient antibodies. The need for early treatment mandates outpatient clinical trials in parallel with inpatient trials. Early outpatient COVID-19 convalescent plasma transfusion with high antibody content within 9days of symptom onset has proven effective in blunting disease progression and reducing hospitalization, thus reducing hospital overcrowding in a pandemic. Convalescent plasma offers the opportunity for hope by enabling community participation in outpatient curative therapy while monoclonal therapies, vaccines, and drugs are being developed. Maintaining the appropriate infrastructure for antibody infusion in both outpatient and inpatient facilities is critical for future pandemic readiness.

Comparison of three methodologies for measuring intraocular pressure in healthy cats.

Measuring intraocular pressure (IOP) is crucial for identifying potentially damaging changes in the eyes, including diseases as glaucoma and uveitis. This study compared intraocular pressure (IOP) measurements in cats using the Tonovet and Tonovet Plus (rebound), Tono-Pen Avia Vet (applanation), and Kowa HA-2 (Goldman's methodology applanation) tonometers. 55 healthy cats (108 eyes) were assessed through three distinct studies: An ex vivo experiment (10 eyes of five cats) to correlate IOP manometry and tonometry values and ascertain the correlation coefficient (r2); an in vivo study (10 eyes of five sedated cats) to contrast manometer and tonometer readings; and an outpatient clinical trial (80 eyes of 45 cats) to analyze only tonometer measurements. The r 2 values observed in the ex vivo study were Tonovet (0.923), Tonovet Plus (0.925), Tono-Pen Avia Vet (0.877), and Kowa HA-2 (0.901). The IOP values in mmHg in the in vivo study were as follows: Manometer (16.1 ± 2.7), Tonovet (21.1 ± 3.6), Tonovet Plus (19.7 ± 7.2), Tono-Pen Avia Vet (17.6 ± 7.9), and Kowa HA-2 (16.8 ± 2.0). In the outpatient clinical study, the IOP values in mmHg were as follows: Tonovet (19.7 ± 6.6), Tonovet Plus (17.1 ± 5.4), Tono-Pen Avia Vet (16.3 ± 4.3), and Kowa HA-2 (14.5 ± 2.2). IOP and manometry readings were strongly correlated by all tonometers. In the clinical setting, the most and least IOP measurements were recorded using Tonovet and Kowa HA-2, respectively, stressing the importance of an IOP reference table for each tonometer in feline practice.

Temporal trends and characteristics associated with racial, ethnic, and sex representation in COVID-19 clinical trials: A systematic review and meta-analysis

BackgroundEarly in the pandemic, extensive attention was cast on limited inclusion of historically underrepresented patient populations in COVID-19 clinical trials. How diverse representation improved following these initial reports remains unclear. MethodsPubMed, Embase and the Cochrane Library were searched (through April 2024) for US-based COVID-19 trials. Utilizing random-effects, we compared expected proportions of trial participants from racial and ethnic groups and of female sex between trials enrolling primarily in 2020 versus primarily 2021–2022. Meta-regression was performed to assess associations between trial characteristics and group representation. ResultsWe retrieved 157 studies comprising 198,012 participants. White (2020: 63.1% [95% CI, 60.8%–67.3%]; 2021–2022: 73.8% [95% CI, 71.5%–76.0%]) and female representation (2020: 46.1% [95% CI, 44.7%–47.4%)]; 2021–2022: 51.1% [95% CI, 49.3%–52.8%) increased across enrollment periods. Industry-sponsored trials were associated with higher White (coefficient, 0.10 [95% CI, 0.03–0.18]) and Hispanic or Latinx representation (coefficient, 0.16 [95% CI, 0.08–0.25]) and lower Asian (coefficient, −0.03 [95% CI, −0.06– –0.003]) and female representation (coefficient, −0.03 [95% CI, −0.07– –0.002]). Outpatient trials were associated with higher White (coefficient, 0.20 [95% CI, 0.13–0.26]) and female representation (coefficient, 0.16 [95% CI, 0.13–0.18]), and lower Black representation (coefficient, −0.10 [95% CI, −0.10– –0.08]). ConclusionsDespite improved female representation in COVID-19 trials over time, there was no clear increase in non-White representation. Trial characteristics such as primary sponsor, clinical setting, and intervention type correlate with representation of specific demographic groups and should be considered in future efforts to improve participant diversity.

Matched vs Nonmatched Placebos in a Randomized Trial of COVID-19 Treatments

Matched placebo interventions are complex and resource intensive. Recent evidence suggests matched placebos may not always be necessary. Previous studies have predominantly evaluated potential bias of nonmatched placebos (ie, differing on dose, frequency of administration, or formulation) in pain and mental health, but to date no systematic examination has been conducted in infectious disease. To test for differences between nonmatched and matched placebo arms with respect to clinical outcome measures across multiple therapeutics for COVID-19. In a comparative effectiveness research study, a post hoc analysis was conducted of data on individual patients enrolled in a large, multiarm, platform randomized clinical trial in symptomatic adult outpatients with COVID-19 between January 15, 2021, to September 28, 2023, in which the outcomes of both matched and nonmatched placebo groups were reported. Bayesian and frequentist covariate-adjusted techniques were compared with 7 intervention-placebo pairs. Seven matched and nonmatched placebo pairs (for a total of 7 comparisons) were evaluated throughout the primary platform trial. Comparisons were made between treatment and its associated matched (concurrent) placebo, as well as with nonmatched placebo (alone and in combination) assessed at a similar time point. Outcomes assessed included hospitalizations, EuroQol 5-Dimension 5-level scores, and PROMIS Global-10 scores. A total of 7 intervention-control pairs (N = 2684) were assessed, including 1620 (60.4%) women, with mean (SD) age, 47 (15.2) years; the most common comorbidities were obesity (41.9%) and hypertension (37.9%). In a meta-analysis with decoupled SEs, accounting for overlapping placebo patients, the overall odds ratio (OR) of nonmatched compared with matched placebo was 1.01 (95% credible interval, 0.77-1.32), with posterior probability of equivalence, defined as 0.8 ≤ OR ≤ 1.2 (a deviation from perfect equivalence ie, OR = 1, by no more than 0.2) of 85.4%, implying no significant difference. Unadjusted analysis of the event rate difference between all nonmatched and matched placebo groups did not identify any notable differences across all 7 treatment-placebo combinations assessed. Similar analysis that was conducted for patient-reported quality of life outcomes did not yield statistically significant differences. In this post hoc study of a randomized clinical platform trial, pooling matched and nonmatched placebo patient data did not lead to inconsistencies in treatment effect estimation for any of the investigational drugs. These findings may have significant implications for future platform trials, as the use of nonmatched placebo may improve statistical power, or reduce barriers to placebo implementation.

Hospitalization Endpoint in Clinical Trials of Outpatient Settings: using Anti-SARS-COV-2 Therapy as an Example.

In response to the COVID-19 pandemic, the World Health Organization (WHO) developed a set of outcome measures for trials primarily aimed at hospitalised patients. However, a gap exists in defining outcome standards for non-hospitalised patients. Therefore, this study aims to discuss hospitalisation as a primary outcome in outpatient trials and its potential pitfalls, specifically focusing on trials related to anti-SARS-COV-2 therapy. In this narrative review, researchers thoroughly searched MEDLINE and ClinicalTrials.gov from January 2020 to December 2022, targeting Phase III randomized controlled trials involving outpatients with mild-to-moderate COVID-19. The trials were specifically related to anti-SARS-COV-2 monoclonal antibodies or antiviral agents. The study collected essential data, including the type of intervention, comparator, primary objective, primary endpoint, and the use of estimands in the trial. The search identified 12 trials that evaluated the efficacy of anti-SARS COV-2 therapies in a predefined population. Three studies used hospitalisation and death as primary endpoints in high-risk patients receiving monoclonal antibodies. Nine studies assessed the efficacy of several antiviral agents: four trials used hospitalisation and death as the main endpoints, while others used different measures such as virologic measures using the Reverse Transcription-Polymerase Chain Reaction test (RT-PCR), the eight-point WHO ordinal scale, symptom alleviation by Day 7 and time to clinical response. Choosing hospitalization as an endpoint may provide meaningful data such as the cost-effectiveness ratio of a drug. However, different hospital utilisation patterns and investigator decisions could bias clinical outcomes if no specific criteria are considered. Therefore, investigators should have clear criteria for determining variables that influence this measure.

Perceived Physical Health and Cognitive Behavioral Therapy vs Supportive Psychotherapy Outcomes in Adults With Late-Life Depression

Physical diseases co-occur with late-life depression (LLD). The influence of physical diseases and the subjective perception of physical health (PPH) on treatment outcome in LLD, however, is not well understood. To assess the association of physical diseases and PPH with the outcomes of 2 different types of psychotherapy in LLD. This post hoc secondary analysis of a multicenter, observer-blinded, controlled, parallel-group randomized clinical trial assessed participants 60 years or older with moderate to severe depression recruited at 7 psychiatric-psychotherapeutic outpatient trial sites in Germany from October 1, 2018, to November 11, 2020. Data analysis was performed from April 1 to October 31, 2023. Patients received LLD-specific cognitive behavioral therapy (LLD-CBT) or supportive unspecific intervention (SUI). Depression severity, response, and remission were measured during treatment and at 6-month follow-up by the change in the 30-item Geriatric Depression Scale (GDS) score. Physical health and PPH were assessed by the number of physical diseases, Charlson Comorbidity Index (CCI), and the World Health Organization Quality of Life Brief Version physical health subscale. A total of 251 patients were randomized to LLD-CBT (n = 126) or SUI (n = 125), of whom 229 (mean [SD] age, 70.2 [7.1] years; 151 [66%] female) were included in the intention-to-treat analysis. Patients with low and moderate PPH at baseline had significantly less reduction in the GDS score across both treatment groups than patients with high PPH (estimated marginal mean difference [EMMD], 2.67; 95% CI, 0.37-4.97; P = .02 for low PPH and EMMD, 1.82; 95% CI, 0.22-3.42; P = .03 for moderate vs high PPH). Higher PPH at baseline was associated with higher likelihood of response (odds ratio [OR], 1.04; 95% CI, 1.00-1.06; P = .009) and remission at the end of treatment (OR, 1.04; 95% CI, 1.02-1.08; P = .002) and response (OR, 1.05; 95% CI, 1.02-1.08; P < .001) and remission at follow-up (OR, 1.06; 95% CI, 1.03-1.10; P < .001) across both treatment groups. However, a significant interaction of PPH with treatment group was observed with low PPH at baseline being associated with significantly larger reduction in GDS scores in SUI compared with LLD-CBT at the end of treatment (EMMD, -6.48; 95% CI, -11.31 to -1.64; P = .009) and follow-up (EMMD, -6.49; 95% CI, -11.51 to -1.47; P = .01). In contrast, patients with high PPH at baseline had a significantly greater reduction in GDS scores in LLD-CBT compared with SUI at all time points (week 5: EMMD, -4.08; 95% CI, -6.49 to -1.67; P = .001; end-of-treatment: EMMD, -3.67; 95% CI, -6.72 to -0.61; P = .02; and follow-up: EMMD, -3.57; 95% CI, -6.63 to -0.51; P = .02). The number of physical diseases or CCI at baseline did not have an effect on the change in GDS score, response, or remission, neither across both groups nor within either group. In this secondary analysis of a randomized clinical trial, subjective PPH was associated with treatment outcome, response, and remission in psychotherapy of LLD. Patients with LLD responded differently to LLD-CBT and SUI, depending on their baseline PPH score. Treatment approaches for patients with LLD should address PPH in personalized interventions. ClinicalTrials.gov Identifier: NCT03735576; Deutsches Register Klinischer Studien Identifier: DRKS00013769.

Rapid reduction of depressive symptoms with minimal dissociation: results from the KET01-02 and KET01-03 trials with oral prolonged-release (PR) ketamine KET01

IntroductionCurrent ketamine-based therapies for treatment-resistant depression (TRD) often induce dissociative effects. A novel oral PR ketamine formulation (KET01) results in a low and delayed peak concentration of ketamine, high hydroxynorketamine concentration, and is associated with limited dissociative properties.ObjectivesTo investigate efficacy, safety, and pharmacokinetics of KET01 in TRD.MethodsKET01-02 was a randomized, double-blind phase 2 trial in outpatients with TRD comparing adjunct 120 mg (n=42) or 240 mg (n=40) oral KET01 once-daily for 3 weeks to placebo (PBO, n=40). The primary endpoint was change from baseline in the MADRS mean score on Day 21. KET01-03 was a randomized, double-blind, cross-over phase I trial in 26 healthy volunteers comparing single doses of 240 mg oral KET01 and 84 mg an approved intranasal formulation of eketamine. The primary endpoint was maximum change of Clinician-Administered Dissociative States Scale (CADSS) score from baseline.ResultsKET01-03 trial; the mean (±SD) maximum change of CADSS score within 24 hours after dosing was 29.6±12.5 for intranasal eketamine and 0.7±1.7 for KET01 (p&lt;0.00000000001). KET01-02 trial; no differences in CADSS score (range: 0.2 to 1.3), and heart rate and blood pressure were observed between the groups on Day 1 and beyond. 10%, 12%, and 15% of patients in the PBO, 120 mg/day, and 240 mg/day KET01 groups, respectively had CADSS score &gt;4 and increase from baseline. At 7 hours post first KET01 dose (240 mg), plasma concentration of ketamine (38.7±27.0 ng/ml) was lower than its metabolites norketamine (267.5±81.6 ng/ml) and hydroxynorketamine (190.2±85.5 ng/ml). 240 mg/day KET01 induced clinically relevant reduction from baseline in MADRS score already within the first 7 hours of treatment (-7.65; Δ vs PBO: -2.22, n.s.), with a statistically significant separation on Day 4 (-10.02; Δ vs PBO: -3.66, p=0.020) and Day 7 (-12.21; Δ vs PBO: -3.95, p=0.042). MADRS score decrease was sustained throughout Day 21 (-13.15; Δ vs PBO: -1.82, n.s.), and during 4-week follow-up (-12.51; Δ vs PBO: -3.35, n.s.). Treatment-emergent adverse events occurred in 47.5%, 50.0%, and 62.5% of patients in the PBO, 120 mg/day, and 240 mg/day KET01 group, respectively.ConclusionsOral 240 mg/day KET01 induces a rapid, and clinically relevant reduction of depressive symptoms with only minimal signs of dissociation, potentially due to lower ketamine levels and increased norketamine and hydroxynorketamine levels compared to intravenous administration. Our results suggest that KET01 may be an efficacious and safe take-at-home adjunct treatment for TRD.Disclosure of InterestC. zu Eulenburg Employee of: HMNC Brain Health, E. Papanastasiou Employee of: HMNC Brain Health, K. Schmid Employee of: Develco Pharma, A. Damyanova Employee of: HMNC Brain Health, A. Glas Employee of: HMNC Brain Health, C. Strote Employee of: HMNC Brain Health, L. Arvastson Employee of: HMNC Brain Health, H. Eriksson Employee of: HMNC Brain Health

Efficacy and safety of peppermint oil for the treatment in Japanese patients with irritable bowel syndrome: a prospective, open-label, and single-arm study

BackgroundIn Europe, an herbal medicine containing peppermint oil is widely used in patients with irritable bowel syndrome (IBS). In Japan, however, no clinical evidence for peppermint oil in IBS has been established, and it has not been approved as a drug for IBS. Accordingly, we conducted a clinical study to confirm the efficacy and safety of peppermint oil (ZO-Y60) in Japanese patients with IBS.MethodsThe study was a multi-center, open-label, single-arm, phase 3 trial in Japanese outpatients with IBS aged 17–60 years and diagnosed according to the Rome III criteria. The subjects were treated with an oral capsule of ZO-Y60 three times a day before meals, for four weeks. The efficacy of ZO-Y60 was evaluated using the patient’s global assessment (PtGA), IBS symptom severity score, stool frequency score, stool form score, and physician’s global assessment (PGA). The safety of ZO-Y60 was also assessed.ResultsSixty-nine subjects were treated with ZO-Y60. During the four-week administration of ZO-Y60, the improvement rate of the PtGA was 71.6% (48/67) in week 2 and 85.1% (57/67) in week 4. It was also suggested that ZO-Y60 is effective against any type of IBS (IBS with constipation, IBS with diarrhea, and mixed/unsubtyped IBS). The improvement rate of the PGA was 73.1% (49/67) in week 2 and 85.1% (57/67) in week 4, also confirming the efficacy of ZO-Y60. Adverse events were observed in 14 subjects (20.3%), however, none of these adverse events were categorized as serious.ConclusionThe efficacy of treatment was confirmed, subjective symptoms were improved, as was observed in previous clinical studies of ZO-Y60 conducted outside of Japan. All adverse reactions were previously known and were non-serious. These findings suggest that peppermint oil may be effective in the Japanese population and that it has an acceptable safety profile.Trial registrationJAPIC Clinical Trials Information number: JapicCTI-121727 https://jrct.niph.go.jp/en-latest-detail/jRCT1080221685. Registration date: 2012–01-10.

Abstract 35: Integrating Clinical Trials Into Comprehensive Stroke Education for Inpatient Nurses

Introduction: A major challenge in the implementation of clinical trials is the lack of integration of research into the clinical practice of frontline staff. The University of Minnesota partnered with the M Health Fairview (MHFV) System to incorporate stroke clinical trials into the annual comprehensive stroke education courses. While not required by the stroke accreditation curriculum standards, embedding research topics into ongoing stroke education is a novel practice that broadly increases awareness of clinical research with the frontline staff caring for stroke patients. Methods: In 2019, the comprehensive stroke class was updated to include a section for stroke trials. The research topics include: a brief description of study team roles, an overview of the impact of clinical trials on EBP, results for published trials, updates on current clinical trials, and the impact on nursing workflow. The number of attendees for each session from 2019-June 2023 were recorded along with anonymous comments about the presentation. The total number of subjects enrolled in acute, inpatient, and outpatient stroke trials in MHFV were compiled. Results: The comprehensive stroke class was attended by MHFV nurses 1,667 times. Interest in research was noted 77 times in the comments and research was ranked 3rd “most interesting” topic presented in 2019. A total of 276 patients were enrolled in stroke research in that timeframe. Conclusion: While no direct correlation can be drawn to trial enrollment, the volume of learners demonstrates broad dissemination of stroke trials information to frontline staff caring for stroke patients and the collection of positive feedback shows an interest in the topic. Incorporating clinical trials education into established comprehensive stroke education increases awareness of clinical trials and facilitates integration of research into clinical workflows with a higher acceptance of clinical trial efforts by frontline staff.

Sex-specific disparities in COVID-19 outcomes.

Sex-specific disparities in morbidity and mortality of COVID-19 illness are not well understood. Neutralizing antibodies (Ab) may protect against severe COVID-19 illness. We investigated the association of sex with disease progression and SARS-CoV-2 Ab response. In this exploratory analysis of the phase 3, multicenter, randomized, placebo-controlled Convalescent Plasma in Outpatients (C3PO) trial, we examined whether sex was associated with progression to severe illness, defined as a composite of all-cause hospitalization, emergency/urgent care visit, or death within 15 days from study enrollment. Patients had a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test, symptom onset within 7 days, stable condition for emergency department discharge, and were either ≥50 years old or had at least one high-risk feature for disease progression. Patients received blinded convalescent plasma or placebo in a 1:1 fashion and were evaluated on days 15 and 30 after infusion. Blood samples were collected on day 0 (pre-/post-infusion), 15, and 30 to measure Ab levels with the Broad Institute using the Plaque Reduction Neutralization Test assay. Of 511 patients enrolled (median age 54 [Iinterquartile range 41-62] years, 46% male, 66% white, 20% black, 3.5% Asian), disease progression occurred in 36.7% of males and 25.9% of females (unadjusted risk difference 10.8%, 95% confidence interval [CI], 2.8-18.8%). Sex-disparities did not persist when adjusted for treatment group, age, viremic status, symptom onset, and tobacco use (adjusted risk difference 5.6%, 95% confidence interval [CI], -2.2% to 13.4%), but were present in the subgroup presenting 3 or more days after symptom onset (adjusted risk difference 12.6%, 95% CI, 3.4% to 21.9%). Mean baseline Ab levels (log scale) available for 367 patients were similar between sexes (difference 0.19 log units, 95% CI, -0.08 to 0.46). The log-scale mean increase from baseline to day 15 after adjusting for treatment assignment and baseline levels was larger in males than females (3.26vs. 2.67). A similar difference was noted when the groups were subdivided by outcome. Progression of COVID-19 was similar in males and females when adjusted for age, tobacco use, and viremia status in this study. However, in the cohort presenting 3 or more days after symptom onset, COVID-19 outcomes were worse in males than females. Neutralizing Ab levels increased more in males but did not correlate with sex differences in outcomes.

What to Expect With Pregnant or Postpartum Prescribing of Extended-Release Buprenorphine (CAM2038).

Weekly and monthly CAM2038 (Brixadi®) extended-release subcutaneous buprenorphine (XR bup) has been available in Europe and Australia for several years and was approved by the Food and Drug Administration in May 2023. Little is known about the clinical experience of patients and providers using this new medication during prenatal care. Two cases of pregnant persons with opioid use disorder receiving weekly XR bup in an ongoing randomized multi-site outpatient clinical trial are presented along with a brief review of the pharmacology and literature on XR bup formulations. The cases in pregnancy illustrate how treatment with the weekly formulation is initiated including how to make dose adjustments, which may be necessary given the longer half-life; it takes 1 month to achieve steady state. Injection site pain with medication administration was time limited and managed readily. Other injection site reactions experienced included subcutaneous erythema and induration that was delayed in onset and typically mild, resolving with minimal intervention. Delivery management and breastfeeding recommendations while on weekly XR bup were not different compared to sublingual buprenorphine (SL bup). Weekly XR bup is a new treatment for opioid use disorder that may be used in the obstetric population. Obstetric and addiction medicine clinicians should be aware of this new formulation as its use is expected to increase.

Outpatient randomized controlled trials to reduce COVID-19 hospitalization: Systematic review and meta-analysis.

This COVID-19 outpatient randomized controlled trials (RCTs) systematic review compares hospitalization outcomes amongst four treatment classes over pandemic period, geography, variants, and vaccine status.Outpatient RCTs with hospitalization endpoint were identified in Pubmed searches through May 2023, excluding RCTs <30 participants (PROSPERO-CRD42022369181). Risk of bias was extracted from COVID-19-NMA, with odds ratio utilized for pooled comparison.Searches identified 281 studies with 61 published RCTs for 33 diverse interventions analyzed. RCTs were largely unvaccinated cohorts with at least one COVID-19 hospitalization risk factor. Grouping by class, monoclonal antibodies (mAbs)(OR = 0.31 [95% CI = 0.24-0.40]) had highest hospital reduction efficacy, followed by COVID-19 convalescent plasma(CCP) (OR = 0.69 [95% CI = 0.53-0.90]), small molecule antivirals (OR = 0.78 [95% CI = 0.48-1.33]), and repurposed drugs (OR = 0.82 [95% CI: 0.72-0.93]). Earlier in disease onset interventions performed better than later. This meta-analysis allows approximate head-to-head comparisons of diverse outpatient interventions.Omicron sublineages (XBB and BQ.1.1) are resistant to mAbsDespite trial heterogeneity, this pooled comparison by intervention class indicated oral antivirals are the preferred outpatient treatment where available, but intravenous interventions from convalescent plasma to remdesivir are also effective and necessary in constrained medical resource settings or for acute and chronic COVID-19 in the immunocompromised.

Development of a proteomic signature associated with severe disease for patients with COVID-19 using data from 5 multicenter, randomized, controlled, and prospective studies

Significant progress has been made in preventing severe COVID-19 disease through the development of vaccines. However, we still lack a validated baseline predictive biologic signature for the development of more severe disease in both outpatients and inpatients infected with SARS-CoV-2. The objective of this study was to develop and externally validate, via 5 international outpatient and inpatient trials and/or prospective cohort studies, a novel baseline proteomic signature, which predicts the development of moderate or severe (vs mild) disease in patients with COVID-19 from a proteomic analysis of 7000 + proteins. The secondary objective was exploratory, to identify (1) individual baseline protein levels and/or (2) protein level changes within the first 2 weeks of acute infection that are associated with the development of moderate/severe (vs mild) disease. For model development, samples collected from 2 randomized controlled trials were used. Plasma was isolated and the SomaLogic SomaScan platform was used to characterize protein levels for 7301 proteins of interest for all studies. We dichotomized 113 patients as having mild or moderate/severe COVID-19 disease. An elastic net approach was used to develop a predictive proteomic signature. For validation, we applied our signature to data from three independent prospective biomarker studies. We found 4110 proteins measured at baseline that significantly differed between patients with mild COVID-19 and those with moderate/severe COVID-19 after adjusting for multiple hypothesis testing. Baseline protein expression was associated with predicted disease severity with an error rate of 4.7% (AUC = 0.964). We also found that five proteins (Afamin, I-309, NKG2A, PRS57, LIPK) and patient age serve as a signature that separates patients with mild COVID-19 and patients with moderate/severe COVID-19 with an error rate of 1.77% (AUC = 0.9804). This panel was validated using data from 3 external studies with AUCs of 0.764 (Harvard University), 0.696 (University of Colorado), and 0.893 (Karolinska Institutet). In this study we developed and externally validated a baseline COVID-19 proteomic signature associated with disease severity for potential use in both outpatients and inpatients with COVID-19.

The modified Medical Research Council scale misclassifies exertional breathlessness among people referred for exercise testing.

Exertional breathlessness is a major symptom in cardiorespiratory disease and is often assessed using the modified Medical Research Council (mMRC) questionnaire. The mMRC might underestimate exertional breathlessness in people with impaired exercise capacity who have reduced their physical activity to avoid the symptom. We aimed to evaluate the ability of mMRC to detect abnormally high exertional breathlessness or abnormally low exercise capacity during incremental cycle exercise testing (IET). A secondary analysis of data from a randomised controlled trial of outpatients aged 18 years or older referred for IET was carried out. Participants completed the mMRC before IET. Abnormally high exertional breathlessness was defined as a breathlessness (Borg 0-10) intensity response more than the upper limit of normal. Abnormally low exercise capacity was defined using published reference equations. The sensitivity, specificity, accuracy and discriminative ability of each mMRC rating to detect each outcomewas calculated. 92 participants were included; the mean age was 59 years, 61% were male, and 64% and 15% had mMRC 1 and ≥2, respectively. An mMRC ≥2 had the highest accuracy (71%) to detect abnormally high exertional breathlessness, with a specificity of 93% but a sensitivity of only 28%, failing to identify 72% of people with abnormally high exertional breathlessness. The accuracy, specificity and sensitivity for abnormally low exercise capacity was 64%, 88% and 19%, respectively. Among people referred for clinical exercise testing, the mMRC dyspnoea scale misclassified exertional breathlessness and exercise capacity assessed using cycle IET, with substantial underdetection. A mMRC dyspnoea rating of 0-1 does not preclude the presence of abnormally high exertional breathlessness or abnormally low exercise capacity.

48.1 Reliability and Accuracy of Scores Using 10- or 20-Item Short Forms of the Positive and Negative Syndrome Scale (PANSS) Replicated in 3 Large Outpatient Trials

48.1 Reliability and Accuracy of Scores Using 10- or 20-Item Short Forms of the Positive and Negative Syndrome Scale (PANSS) Replicated in 3 Large Outpatient Trials

Open label trial of lofexidine-assisted non-opioid induction onto naltrexone extended-release injection for opioid use disorder

ABSTRACT Background: Opioid use disorder (OUD) continues to be major public health problem in the US and innovative medication strategies are needed. The extended-release injectable formulation of naltrexone (ER-NTX), an opioid receptor antagonist, is an effective treatment for OUD, but the need for an opioid-free period during the induction phase of treatment is a barrier to treatment success, particularly in the outpatient setting. Lofexidine, an alpha-2-adrenergic agonist, is an effective treatment for opioid withdrawal. Objectives: To evaluate the feasibility, safety, and tolerability of lofexidine for facilitating induction onto ER-NTX in the management of OUD. Methods: In an open-label, uncontrolled, 10-week outpatient clinical trial, 20 adults (four women) with OUD were treated with a fixed-flexible dosing strategy (maximum 0.54 mg 4×/daily) of lofexidine for up to 10 days to manage opioid withdrawal prior to receiving ER-NTX. The COVID-19 pandemic resulted in a modification of the study methods after enrolling 10 participants who attended all visits in person. The second group of 10 participants attended most induction period visits remotely. Results: Overall, 10 of the 20 participants (50%) achieved the primary outcome by receiving the first ER-NTX injection. Rates of induction success did not differ by the presence of fentanyl or remote visit attendance, although the small sample size provided limited statistical power. Six out of 20 participants (30%) initiated on lofexidine required dose adjustments. There were no study-related serious adverse events. Conclusions: This study provides preliminary evidence supporting the feasibility of inducting individuals with OUD onto ER-NTX using lofexidine.

Dietary supplements to reduce symptom severity and duration in people with SARS-CoV-2: a double-blind randomised controlled trial

BackgroundCOVID-19 has caused morbidity, hospitalisation and mortality worldwide. Despite effective vaccines, there is still a need for effective treatments, especially for people in the community. Dietary supplements have long been...