Individuals In Clinical Trials Research Articles

First-in-Human Phase 1 Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of DISC-0974, an Anti-Hemojuvelin Antibody, in Healthy Participants.

Pathologic elevations in hepcidin, a key regulator of iron homeostasis, contribute to anemia of inflammation in chronic disease. DISC-0974 is a monoclonal antibody that binds to hemojuvelin and blocks bone morphogenetic protein signaling, thereby suppressing hepcidin production. Reduction of systemic hepcidin levels is predicted to increase iron absorption and mobilize stored iron into circulation, where it may be utilized by red blood cell (RBC) precursors in the bone marrow to improve hemoglobin levels and to potentially alleviate anemia of inflammation. We conducted a first-in-human, double-blind, placebo-controlled, single-ascending dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of DISC-0974 in healthy participants. Overall, 42 participants were enrolled and received a single dose of placebo or DISC-0974 at escalating dose levels (7-56mg), administered intravenously (IV) or subcutaneously (SC). DISC-0974 was well tolerated, with a safety profile comparable to that of placebo. Pharmacokinetic data was dose and route related, with a terminal half-life of approximately 7 days. The bioavailability of SC dosing was ∼50%. Pharmacodynamic data showed dose-dependent decreases in serum hepcidin, with reductions of nearly 75% relative to baseline at the highest dose level tested, and corresponding increases in serum iron in response to DISC-0974 administration. Dose-dependent changes in serum ferritin and hematology parameters were also observed, indicating mobilization of iron stores and downstream effects of enhanced hemoglobinization and production of RBCs. Altogether, these data are consistent with the mechanism of action of DISC-0974 and support the selection of a biologically active dose range for evaluation in clinical trials for individuals with anemia of inflammation.

Validation of a modified version of the gross motor function measure in PPPR5D related neurodevelopmental disorder

BackgroundProtein phosphatase 2 regulatory subunit B’ Delta (PPP2R5D)-related neurodevelopmental disorder is a rare genetic condition caused by pathogenic variants in the PPP2R5D gene. Clinical signs include hypotonia, gross motor delay, intellectual disability (ID), epilepsy, speech delays, and abnormal gait among other impairments. As this disorder was recognized within the last decade, there are only 103 people published diagnoses to date. A thorough understanding of the motor manifestations of this disorder has not yet been established. Knowledge of the natural history of PPP2R5D related neurodevelopmental disorder will lead to improved standard of care treatments as well as serve as a baseline foundation for future clinical trials. Appropriate outcome measures are necessary for use in clinical trials to uniformly measure function and monitor potential for change. The aim of this study was to validate the gross motor function measure (GMFM) in children and adults with PPP2R5D-related neurodevelopmental disorder in order to better characterize the disorder.ResultsThirty-eight individuals with PPP2R5D pathogenic variants, median age 8.0 years (range 1–27) were evaluated. Gross motor, upper limb and ambulatory function were assessed using the GMFM-66, six-minute walk test (6MWT), 10-meter walk run (10MWR), timed up and go (TUG), and revised upper limb module (RULM). The pediatric disability inventory computer adapted test (PEDI-CAT) captured caregiver reported assessment. Median GMFM-66 score was 60.6 (SD = 17.3, range 21.1–96.0). There were strong associations between the GMFM-66 and related mobility measures, 10MWR (rs = −0.733; p < 0.001), TUG (rs= −0.747; p = 0.003), 6MWT (r = 0.633; p = 0.006), RULM (r = 0.763; p < 0.001), PEDICAT-mobility (r = 0.855; p < 0.001), and daily activities (r = 0.822; p < 0.001) domains.ConclusionsThe GMFM is a valid measure for characterizing motor function in individuals with PPP2R5D related neurodevelopmental disorder. The GMFM-66 had strong associations with the RULM and timed function tests which characterized gross motor, upper limb and ambulatory function demonstrating concurrent validity. The GMFM-66 was also able to differentiate between functional levels in PPP2R5D related neurodevelopmental disorder demonstrating discriminant validity. Future studies should examine its sensitivity to change over time, ability to identify sub-phenotypes, and suitability as an outcome measure in future clinical trials in individuals with PPP2R5D variants.

The Moderating Effects of Cognitive Processes on Pain-related Outcomes

Although evidence supports the importance of pain-related thoughts (ie, cognitive content, or what people think) as predictors of pain and pain-related function, evidence regarding the role of cognitive processes (ie, how people think about pain, eg, by accepting pain, not making judgments about pain, or being absorbed by the pain experience) in adjustment to chronic pain is in its early stages. Using baseline data from a clinical trial of individuals with chronic low back pain (N = 327), the study aimed to increase knowledge regarding the associations between cognitive processes, pain intensity, pain interference, and depression. The results indicate that a number of cognitive processes are significantly related to pain intensity when controlling for catastrophizing, although the pattern of associations found was opposite to those anticipated. One cognitive process (pain absorption) was found to be significantly associated with pain interference, and 9 of 10 cognitive processes were significantly associated with depression when controlling for catastrophizing. In each case, the processes thought to be adaptive were negatively associated with pain interference and depression, and processes thought to be maladaptive evidenced the opposite pattern. The findings are consistent with—but do not prove, given the cross-sectional nature of the data—the possibility that cognitive processes play an important role in adjustment to chronic pain. The potential role these variables play in depression was particularly noteworthy. Longitudinal and experimental studies to evaluate the causal nature of the associations identified are warranted. PerspectiveThe study findings highlight the potential importance of cognitive process variables (ie, how people think) in adjustment to chronic pain. Research to evaluate cognitive processes as potential mechanism variables in pain treatment is warranted.

Navigating the outcome maze: a scoping review of outcomes and instruments in clinical trials in genetic neurodevelopmental disorders and intellectual disability.

Individuals with genetic neurodevelopmental disorders (GNDs) or intellectual disability (ID) are often affected by complex neuropsychiatric comorbidities. Targeted treatments are increasingly available, but due to the heterogeneity of these patient populations, choosing a key outcome and corresponding outcome measurement instrument remains challenging. The aim of this scoping review was to describe the research on outcomes and instruments used in clinical trials in GNDs and ID. Clinical trials in individuals with GNDs and ID for any intervention over the past 10 years were included in the review. MEDLINE, PsycINFO, and Cochrane CENTRAL were searched. Titles and abstracts were independently screened for eligibility with a subsample of 10% double-screening for interrater reliability. Data from full texts were independently reviewed. Discrepancies were discussed until consensus was reached. Information was recorded on patient populations, interventions, designs, outcomes, measurement instruments, and type of reporter when applicable. Qualitative and descriptive analyses were performed. We included 312 studies reporting 91 different outcomes, with cognitive function most frequently measured (28%). Various outcome measurement instruments (n = 457) were used, with 288 in only a single clinical trial. There were 18 genetic condition-specific instruments and 16 measures were designed ad-hoc for one particular trial. Types of report included proxy-report (39%), self-report (22%), clinician-report (16%), observer-report (6%), self-assisted report (1%), or unknown (16%). This scoping review of current practice reveals a myriad of outcomes and outcome measurement instruments for clinical trials in GNDs and ID. This complicates generalization, evidence synthesis, and evaluation. It underlines the need for consensus on suitability, validity, and relevancy of instruments, ultimately resulting in a core outcome set. A series of steps is proposed to move from the myriad of measures to a more unified approach.

Recruitment and Retention of Underrepresented Minorities in Interventional Alzheimer’s Disease Clinical Trials

AbstractBackgroundAlzheimer’s disease is a progressive neurodegenerative disorder that affects thinking, and behavior and is the most common cause of dementia. In Alzheimer’s disease (AD) clinical trials, there is a severe lack of underrepresented and marginalized populations. Despite overwhelming evidence that these groups are more likely to develop AD, various recruitment barriers impair them from being accepted into current AD clinical studies, which threatens these findings' overall generalizability and scientific impact. As a result, there is less understanding of overall needs, no mechanism for identifying and comparing disease variations, and a limited range of available interventions. In this study, we aim to analyze the recruitment, reporting, and retention strategies of Hispanic/Latinx and Black individuals in AD Clinical Trials for the last 35 years to create a novel model system to increase the diversity and inclusion of minoritized groups in Alzheimer’s Clinical Trials.MethodWe extracted the data from the clinicaltrials.gov database and applied the inclusion criteria: Year: 1999‐Present, Population: Older Adults (65&gt;), Alzheimer’s Diagnosed, and Healthy. Intervention: Pharmaceutical/drug. Funding: NIH, Industry. Status: Completed. For our outcome variables, we included the following: Reported and non‐reported recruitment demographic, the inclusion of white, Hispanic/Latin, Black/African American, Asian, and Unknown. For our analyses, we performed a Linear regression on cohort demographic makeup in five‐year intervals, reported vs. non‐reported demographic, and the percentage of ethnicity recruited.ResultOur search yielded n = 117 clinical trials. 28% of NIH‐sponsored drug‐based clinical trials have reported cohort demographic makeup. 61% of Industry‐sponsored drug‐based reported cohort demographic make‐up.ConclusionWe found that despite the increasing research focusing on the importance of the inclusion of underrepresented individuals in clinical trials. The number of underrepresented minorities in AD clinical trials continues to be significantly and alarmingly low, hindering the scientific process of developing therapeutic methods for Alzheimer’s Disease. Moreover, several laws and policies have been released to enforce the reporting of ethnicity/race of clinical trials cohort have not been adequately enforced and followed, raising concerns for policy efficacy.

Enrollment of Spanish-speaking Latinx adults in clinical trials: Five lessons learned from a randomized study in substance use treatment

Latinx individuals are the largest ethnic minoritized group in the United States (US) at 19% of the population. However, they remain underrepresented in clinical research, accounting for less than 8% of clinical trial participants. Consideration of cultural values could help overcome barriers to inclusion in clinical trials and result in better recruitment and retention of Latinx individuals. In this commentary, we describe general guidance on culturally responsive modifications to facilitate the successful recruitment and retention of Spanish-speaking Latinx participants in Randomized Clinical Trials (RCTs) for substance use. We identify five culturally responsive strategies to help enroll participants in RCTs: 1. Create an ethnically diverse research team, 2. Assess available community partners, 3. Familiarize oneself with the target community, 4. Establish confianza (trust) with participants, and 5. Remain visible to participants and staff from recruitment sites. Representation of Latinx individuals in clinical trials is essential to ensure treatments are responsive to their needs and equitydriven. Some of these strategies can further research in helping to promote the participation of Latinx individuals experiencing substance use concerns, including outreach to those not seeking treatment.

Qualitative Exploration in Exit Interviews of Changes Observed in Clinical Trials for Individuals with Autism Spectrum Disorder Without Intellectual Disability.

To explore, from the perspective of Study Partners (SPs; eg, caregivers) of clinical trial participants with autism spectrum disorder (ASD), any changes experienced in socialization and communication over the clinical trial, how these changes manifested, and the impact these changes had on the autistic individual, the SP, and family. This helps interpret whether changes in trial outcomes were meaningful. Interviews were conducted with the SPs of individuals with ASD, without intellectual disability, from 2 clinical trials: 86 children (aged 5-12 years) or adolescents (aged 13-17 years) who took part in the aV1ation trial (83.7% male), and 41 adults (aged 18+ years) who took part in the V1aduct trial (80.5% male). The primary endpoint for both trials was change from baseline in the VinelandTM-II two-domain composite, consisting of the mean of the Socialization and Communication domains. In these interviews the participants verbally indicated level of change for each of these key domains on 7-point change scales. Improvements in the Socialization domain enabled greater awareness of the feelings of others and allowed for stronger empathy and kindness. Improvements in the Communication domain allowed for the autistic individual to be better at listening and better at self-expression. Together, changes in these two domains, which were considered most important, allowed for richer, deeper relationships. Study Partners noted that improvements in these domains allowed for better integration within the family unit, decreased stress, and increased optimism about the autistic individual's future. The impacts of changes in either domain were synergistic, combining together to create positive experiences which in turn led to further positive impacts in other skills. These qualitative insights provide context to the changes that were observed during the clinical trial and captured using the VinelandTM-II, illustrating the meaning of these changes to the individuals with ASD without intellectual disability and their families, and the impact that they have on people's everyday lives and overall health-related quality of life.

Immune checkpoint inhibitors in elderly patients with lung cancer: evidence from phase 3 trials.

In this article, we aimed to summarize the results from recent phase III clinical trials that have evaluated the use of immune checkpoint inhibitors (ICIs) in elderly patients with lung cancer. Lung cancer is the second most diagnosed malignant tumor and the leading cause of cancer-related deaths worldwide. ICIs have a significant role in the treatment of lung cancer, both as monotherapy and combination therapy prolonged survival benefits. At present, a significant proportion of clinical patients comprise individuals aged 70 years or older. However, the inclusion of elderly patients, particularly in clinical trials involving immunotherapy, remains inadequate, with a limited number of participants from this age group. The lack of evidence regarding the use of ICIs in elderly patients is primarily attributed to the significant underrepresentation of elderly individuals in clinical trials. In this article, we summarize the results from recent phase III clinical trials that have evaluated the use of ICIs as first-line or second-line monotherapy, in combination with chemotherapy and other immunotherapies in elderly patients with lung cancer.

One episode of low intensity aerobic exercise prior to systemic AAV9 administration augments transgene delivery to the heart and skeletal muscle

IntroductionThe promising potential of adeno-associated virus (AAV) gene delivery strategies to treat genetic disorders continues to grow with an additional three AAV-based therapies recently approved by the Food and Drug Administration and dozens of others currently under evaluation in clinical trials. With these developments, it has become increasingly apparent that the high doses currently needed for efficacy carry risks of toxicity and entail enormous manufacturing costs, especially for clinical grade products. Strategies to increase the therapeutic efficacy of AAV-mediated gene delivery and reduce the minimal effective dose would have a substantial impact on this field. We hypothesized that an exercise-induced redistribution of tissue perfusion in the body to favor specific target organs via acute aerobic exercise prior to systemic intravenous (IV) AAV administration could increase efficacy.BackgroundAerobic exercise triggers an array of downstream physiological effects including increased perfusion of heart and skeletal muscle, which we expected could enhance AAV transduction. Prior preclinical studies have shown promising results for a gene therapy approach to treat Barth syndrome (BTHS), a rare monogenic cardioskeletal myopathy, and clinical studies have shown the benefit of low intensity exercise in these patients, making this a suitable disease in which to test the ability of aerobic exercise to enhance AAV transduction.MethodsWild-type (WT) and BTHS mice were either systemically administered AAV9 or completed one episode of low intensity treadmill exercise immediately prior to systemic administration of AAV9.ResultsWe demonstrate that a single episode of acute low intensity aerobic exercise immediately prior to IV AAV9 administration improves marker transgene delivery in WT mice as compared to mice injected without the exercise pre-treatment. In BTHS mice, prior exercise improved transgene delivery and additionally increased improvement in mitochondrial gene transcription levels and mitochondrial function in the heart and gastrocnemius muscles as compared to mice treated without exercise.ConclusionsOur findings suggest that one episode of acute low intensity aerobic exercise improves AAV9 transduction of heart and skeletal muscle. This low-risk, cost effective intervention could be implemented in clinical trials of individuals with inherited cardioskeletal disease as a potential means of improving patient safety for human gene therapy.

Positron Emission Tomography Quantitative Assessment of Off-Target Whole-Body Biodistribution of I-124-Labeled Adeno-Associated Virus Capsids Administered to Cerebral Spinal Fluid.

Based on studies in experimental animals demonstrating that administration of adeno-associated virus (AAV) vectors to the cerebrospinal fluid (CSF) is an effective route to transfer genes to the nervous system, there are increasing number of clinical trials using the CSF route to treat nervous system disorders. With the knowledge that the CSF turns over four to five times daily, and evidence in experimental animals that at least some of CSF administered AAV vectors are distributed to systemic organs, we asked: with AAV administration to the CSF, what fraction of the total dose remains in the nervous system and what fraction goes off target and is delivered systemically? To quantify the biodistribution of AAV capsids immediately after administration, we covalently labeled AAV capsids with iodine 124 (I-124), a cyclotron generated positron emitter, enabling quantitative positron emission tomography scanning of capsid distribution for up to 96 h after AAV vector administration. We assessed the biodistribution to nonhuman primates of I-124-labeled capsids from different AAV clades, including 9 (clade F), rh.10 (E), PHP.eB (F), hu68 (F), and rh91(A). The analysis demonstrated that 60-90% of AAV vectors administered to the CSF through either the intracisternal or intrathecal (lumbar) routes distributed systemically to major organs. These observations have potentially significant clinical implications regarding accuracy of AAV vector dosing to the nervous system, evoking systemic immunity at levels similar to that with systemic administration, and potential toxicity of genes designed to treat nervous system disorders being expressed in non-nervous system organs. Based on these data, individuals in clinical trials using AAV vectors administered to the CSF should be monitored for systemic as well as nervous system adverse events and CNS dosing considerations should account for a significant AAV systemic distribution.

OGTT Metrics Surpass Continuous Glucose Monitoring Data for T1D Prediction in Multiple-Autoantibody-Positive Individuals.

The value of continuous glucose monitoring (CGM) for monitoring autoantibody (AAB)-positive individuals in clinical trials for progression of type 1 diabetes (T1D) is unknown. Compare CGM with oral glucose tolerance test (OGTT)-based metrics in prediction of T1D. At academic centers, OGTT and CGM data from multiple-AAB relatives were evaluated for associations with T1D diagnosis. Participants were multiple-AAB-positive individuals in a TrialNet Pathway to Prevention (TN01) CGM ancillary study (n = 93). The intervention was CGM for 1 week at baseline, 6 months, and 12 months. Receiver operating characteristic (ROC) curves of CGM and OGTT metrics for prediction of T1D were analyzed. Five of 7 OGTT metrics and 29/48 CGM metrics but not HbA1c differed between those who subsequently did or did not develop T1D. ROC area under the curve (AUC) of individual CGM values ranged from 50% to 69% and increased when adjusted for age and AABs. However, the highest-ranking metrics were derived from OGTT: 4/7 with AUC ∼80%. Compared with adjusted multivariable models using CGM data, OGTT-derived variables, Index60 and DPTRS (Diabetes Prevention Trial-Type 1 Risk Score), had higher discriminative ability (higher ROC AUC and positive predictive value with similar negative predictive value). Every 6-month CGM measures in multiple-AAB-positive individuals are predictive of subsequent T1D, but less so than OGTT-derived variables. CGM may have feasibility advantages and be useful in some settings. However, our data suggest there is insufficient evidence to replace OGTT measures with CGM in the context of clinical trials.

Enrollment of Older Patients, Women, and Racial and Ethnic Minority Individuals in Valvular Heart Disease Clinical Trials: A Systematic Review.

Inadequate representation of older patients, women, and racial minority individuals in cardiovascular clinical trials limits both the generalizability of trial findings and inclusivity in access to novel therapies and therapeutic strategies. To report on temporal trends in the representation of older patients, women, and racial and ethnic minority individuals in clinical trials studying treatments for valvular heart disease. All published clinical trials enrolling more than 100 adults with any valvular heart disease published between 2005 and 2020 were included after searches with PubMed and ClinicalTrials.gov. Data on age, sex, race, and ethnicity reported in the included studies were collected. Trials were assigned to 4 time periods based on the publication date, and temporal trends were analyzed in the representation of older patients, women, and racial and ethnic minority individuals. A total of 139 clinical trials with 51 527 participants were identified. Of these trials, 103 (74%) investigated aortic valve disease and the remainder mitral valve disease. Overall, 63 trials (45.3%) enrolled patients only in Europe, 24 (17.3%) only in North America, and 19 (13.7%) in multiple geographical regions. The weighted mean (SD) age of enrolled patients was 68.4 (11.4) years, increasing nonsignificantly from 61.9 (5.9) years in 2005-2008 to 72.8 (9.6) years in 2017-2020 (P = .09 for trend). The overall proportion of women enrolled in valvular heart disease trials was 41.1%, with no significant changes over time. Data on race and ethnicity of trial participants were reported in 13 trials (9.4%), in which trial-level representation of American Indian/Alaska Native, Asian, Black/African American, Hispanic, and Native Hawaiian/Pacific Islander patients ranged from 0.27% to 43.9%. There were no significant temporal trends noted in the enrollment of racial and ethnic minority populations. The representation of women in clinical trials was positively associated with enrollment rates of older patients and underrepresented racial and ethnic groups. This review found that over the past 2 decades, women and racial and ethnic minority individuals have remained underrepresented in North American valvular heart disease clinical trials. Further work is needed to improve the reporting of race and ethnicity data and address barriers to trial enrollment for older patients, women, and racial and ethnic minority individuals.

Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS)

BackgroundAngelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms.MethodsFifty-five individuals with AS (aged < 5 years: n = 16, 5–12 years: n = 27, ≥ 18 years: n = 12; deletion genotype: n = 40, nondeletion genotype: n = 15) and 20 typically developing children (aged 1–12 years) were enrolled across six USA sites. Several clinical outcome assessments and digital health technologies were tested, together with overnight 19-lead electroencephalography (EEG) and additional polysomnography (PSG) sensors. Participants were assessed at baseline (Clinic Visit 1), 12 months later (Clinic Visit 2), and during intermittent home visits.ResultsThe participants achieved high completion rates for the clinical outcome assessments (adherence: 89–100% [Clinic Visit 1]; 76–91% [Clinic Visit 2]) and varied feasibility of and adherence to digital health technologies. The coronavirus disease 2019 (COVID-19) pandemic impacted participants’ uptake of and/or adherence to some measures. It also potentially impacted the at-home PSG/EEG recordings, which were otherwise feasible. Participants achieved Bayley-III results comparable to the available natural history data, showing similar scores between individuals aged ≥ 18 and 5–12 years. Also, participants without a deletion generally scored higher on most clinical outcome assessments than participants with a deletion. Furthermore, the observed AS EEG phenotype of excess delta-band power was consistent with prior reports.ConclusionsAlthough feasible clinical outcome assessments and digital health technologies are reported herein, further improved assessments of meaningful AS change are needed. Despite the COVID-19 pandemic, remote assessments facilitated high adherence levels and the results suggested that at-home PSG/EEG might be a feasible alternative to the in-clinic EEG assessments. Taken altogether, the combination of in-clinic/at-home clinical outcome assessments, digital health technologies, and PSG/EEG may improve protocol adherence, reduce patient burden, and optimize study outcomes in AS and other rare disease populations.

Improving Racial and Ethnic Equity in Clinical Trials Enrolling Pregnant and Lactating Individuals.

Racial and ethnic marginalized populations have historically been poorly represented, underrecruited, and underprioritized across clinical trials enrolling pregnant and lactating individuals. The objectives of this review are to describe the current state of racial and ethnic representation in clinical trials enrolling pregnant and lactating individuals and to propose evidence-based tangible solutions to achieving equity in these clinical trials. Despite efforts from federal and local organizations, only marginal progress has been made toward achieving equity in clinical research. This continued limited inclusion and transparency in pregnancy trials exacerbates health disparities, limits the generalizability of research findings, and may heighten the maternal child health crisis in the United States. Racial and ethnic underrepresented communities are willing to participate in research; however, they face unique barriers to access and participation. Multifaceted approaches are required to facilitate the participation of marginalized individuals in clinical trials including partnering with the local community to understand their priorities, needs, and assets; establishing accessible recruitment strategies; creating flexible protocols; supporting participants for their time; and increasing culturally congruent and/or culturally sensitive research staff. This article also highlights exemplars in pregnancy research.

Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease

An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau–positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast+ individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.

198 Meta-analysis of Transgender Exclusion from PrEP Clinical Trials

OBJECTIVES/GOALS: To evaluate access to Pre-Exposure Prophylaxis (PrEP) medications for transgender individuals examining how systemic and sociocultural obstacles play a role. Additionally, analyzing the impact of trans-exclusion in clinical trials investigating PrEP efficacy on the trans-HIV care model. METHODS/STUDY POPULATION: By examining the clinicaltrials.gov database, inclusion and exclusion criteria will be collected for Phase III trials of FTC/TAF (Descovy) and FTC/TDF (Truvada) as PrEP for Human Immunodeficiency Virus (HIV). Secondly, trends of physicians’ prescription of PrEP will be analyzed to track post-approval usage and deduce the acceptance and adherence of PrEP by transgender patients. Thirdly, post-approval marketing strategies of PrEP medications will be documented to see key demographics that biopharmaceutical companies are targeting. Finally, relevant literature about trans healthcare will be analyzed to identify key short fallings to support conclusions and justify recommendations for greater transgender clinical trial enrollment and reformations to current standard practices. RESULTS/ANTICIPATED RESULTS: After a preliminary literature review of published Phase III trials for Descovy and Truvada , there is a marked lack of transgender patient enrollment. Contemporary literature argues that this lag in enrollment has downstream effects on trust and acceptance of PrEP as safe and effective by cohorts in the transgender community. The examination of prescribing information for Descovy and Truvada for PrEP reveals a minimal effort to advise doctors of the increased risk for infection in the transgender demographic. Through continued research, I expect to elaborate on the cross-discipline impacts of trans-exclusion, including increased rates of HIV infection, sociocultural and financial barriers to PrEP, and stigmatizing doctor interactions with transgender patients. DISCUSSION/SIGNIFICANCE: The current trans-HIV treatment paradigm lags behind in its sensitivity and nuance, preventing the most equitable distribution of care. Only with more inclusion of transgender individuals in clinical trials can we hope to promote greater awareness and trust for PrEP as effective for HIV.

Meaningful Clinical Changes in Alzheimer Disease Measured With the iADRS and Illustrated Using the Donanemab TRAILBLAZER-ALZ Study Findings.

To provide relevant background of the Integrated Alzheimer's Disease Rating Scale (iADRS), with examples, to assist the reader with the interpretation of iADRS findings from the TRAILBLAZER-ALZ study. The iADRS is an integrated measure of global Alzheimer disease (AD) severity for use in the clinical trial environment. It provides a single score that captures commonalities across cognitive and functional ability domains, reflecting disease-related impairment, while minimizing noise not related to disease progression that may exist within each domain. In AD, disease-modifying therapies (DMTs) are expected to slow the rate of clinical decline, changing the trajectory of disease progression. The overall percent slowing of disease progression with treatment is a more informative outcome of effect than absolute point differences between treatment and placebo groups at any given time point because the latter is influenced by treatment period and disease severity. The TRAILBLAZER-ALZ trial was a phase 2 study designed to evaluate the safety and efficacy of donanemab in participants with early symptomatic AD; the primary outcome measure was the change from baseline to 76 weeks on the iADRS. In the TRAILBLAZER-ALZ study, donanemab slowed disease progression by 32% at 18 months (p = 0.04 vs placebo), demonstrating clinical efficacy. At the patient level, one can assess whether the DMT effect is clinically meaningful by estimating the threshold of change consistent with clinically meaningful worsening; based on the TRAILBLAZER-ALZ findings, treatment with donanemab would delay reaching this threshold by approximately 6 months. The iADRS is capable of accurately describing clinical changes associated with disease progression and detecting treatment effects and is an effective assessment tool for use in clinical trials of individuals with early symptomatic AD.

A Comparison of FDA and EMA Pregnancy and Lactation Labeling.

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have robust collaboration and dialogue around the need for data and the inclusion of pregnant and lactating individuals in clinical trials. Despite this collaboration, the two agencies have their own standards for the format and content of labeling for these populations. To understand these differences, the pregnancy and lactation labeling sections for 31 approved drugs were compared, and trends were assessed for use of language concordance and discordance related to use during pregnancy and lactation between the 2 agencies. Further analysis evaluated the presence of human data included in the labeling. The EMA and the FDA had high discordance between pregnancy and lactation labeling language, in 68% and 71% of labeling, respectively, and only 10% of pregnancy labeling and 16% of lactation labeling include human data. Concordance in labeling language is not the norm but occurs when there is a sizeable body of human data, animal data suggesting a particular safety issue, drug mechanism of action information, or disease-specific considerations. This study highlights the need for more human data to inform prescribing decisions in these populations. The results also suggest that there is an opportunity for alignment in labeling across regions.

The use of surface EMG in neurorehabilitation following traumatic spinal cord injury: A scoping review

ObjectiveSurface electromyography (sEMG) is a common electrophysiological assessment used in clinical trials in individuals with spinal cord injury (SCI). This scoping review summarizes the most common sEMG techniques used to address clinically relevant neurorehabilitation questions. We focused on the role of sEMG assessments in the clinical practice and research studies on neurorehabilitation after SCI, and how sEMG reflects the changes observed with rehabilitation. Additionally, this review emphasizes the limitations and pitfalls of the sEMG assessments in the field of neurorehabilitation after SCI. MethodsA comprehensive search of Medline (Ovid), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase, Emcare, Cumulative Index to Nursing & Allied Health Literature, and PubMed was conducted to find peer-reviewed journal articles that included individuals post-SCI that participated in neurorehabilitation interventions using sEMG assessments. This is a scoping review using a systematic search (hybrid review). ResultsOf 4522 references captured in the primary database searches, 100 references were selected and included in the scoping review. The main focus of the studies was on neurorehabilitation using sEMG biofeedback, brain stimulation, locomotor training, neuromuscular electrical stimulation (NMES), paired-pulse stimulation, pharmacology, posture and balance training, spinal cord stimulation, upper limb training, vibration, and photobiomodulation. ConclusionsMost studies employed sEMG amplitude to understand the effects of neurorehabilitation on muscle activation during volitional efforts or reduction of spontaneous muscle activity (e.g., spasms, spasticity, and hypertonia). Further studies are needed to understand the long-term reliability of sEMG amplitude, to circumvent normalization issues, and to provide a deeper physiological background to the different sEMG analyses. SignificanceThis scoping review reveals the potential of sEMG in exploring promising neurorehabilitation strategies following SCI and discusses the barriers limiting its widespread use in the clinic.

Fragile X Mental Retardation Protein and Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome: A Pilot Study.

Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Nevertheless, animal and human studies regarding the link between FMRP and mGluR5 expression provide inconsistent or conflicting findings about the nature of those relationships. Since multiple clinical trials of glutamatergic agents in humans with FXS did not demonstrate the amelioration of the behavioral phenotype observed in animal models of FXS, we sought measure if mGluR5 expression is increased in men with FXS to form the basis for improved clinical trials. Unexpectedly marked reductions in mGluR5 expression were observed in cortical and subcortical regions in men with FXS. Reduced mGluR5 expression throughout the living brains of men with FXS provides a clue to examine FMRP and mGluR5 expression in FXS. In order to develop the findings of our previous study and to strengthen the objective tools for future clinical trials of glutamatergic agents in FXS, we sought to assess the possible value of measuring both FMRP levels and mGluR5 expression in men with FXS. We aimed to show the value of measurement of FMRP levels and mGluR5 expression for the diagnosis and treatment of individuals with FXS and related conditions. We administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a specific mGluR5 radioligand for quantitative measurements of the density and the distribution of mGluR5s, to six men with the full mutation (FM) of FXS and to one man with allele size mosaicism for FXS (FXS-M). Utilizing the seven cortical and subcortical regions affected in neurodegenerative disorders as indicator variables, adjusted linear regression of mGluR5 expression and FMRP showed that mGluR5 expression was significantly reduced in the occipital cortex and the thalamus relative to baseline (anterior cingulate cortex) if FMRP levels are held constant (F(7,47) = 6.84, p < 0.001).These findings indicate the usefulness of cerebral mGluR5 expression measured by PET with [18F]FPEB and FMRP values in men with FXS and related conditions for assessments in community facilities within a hundred-mile radius of a production center with a cyclotron. These initial results of this pilot study advance our previous study regarding the measurement of mGluR5 expression by combining both FMRP levels and mGluR5 expression as tools for meaningful clinical trials of glutamatergic agents for men with FXS. We confirm the feasibility of this protocol as a valuable tool to measure FMRP levels and mGluR5 expression in clinical trials of individuals with FXS and related conditions and to provide the foundations to apply precision medicine to tailor treatment plans to the specific needs of individuals with FXS and related conditions.