Completed Trials Research Articles

Assessment of Inflammatory Biomarkers and Incident Atrial Fibrillation in Older Adults.

Available evidence supports the importance of inflammation in atrial fibrillation (AF) pathogenesis, yet general anti-inflammatory therapies have failed to show benefit for prevention of the arrhythmia. Better understanding of the specific inflammatory pathways involved is necessary to advance therapeutics. We evaluated 9 circulating markers of inflammation measured by immunoassays and incidence of AF in a population-based older cohort. Biomarkers included measures of general inflammation and the NLR (nucleotide-binding oligomerization domain-like receptor) family pyrin domain containing 3 inflammasome, TNF-α (tumor necrosis factor α), monocyte activation markers, and sIL-2 (soluble interleukin-2). Among 5726 participants (median age 72 years), 1836 developed AF over median follow-up of 11.5 years. After adjustment for conventional risk factors, 5 biomarkers were positively associated with incident AF: IL-6 (interleukin-6), hazard ratio (HR), 1.14 (95% CI, 1.07-1.21); hs-CRP (high-sensitivity C-reactive protein), HR, 1.05 (95% CI, 1.01-1.09); white blood cell count, HR, 1.18 (95% CI, 1.04-1.35); sTNFR1 (soluble TNF receptor 1), HR, 1.21 (95% CI, 1.05-1.39); and sIL-2Rα (sIL-2 receptor α), HR, 1.16 (95% CI, 1.05-1.29) (all per doubling of biomarker). sCD14, sCD163, IL-18, and IL-1 receptor antagonist showed no association with AF. Upon concurrent adjustment for all biomarkers, only IL-6 remained significantly associated with the arrhythmia, HR, 1.17 (95% CI, 1.07-1.26). Among older adults, IL-6, hs-CRP, white blood cell count, sTNFR1, and sIL-2Rα were positively associated with incident AF, but only IL-6 retained significance on concurrent adjustment. These findings newly document associations for sTNFR1 and sIL-2Rα and lend support to a preeminent role for IL-6 in development of this arrhythmia. The efficacy of IL-6 blockade for AF prevention awaits completion of appropriate clinical trials.

Use of mesoglycan in the acute phase of hemorrhoidal disease (the CHORMES study): study protocol for a double-blind, randomized controlled trial

BackgroundHemorrhoidal disease (HD) is associated with substantial economic burden and negative effects on health-related quality of life (HRQoL). The aCute HaemORrhoids treatment with MESoglycan (CHORMES) study aims to evaluate the effects of orally administered mesoglycan, a natural preparation of glycosaminoglycans with antithrombotic and profibrinolytic properties, as an acute treatment in patients with HD.MethodsCHORMES is a phase 2, double-blind, randomized controlled trial being conducted at two centers in Italy. Adults aged 18–75 years with Grade I–III HD according to Goligher classification or external thrombosed hemorrhoids, and a Hemorrhoidal Disease Symptom Score (HDSS) of ≥ 5, will be randomly allocated in a 1:1 ratio to mesoglycan or placebo and will be treated for 40 days (two capsules for the first 5 days and one capsule for the subsequent 35 days twice daily [after breakfast and dinner], equivalent to 200 mg in the first 5 days and 100 mg subsequently). Concomitant use of analgesics is permitted in both treatment groups. The trial aims to enroll 50 patients, with 25 patients in each treatment group. The primary objective of the trial is to evaluate the efficacy of mesoglycan in reducing symptoms of HD, assessed via change in HDSS from baseline (day 0) to day 40 in the intention-to-treat population. Secondary objectives include changes in HRQoL from baseline to day 40 using the Short Health Scale for Hemorrhoidal Disease, safety (adverse effects, physical assessments, vital signs and laboratory parameters in the safety population), fecal continence assessed using the Vaizey score, bleeding assessed using the Bleeding score, the amount and type of analgesic taken, and pain. Patient enrolment began on 11 December 2023, and trial completion is expected by December 2024.DiscussionThe CHORMES trial will evaluate the efficacy and safety of mesoglycan, in addition to its impact on HRQoL, analgesic use and pain, in patients with HD. The results of the trial will assist clinicians in determining the most effective treatment for patients with HD.Trial registrationClinicalTrials.gov NCT06101992. Prospectively registered on 26 October 2023 at https://clinicaltrials.gov/ct2/show/NCT06101992.

Hydroxyurea therapy for neurological and cognitive protection in pediatric sickle cell anemia in Uganda (BRAIN SAFE II): Protocol for a single-arm open label trial

BackgroundChildren with sickle cell anemia (SCA) in Sub-Saharan Africa are at high risk of sickle cerebrovascular injury (SCVI). Hydroxyurea, a commonly used disease-modifying therapy, may reduce SCVI resulting in potential impact on reducing stroke and cognitive dysfunction. We aim to test the impact of daily hydroxyurea therapy on these outcomes in Ugandan children with SCA. We hypothesized that hydroxyurea therapy over 36 months will prevent, stabilize or improve these complications of SCA. MethodsThe BRAIN SAFE II study is an open label, single arm trial of daily hydroxyurea in 270 children with SCA (HbSS) in Uganda, ages 3–9 years. Following baseline assessments, participants began hydroxyurea therapy and are followed according to local guidelines. Standard hydroxyurea dose is escalated to maximum tolerated dose (MTD). SCVI is assessed by cerebral arterial velocity using Doppler ultrasound, with cognitive function determined by formal neurocognitive testing (primary outcomes). Structural SCVI is assessed by magnetic resonance imaging (MRI) and angiography (MRA) in a sub-sample of 90 participants ages >5 years. At trial midpoint (18 months) and completion (36 months), outcomes of age-specific assessments will be compared to baseline, as well as biomarkers of anemia, inflammation and malnutrition (secondary outcomes) to determine their relationships to primary outcomes. ConclusionThis trial will examine the impact of hydroxyurea on preventing or ameliorating SCA SCVI in children, assessed by reducing incident stroke, stroke risk and neurocognitive dysfunction. Trial results will provide critical insight into the role of hydroxyurea therapy on critical manifestations of SCVI in children with SCA. Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04750707 (registered 11 February 2021). Protocol versionBRAIN SAFE II Protocol Version 3.0, Mar 02, 2022.

Formulation development of dual-compartment topical inserts combining Tenofovir Alafenamide and Elvitegravir for flexible on-demand HIV prevention

Pre-exposure prophylaxis (PrEP) has emerged as a prominent approach for the prevention of HIV infections. While the latest advances have resulted in effective oral and injectable product options, there are still gaps in on-demand, event-driven, topical products for HIV prevention that are safe and effective. Here we describe the formulation development of a dual-compartment topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) that may be administered when needed, vaginally or rectally, pre- or post-coitus, for flexible HIV prophylaxis. Specifically, we describe the lab-scale formulation development, preclinical mucosal safety and pharmacokinetics (PK) testing in rabbits, long-term stability, and scale-up clinical manufacturing of the lead TAF/EVG (20 mg/16 mg) inserts, which are currently in clinical stages of development. As designed, the inserts are small, discreet and portable, offering a number of promising attributes, such as simple and robust direct-compression manufacturing, fast initial disintegration/dissolution, and suitable mechanical strengths showing low hardness (<8 kg), friability (<1 %), and moisture content (<1 %). The inserts initiated disintegration quickly (~ ≤ 15 min) providing full in vitro release (>90 %) of TAF and EVG within 60 min of dissolution. The lead insert was selected from formulation prototypes that met the evaluation criteria for manufacturability and characterization, together with a dose-ranging PK study in non-human primates. Successful technology transfer for clinical development of the lead TAF/EVG (20 mg/16 mg) insert was confirmed under cGMP conditions. Based on the 12 months (lab-scale) and 24 months (clinical batch) stability data, the TAF/EVG inserts are projected to have a long shelf life of over 2 years, if stored at or below 30 °C/65 % RH. Overall, these newly designed topical inserts have formulation properties that enable stable storage and fast release of the antiretroviral payload from a small, portable and discreet dosage form. They are safe and effective when applied vaginally or rectally, before or after coitus, providing the basis for a new method of flexible on-demand HIV prevention for cisgender and transgender women and men. The TAF/EVG inserts are currently the most clinically advanced on-demand topical product, as attested by their completed and ongoing clinical trials.

Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study.

Findings from Kronos Early Estrogen Prevention Study (KEEPS)-Cog trial suggested no cognitive benefit or harm after 48 months of menopausal hormone therapy (mHT) initiated within 3 years of final menstrual period. To clarify the long-term effects of mHT initiated in early postmenopause, the observational KEEPS Continuation Study reevaluated cognition, mood, and neuroimaging effects in participants enrolled in the KEEPS-Cog and its parent study the KEEPS approximately 10 years after trial completion. We hypothesized that women randomized to transdermal estradiol (tE2) during early postmenopause would show cognitive benefits, while oral conjugated equine estrogens (oCEE) would show no effect, compared to placebo over the 10 years following randomization in the KEEPS trial. The KEEPS-Cog (2005-2008) was an ancillary study to the KEEPS (NCT00154180), in which participants were randomized into 3 groups: oCEE (Premarin, 0.45 mg/d), tE2 (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d for 12 d/mo) or placebo pills and patch for 48 months. KEEPS Continuation (2017-2022), an observational, longitudinal cohort study of KEEPS clinical trial, involved recontacting KEEPS participants approximately 10 years after the completion of the 4-year clinical trial to attend in-person research visits. Seven of the original 9 sites participated in the KEEPS Continuation, resulting in 622 women of original 727 being invited to return for a visit, with 299 enrolling across the 7 sites. KEEPS Continuation participants repeated the original KEEPS-Cog test battery which was analyzed using 4 cognitive factor scores and a global cognitive score. Cognitive data from both KEEPS and KEEPS Continuation were available for 275 participants. Latent growth models (LGMs) assessed whether baseline cognition and cognitive changes during KEEPS predicted cognitive performance at follow-up, and whether mHT randomization modified these relationships, adjusting for covariates. Similar health characteristics were observed at KEEPS randomization for KEEPS Continuation participants and nonparticipants (i.e., women not returning for the KEEPS Continuation). The LGM revealed significant associations between intercepts and slopes for cognitive performance across almost all domains, indicating that cognitive factor scores changed over time. Tests assessing the effects of mHT allocation on cognitive slopes during the KEEPS and across all years of follow-up including the KEEPS Continuation visit were all statistically nonsignificant. The KEEPS Continuation study found no long-term cognitive effects of mHT, with baseline cognition and changes during KEEPS being the strongest predictors of later performance. Cross-sectional comparisons confirmed that participants assigned to mHT in KEEPS (oCEE and tE2 groups) performed similarly on cognitive measures to those randomized to placebo, approximately 10 years after completion of the randomized treatments. These findings suggest that mHT poses no long-term cognitive harm; conversely, it provides no cognitive benefit or protective effects against cognitive decline. In these KEEPS Continuation analyses, there were no long-term cognitive effects of short-term exposure to mHT started in early menopause versus placebo. These data provide reassurance about the long-term neurocognitive safety of mHT for symptom management in healthy, recently postmenopausal women, while also suggesting that mHT does not improve or preserve cognitive function in this population.

Thapsigargin and its prodrug derivatives: exploring novel approaches for targeted cancer therapy through calcium signaling disruption.

Thapsigargin, a sesquiterpene lactone derived from Thapsia garganica L., has demonstrated mixed potential as an anticancer agent due to its potent ability to disrupt calcium signaling and induce apoptosis. This review evaluates the chemopreventive and chemotherapeutic potential of thapsigargin, focusing on its molecular mechanisms and toxicity. An extensive literature review of studies published since 2015 was conducted using databases such as PubMed/MedLine and Science Direct. Findings indicate that thapsigargin's primary mechanism is the inhibition of sarco/endoplasmic reticulum calcium ATPase, leading to endoplasmic reticulum stress and cell death in various cancer types. Despite these effects, thapsigargin's non-specific cytotoxicity results in significant side effects, including organ damage and histamine-related reactions. Recent advances in targeted delivery, especially with the prodrug mipsagargin, initially suggested promise in minimizing these toxicities by selectively activating in cancer cells expressing prostate-specific membrane antigen (PSMA). However, the completion of clinical trials with no ongoing studies suggests that the viability of mipsagargin and other prodrugs remains uncertain, especially in light of the toxicities observed. While thapsigargin and its derivatives present a potential pathway in cancer treatment, their future role in oncology requires careful re-evaluation.

Worldwide Clinical and Real-World Exposure to Baricitinib

Introduction: Baricitinib (BARI), an oral selective JAK inhibitor, is approved in many geographies for adults with rheumatoid arthritis or alopecia areata and for patients as young as age 2 years with atopic dermatitis or juvenile idiopathic arthritis. It is also approved in the US for hospitalized patients with COVID-19 infection. We report the worldwide clinical trial and real-world exposure to BARI across a range of diseases, ages and racial backgrounds. Methods: Real-world patient exposure estimates were calculated based on total mg sold, average daily dose, and average length of therapy as reported to regulatory agencies through the cumulative timeframe ending Jan. 31, 2024. Clinical trial exposures were based on actual exposures from completed trials through Feb. 13, 2024, and estimates were made for ongoing blinded trials based on the enrolment/randomization schemes Results: In the real-world setting, an estimated 1,836,600 patients have been exposed to the following BARI doses: 1 mg, ~2,000 (0.1%); 2 mg, ~524,900 (28.6%); 4 mg, ~1,309,600 (71.3%). Of these estimated exposures, ~ 57% were for COVID-19 with the remaining for all other indications combined. Across 59 clinical trials (completed and ongoing), an estimated 14,660 subjects (548 healthy volunteers and 14,112 patients) have received BARI since June 2008. Exposures from completed studies include 10,276 patients (62% female), 399 of whom were &lt;18 yrs of age (≤1 month, N=4; 1 month - ≤2 yrs, N=24; &gt;2 - ≤12 yrs, N=111; &gt;12 - ≤18 yrs, N=260), 8820 were &gt;18 to ≤65 yrs, 1027 were &gt;65 yrs, and 30 had age unknown. An additional 467 adolescent and pediatric patients down to the age of 2 have been treated with BARI for atopic dermatitis in an ongoing clinical trial, bringing the total number of patients &lt;18 years of age to 866 across dermatologic, rheumatologic, other autoimmunologic, and acute infectious diseases (excluding alopecia areata for which there is an ongoing pediatric trial). Clinical trial exposures by racial and ethnic background are as follows: Asian, N=2,491; Black, N=450; Caucasian, N=6,237; other, N=496; multiple, N=135; unknown, N=467. Conclusion: There has been extensive real-world exposure to BARI across indications and populations, and BARI is a well-studied molecule in clinical trials, across varied disease states, racial populations and ages. Since average daily dose and length of therapy may vary over time, real-world exposures are only an estimate of total patients receiving BARI. Exposures in clinical trials include patients as young as less than 1 month of age up to patients over the age of 65 years. While these exposures do not indicate efficacy or safety, they provide data to establish the overall profile of the drug and can inform on its performance over time across a variety of populations.

Feasibility of recruiting young adults with low socioeconomic status for formative evaluation of a smoking cessation mobile intervention.

Participant recruitment is critical to the success of smoking cessation trials. However, recruitment feasibility studies for inclusion and exclusion criteria commonly used in smoking cessation research remain scarce. We assessed the feasibility of recruiting potential research volunteers (PRVs) under two sets of inclusion criteria to inform eligibility requirements for a smoking cessation mobile intervention trial. We invited PRVs nationwide to participate in qualitative evaluation of a smoking cessation mobile application. To be eligible under Criteria I, participants were aged 18-29 years, neither four-year college graduates nor enrollees, exclusive cigarette smokers, willing to quit within 30 days, and not using cessation aids. Criteria II expanded eligibility to those using cigarettes and non-combustible tobacco products (e.g. e-cigarettes) and willing to quit within 6 months. We calculated recruitment yields and associated costs. Of 10533 PRVs screened for eligibility, 48 were enrolled. Only 54 (0.5%) participants qualified under Criteria I and 164 (1.6%) under Criteria II. Age ineligibility was the top reason for exclusion (66.7%), whereas lifetime smoking, quit timeframe, and other tobacco product use contributed to ineligibility rates ranging from 46.5% to 65.3%. Enrolled participants were equally split by sex and roughly reflected the racial/ethnic composition of the United States. American Indians, who have the highest smoking prevalence, were <5% of enrolled participants. Recruitment costs averaged $106 per PRV. Eligibility requirements used in cessation trials were restrictive for recruitment efforts. Relaxing inclusion criteria will reflect current tobacco use patterns and facilitate the timely completion of trials within budgetary thresholds.

Abstract 4137516: Disparities in Participation: Analyzing Age, Sex, Race, and Ethnicity in Atrial Fibrillation Clinical Trials in the United States

Introduction: Atrial fibrillation (AF) is a prevalent cardiovascular disease that significantly impacts public health in the United States. Although numerous clinical trials aim to optimize AF management, concerns about demographic disparities in trial participation persist. This study assesses the representation of age, sex, race, and ethnicity among participants in AF trials conducted in the US, highlighting potential biases that could affect the generalizability of trial outcomes. Methods: An extensive review of clinical trials registered on ClinicalTrials.gov involving patients with AF up to April 2024 was performed. The search was filtered to include all completed interventional trials across phases 2 to 4 without restrictions on the initiation or completion dates. Data were extracted concerning mean age, age distribution, sex, and the racial and ethnic composition of the trial participants. Results: From the 173 trials analyzed, a total of 1,355,239 participants were included, with an average age of 64.7 years. The demographic breakdown revealed a participant pool consisting predominantly of older adults (&gt;65 years: 70.8%), with a significant underrepresentation of the younger age group (18-65 years: 29.2%). Males constituted 65.2% of the trial population, highlighting a gender imbalance. Racially, 74.1% of participants were White, while African Americans (7.7%) and Asians (5.9%) and other racial groups were notably underrepresented. Ethnic disparities were also evident, with Hispanic participants making up only 11.5% of the study population. Conclusion: The findings demonstrate significant disparities in the age, sex, race, and ethnic backgrounds of AF clinical trial participants in the US. These imbalances could potentially limit the applicability of trial results across the broader, diverse population. Efforts to enhance the diversity of clinical trial cohorts are essential to ensure more equitable health outcomes and the universal applicability of clinical research findings. Future strategies should focus on targeted recruitment and inclusive study designs to address these disparities.

Safety reporting in trials on glaucoma interventions registered in ClinicalTrials.gov and corresponding publications

Accurate, comprehensive, and consistent reporting of adverse events is of great importance for treatment decisions in clinical practice and patient safety. Aiming to evaluate the completeness and transparency of reported adverse events we conducted a retrospective analysis of completed clinical trials on glaucoma interventions registered in ClinicalTrials.gov from September 27, 2009, and updated and with results on or before November 1, 2023, as well as in corresponding journal publications. Any difference in completeness, number, or terminology/description of adverse events and all-cause mortality between ClinicalTrials.gov and the publication was categorized as inconsistent reporting of adverse events. All 79 trials with results both in the registry and a journal publication exhibited at least one inconsistency in reporting adverse events. In 19 publications (24%), the number of serious adverse events was smaller than in the registry. 69 (87%) trials reported more other adverse events in the registry than in the publication. Trials completed after the FDAA mandate for summary reporting of all-cause mortality more often reported this item in the registry but not in the publication. Trials on glaucoma interventions do not consistently report adverse events and thus introduce concerns about study credibility and potential harms of the interventions. Journals and other stakeholders in trial reporting must address this problem to ensure the safety of patients and trust in health interventions.

Regional cerebral perfusion and sympathetic activation during exercise in hypoxia and hypercapnia: preliminary insight into'Cushing's mechanism'.

We examined the interactive influence of hypoxia and exercise, and hypercapnia and exercise,on regional cerebral perfusion and sympathetic activation. Twenty healthy young adults (seven women) completed study trials including (1) rest in normoxia ( : ∼96%, : ∼36mmHg), normocapnic hypoxia ( : ∼84%, : ∼36mmHg), and normoxic hypercapnia ( : ∼98%, : ∼46mmHg) and (2) unilateral rhythmic handgrip exercise (45% of maximal voluntary contraction at 1Hz for 3min) under the same gas conditions. Based on the exercising arm, blood flow in the contralateral internal carotid (ICABF) and ipsilateral vertebral (VABF) arteries, anterior and posterior cerebral O2 delivery ( ), and muscle sympathetic nerve activity (MSNA) were measured in each trial. During exercise in hypoxia, ICABF, VABF, anterior and posterior were significantly lower, whereas total MSNA was significantly greater, than the sum of the responses evoked by either hypoxia or exercise alone. During exercise in hypercapnia, ICABF and anterior were significantly greater, whereas MSNA was lower, than the sum of the responses evoked by either hypercapnia or exercise alone. The VABF and posterior responses to hypercapnic exercise were not different from the summated responses. These findings suggest that the brain is hypoperfused and sympathetic outflow potentiated during hypoxic exercise, and that the brain is hyperperfused and sympathetic discharge constrained during hypercapnic exercise. The contrasting consequences for cerebral perfusion and sympathetic activation indicate a potential involvement of Cushing's mechanism in the autonomic control during exercise in healthy humans. KEY POINTS: Brain O2-demand and -supply are mismatched, and muscle sympathetic nerve activity (MSNA) is enhanced in humans exercising at high altitude; the link between the two phenomena remains elusive. We evaluated the isolated and interactive effects of exercise, hypoxia, and hypercapnia on blood flow in the internal carotid (ICABF) and vertebral (VABF) arteries, and MSNA. The interaction of hypoxia and exercise was hypo-additive for ICABF and VABF and anterior and posterior cerebral O2 delivery ( ), but hyper-additive for MSNA. The interaction of hypercapnia and exercise was hyper-additive for ICABF and anterior , additive for VABF and posterior , and hypo-additive for MSNA. These observations indicate that a suboptimal brain perfusion during hypoxic exercise coincides with a potentiated sympathetic outflow, while a (supra-)optimal brain perfusion during hypercapnic exercise coincides with a suppressed sympathetic outflow. Our findings suggest that Cushing's mechanism may play a role in the autonomic control in exercising humans.

Pragmatic monitoring of emerging efficacy data in randomized controlled trials.

Monitoring the conduct of phase III randomized controlled trials is driven by ethical reasons to protect the study integrity and the safety of trial participants. We propose a group sequential, pragmatic approach for monitoring the accumulating efficacy information in randomized controlled trials. The "Population Health Research Institute boundary" is simple to implement and sensible, as it considers the reduction in uncertainty with increasing information as the study progresses. It is also pragmatic, since it takes into consideration the typical monitoring behavior of monitoring committees of large multicenter trials and is relatively easily implemented. It not only controls the overall Lan-DeMets type I error probability (alpha) spent, but performs better than other group sequential boundaries for the total nominal study alpha. We illustrate the use of our monitoring approach in the early termination of two past completed trials.

Anticancer Effects of New Disulfiram Analogs.

Disulfiram (DSF), an irreversible aldehyde dehydrogenase 2 (ALDH2) inhibitor, is an U.S. Food and Drug Administration (FDA)-approved drug for the treatment of chronic alcoholism. Recent studies have reported an interesting antitumor activity of DSF against a wide range of human malignancies, while a growing number of ongoing and completed clinical trials have provided evidence supporting the repurposing of DSF as an anticancer treatment. Nevertheless, despite its current clinical indications and potential future therapeutic applications for treating various diseases, DSF is associated with serious side effects attributed to the inhibition of ALDH2. We have recently synthesized DSF analogs (2a-v) with limited inhibition of ALDH2. Here, we report the anticancer activity of these molecules by highlighting their effects on cell signaling in Jurkat cells. DSF and two DSF analogs, 2g and 2r, all stimulated apoptotic signaling pathways, although the 2g analog activated more apoptosis-related genes and induced higher levels of apoptosis in vitro. Differential gene expression data suggested that compounds 2g and 2r specifically reprogram target cells to downregulate pathways related to cell growth and division, while upregulating pathways related to apoptosis or differentiation. Interestingly, both compounds 2g and 2r had more differentially expressed genes related to DNA damage pathways (including those related to apoptosis) when compared to DSF, which may offer insights into their mechanisms of action.

The effect of BCG vaccination in the elderly on infectious and non-infectious immune-mediated diseases

Previous research has suggested beneficial heterologous effects of the Bacillus Calmette-Guérin (BCG) vaccine on non-mycobacterial infections and other immune-mediated diseases. During the COVID-19 pandemic, randomized controlled trials BCG-PRIME (n=5349) and BCG-CORONA-ELDERLY (n=1907) investigated the impact of BCG on SARS-CoV-2 infections in older individuals. We extended the follow-up in these studies by one year (BCG-Long Term study), to assess the overall effects of BCG vaccination on infectious and immune-mediated diseases in individuals aged over 60. Prior participants were invited to complete a one-year follow-up survey after their completion of the original trial. Data on vaccinations, hospital admissions, infectious episodes, and new medical diagnoses were collected and compared between BCG- and placebo-vaccinated participants. Variables of interest were combined with the previous trial databases and analyzed using relative risks (RR) and an adjusted Cox regression model accounting for participation probability. The response in the follow-up survey was 60%, including 4238 individuals in the final analysis (2317 had received BCG and 1921 placebo). Incidence and severity of infectious diseases and other diagnoses, including cardiovascular diseases and cancer, did not differ between the groups. The proportion of individuals hospitalized for cardiac arrhythmias after BCG was two-fold higher than reported after placebo (1.6% versus 0.8%, RR 2.0 (95% confidence interval 1.1-3.6)). Cardiac arrhythmia-related hospitalizations were primarily due to exacerbation of pre-existing arrhythmias. The results of the present study confirm that BCG has no relevant effect on non-mycobacterial infectious diseases and other immune-mediated diseases in a population of generally mycobacteria-naïve older Dutch individuals in the two years following vaccination. However, our study suggests that BCG may aggravate pre-existing cardiac arrhythmia, which warrants further investigation.

Effects of a low-cost prosthetic knee on amputee gait over uneven and even terrains.

Limited data are available related to using a low-cost prosthetic knee while walking. To address this gap, this study compared the performance of a low-cost prosthetic knee with 2 more advanced prosthetic knees while walking on even and uneven terrains. Two adult subjects with above-knee amputations completed walking trials using a low-cost prosthetic knee (ReMotion knee) and their personal prosthetic knees (Ottobock 3R60 Pro mechanical knee and Ossur Rheo microprocessor knee) over even and uneven terrains. Several measures of gait performance were obtained including step size, stability, energy expenditure, as well as user perception of ReMotion workload and performance during gait. Effects of the ReMotion knee were different between the mechanical and microprocessor knee user. In addition, subjects perceived the positive aspects associated with the ReMotion knee to be its lightweight feature and their perceived increased in stability during walking while both subjects disliked the inability of the ReMotion knee to adjust to preferred walking speeds. This study provided an understanding of low-cost prosthetic technology among lower-limb amputees compared to prosthetic technology with more technologically advanced assistance. These findings may help guide future low-cost prosthetic knee design considerations for use on various terrains.

Multiscale, mechanistic model of Rheumatoid Arthritis to enable decision making in late stage drug development

Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease that affects about 0.1% to 2% of the population worldwide. Despite the development of several novel therapies, there is only limited benefit for many patients. Thus, there is room for new approaches to improve response to therapy, including designing better trials e.g., by identifying subpopulations that can benefit from specific classes of therapy and enabling reverse translation by analyzing completed clinical trials. We have developed an open-source, mechanistic multi-scale model of RA, which captures the interactions of key immune cells and mediators in an inflamed joint. The model consists of a treatment-naive Virtual Population (Vpop) that responds appropriately (i.e. as reported in clinical trials) to standard-of-care treatment options—Methotrexate (MTX) and Adalimumab (ADA, anti-TNF-α) and an MTX inadequate responder sub-population that responds appropriately to Tocilizumab (TCZ, anti-IL-6R) therapy. The clinical read-outs of interest are the American College of Rheumatology score (ACR score) and Disease Activity Score (DAS28-CRP), which is modeled to be dependent on the physiological variables in the model. Further, we have validated the Vpop by predicting the therapy response of TCZ on ADA Non-responders. This paper aims to share our approach, equations, and code to enable community evaluation and greater adoption of mechanistic models in drug development for autoimmune diseases.

Impact of Discontinuing Both Hypertonic Saline and Dornase Alfa after Elexacaftor-Tezacaftor-Ivacaftor in Cystic Fibrosis.

Rationale: Evaluating approaches to reduce treatment burden is a research priority among people with cystic fibrosis on highly effective modulators, including elexacaftor-tezacaftor-ivacaftor (ETI). Objectives: We sought to evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods: SIMPLIFY participants ≥12 years old on ETI and constituting a subgroup using both HS and DA at study entry were randomized to the HS or DA trial and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run-in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY and a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth, and percent predicted forced expiratory volume in 1 second (ppFEV1) at study entry. Results: Forty-three participants discontinued both therapies by the end of SIMPLIFY, and 63 remained on both, with overall average ppFEV1 of 96.7% at study entry and 3.9 months as the average duration of follow-up from beginning of the first trial to completion of the second trial, including time between trials. No clinically meaningful difference in the change in ppFEV1 from baseline to completion of the second trial was observed between those who discontinued and those who remained on both therapies (difference: 0.22% off-on; 95% confidence interval = -1.60, 2.03). Changes in lung clearance index at 2.5% starting concentration, patient-reported outcomes, and safety outcomes were also comparable. Patient-reported treatment burden, as measured by a Cystic Fibrosis Questionnaire-Revised subscale, significantly decreased in those who discontinued both therapies. Conclusions: SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared with those who remained on both therapies. These data continue to inform a new era of postmodulator care of people with cystic fibrosis.

Qualitative study exploring reintegration of clinical trial participants with HIV to public health services in Johannesburg, South Africa

ObjectivePeople living with HIV (PLHIV) are often recruited from primary healthcare clinics (PHC) into clinical trials. On trial completion, they are transferred back to the facility for continued care and...

The influence of menstrual cycle phase on isokinetic knee flexor and extensor strength in female soccer players: a pilot study

ABSTRACT The prevalence of anterior cruciate ligament injury in female soccer players has been attributed to hormonal fluctuations during the menstrual cycle (MC), with injury incidence greatest during the follicular phase. Eight, eumenorrheic, collegiate soccer players (19.5 ± 0.75 years, 1.62 ± 4.90 cm, 61.12 ± 7.6 kg mean ± SD) completed eccentric knee flexor and concentric knee extensor trials at 60 and 240°·s−1 during the follicular, ovulation and luteal phases of their MC. Peak torque and corresponding angle of peak torque were maintained across all phases of the MC, irrespective of testing modality and speed (p ≥ 0.149). Strength ratios defined using peak torque were also not sensitive to MC phase (p ≥ 0.933). However, Functional Range in eccentric knee flexion was significantly lower during the follicular phase (p = 0.017), at both testing speeds. This supports epidemiological observations but highlights the importance of analysing isokinetic data beyond the peak of the strength curve. Interpretation of isokinetic data should therefore focus on points of “weakness” as opposed to maximum strength, whilst (p)rehabilitative strategies should consider strength through range of motion, and at different speeds. Eccentric hamstring strength was observed to decrease significantly at the higher speed, contrary to observations in elite male players, and potentially reflecting a differential training adaptation.

Factors associated with non-publication of clinical trials in cardiovascular medicine: a cross-sectional analysis

Abstract Background/introduction Cardiovascular medicine is the fourth most-funded area of clinical research as it received an estimate for 7% of the total research funding. Nearly 8% of all clinical trials are cardiovascular-related (1,2). Non-publication of the registered clinical trials wastes money and time, encourages dissemination bias, and creates a body of possibly inaccurate literature, all of which obstruct scientific advancement. (3) Purpose To study the factors associated with the non-publication of cardiovascular clinical trials between January 2000 and June 2022. Methods We performed a cross-sectional analysis using ClinicalTrials.gov to determine all completed, discontinued, published, and unpublished cardiovascular medicine clinical trials between January 2000 and June 2022. For each trial, data on the trial phase, funding source, intervention type, enrolment size, trial completion, and publication status were extracted and subjected to logistic regression to determine clinical trial publication predictor factors. Results Among 3946 trials in cardiovascular medicine registered in ClinicalTrials.gov, there were 3215 completed trials included in the analysis. Of these, 34.2% (n=1100) were unpublished. On multivariate logistic regression, triple-blinded and quadruple-blinded trials were less likely to be unpublished compared to open-label trials (odds ratio [OR] 0.622; 95% confidence interval [CI] 0.45-0.85; p=0.003) and (OR 0.54; CI 0.42-0.69; p&amp;lt;0.001), respectively. Enrolment of 100 participants or more was associated with a decreased likelihood of non-publication (OR 0.46; CI 0.39-0.55; p&amp;lt;0.001). In addition, randomised trials were less likely to be unpublished than non-randomised trials (OR 0.67; CI 0.50-0.88; p=0.004). There was no significant effect of the intervention type, phase of the trial, trial participants' age and gender, or the trial funding resource on the publication status of cardiovascular medicine clinical trials. Conclusions It is observed that a considerable number of clinical trials in cardiovascular medicine remain unpublished. This issue raises some concerns regarding the risks and discomfort participants may encounter during the trial, while no results are added to the literature. Blinding of the trials, enrolment size, and allocation methods are the main predictors of trial publication.Forest plot of logistic regression