Typical Clinical Trial Research Articles

Translational Medicine in Alzheimer's Disease: The Journey of Donanemab From Discovery to Clinical Application

ABSTRACTSubstantial research has been conducted to identify an efficient treatment for Alzheimer's disease (AD). Existing treatments, including cholinesterase inhibitors and N‐methyl D‐aspartate (NMDA) receptor antagonists, do not reverse or slow the disease course but only treat its manifestations. This limitation has brought attention to the need for treatments that modify the amyloid‐beta (Aβ) and tau pathology of the disease. One recent advancement in AD treatment is donanemab, a monoclonal antibody intended to clear Aβ plaques in the brain. It targets pyroglutamyl(3)‐Aβ protein (3–42) to remove Aβ deposits and alter the disease course. This review explores the timeline of donanemab use from discovery to clinical use. The pharmacodynamics and pharmacokinetics of the drug are discussed along with typical and suboptimal preclinical and clinical trial results in terms of efficacy, safety, and tolerability. Thus, donanemab is more effective than donepezil and rivastigmine in removing plaques and improving cognition. At the same time, it is not devoid of safety concerns that are typical of the majority of amyloid‐targeted medicines. The control to end the treatment after plaque cleaning is a unique selling point for some patients, making it more attractive. The innovation and development of donanemab from research to clinical practice are a clear representation of the role of the field of translational medicine in the practical application of new knowledge in the treatment of AD.

Rare Case of Klippel Feil Syndrome Associated with Mirror Movements

Klippel Feil Syndrome (KFS) is a multisystem disorder with the typical clinical trial of short neck, restriction of headand neck movements and low posterior hairline and associated with anomalies of the urogenital, musculoskeletal, neurological andcardiovascular systems. Here is a case report of a young boy with history of abnormal head and upper limbs movements alongwith repeated bowing of head since the age of 6 months. He also had frequent falls with repeated minor trauma to the face.Antenatal and peripartum period was uneventful and child had no neonatal complications with normal development. Onexamination the child had abnormal head position with bowing, short neck and low hair line. Musculoskeletal system examinationrevealed decreased range of passive movements at cervical spine extension and lateral flexion with no focal neurological deficits.Further examination revealed Mirror movements (synkinesis) in the upper limbs. Mirror movements are the involuntarymovements of one body part that mirror intentional movements on the opposite side. Other Systemic examinations were normal.CT Cervical spine showed fusion of the upper three cervical vertebrae and the child was diagnosed as a case of klippel feil syndrometype 2 presenting with mirror movements. This rare case of klippel feil syndrome is being presented with the aim that such casesshould be detected and treated at an early stage to reduce the cosmetic & social stigma to the patient and parents. This casereport also gives a brief overview of associated features of KFS along with its management.

The Typical Nail Lichen Planus Severity Index: An Outcome Instrument for Typical Nail Lichen Planus

Introduction: Despite numerous treatment options for nail lichen planus (NLP), a validated method for measuring the severity of NLP and therapeutic response in clinical trials is absent. The aim of the study was to develop and validate a measurement instrument, Typical Nail Lichen Planus Severity Index (tNLPSI), for typical NLP that could be used in clinical trials. Methods: A total of 48 patients pathologically confirmed with typical NLP were enrolled in this study. Five dermatologists were trained to use the tNLPSI activity scale and the Physician’s Global Assessment (PGA) scale to score samples independently to estimate inter-rater and intra-rater reliability across two sessions. In addition, tNLPSI activity scores were compared with PGA scores to assess the construct validity. Results: The tNLPSI activity scale had excellent internal consistency and inter-rater reliability (Cronbach’s alpha 0.990; ICC = 0.954; 95% CI = 0.930–0.971), and the correlations between the different graders’ scores indicate good consistency (rp = 0.934–0.968). In addition, the tNLPSI activity scale demonstrated high intra-rater reliability (ICC = 0.996; 95% CI = 0.993–0.998), showing good reproducibility. And tNLPSI activity scores and PGA scores showed good construct validity (Spearman’s rho = 0.941 and Spearman’s rho = 0.903–0.935, respectively; p < 0.01). Conclusion: The tNLPSI activity scale was demonstrated to be consistent, reliable, reproducible, and feasible, making it a potential valuable tool for evaluating the treatment response in typical NLP clinical trials.

Evaluating patient and family preferences for acute and preventive pediatric headache treatment.

To describe acute and preventive treatment preferences among youth with migraine and their parents/guardians, and to describe the degree of youth-parent/guardian preference agreement. Headache disorders are common in youth, but little is known about patient and family preferences for headache treatments and outcomes. In this cross-sectional survey, a headache treatment preferences questionnaire was co-created with stakeholders, piloted, and distributed to consenting youth with migraine aged 9-18 years and parents/guardians at a tertiary care headache clinic in western Canada. Response data were summarized for youth and parents/guardians separately, and agreement rates within a youth-parent/guardian pair were compared to a hypothesized agreement rate of 80% for the primary questionnaire items. Seventy-two youth and n = 94 parents/guardians participated, with n = 63 in youth-parent/guardian pairs. Freedom from pain and rapid relief, and reducing pain severity and headache frequency were top acute and preventive treatment priorities, respectively. More than 90% (69/72) agreed that ≥ 50% reduction in headache frequency was a good target. For both acute and preventive interventions, swallowed pill-based options were most often selected as the preferred first-line treatment, with neuromodulation selected as the preferred second-line treatment. The level of agreement within youth-parent/guardian pairs on preferred treatment modalities was lower than hypothesized for acute (63% [40/63], 95% confidence interval [CI] = 52-75%, χ2 = 10.73, p = 0.001) but not for preventive treatment (73% [46/63], 95% CI = 62-84%, χ2 = 1.92, p = 0.166). Regarding which treatment modalities were perceived as most effective, youth-parent agreement was lower than hypothesized for both acute (48% [30/63], 95% CI = 35-60%, χ2 = 41.29, p < 0.001) and preventive treatment (46% [29/63], 95% CI = 34-58%, χ2 = 45.43, p < 0.001). Youth and family preferences aligned qualitatively, but sometimes diverged quantitatively, from typical clinical trial outcomes. The level of agreement within youth-parent/guardian pairs on treatment preferences and perceptions was low. Clinicians should consider both perspectives as they may be divergent.

Direct-to-participant recruitment of mothers and infants: A strategic approach during challenging pandemic times

Under traditional circumstances, most clinical trials rely on in-person operations to identify, recruit, and enroll study participants and to complete study-related visits. During unusual circumstances, such as the COVID-19 pandemic, the typical clinical trial model is challenged and forced to explore alternative approaches to implementing study recruitment, participant enrollment, and data collection strategies. One such alternative is a direct-to-participant approach which leverages electronic resources and relevant technological devices (e.g., smart phones) available to researchers and patients. This approach functions under the assumption that a participant has access to a device that connects to the internet such as a smart phone, tablet, or computer. Researchers are then able to transition a typical paper-based, in-person model to an electronic-based, siteless, remote study. This article describes the challenges clinicians and researchers faced when implementing a direct-to-participant study approach during the COVID-19 pandemic. The lessons learned during this study of infant populations could help increase efficiency of future trials, specifically, by lessening the burden on participants and clinicians as well as streamlining the process for enrollment and data collection. While direct-to-adult participant recruitment is not a novel approach, our findings suggest that studies attempting to recruit the infant population may benefit from such a direct-to-participant approach.

Potential utility of using both APOEε4 and Aβ positivity to enrich clinical trials of tau‐targeting therapies

AbstractBackgroundThe use of enrichment strategies is crucial for selecting individuals with the highest probability of Alzheimer’s disease (AD)‐related progression in typical clinical trial time frames. Although both amyloid‐ß (Aß) pathology and the apolipoprotein E e4 (APOEe4) genotype have been shown to accelerate tau accumulation, it is still not clear whether assessing both APOEe4 genotype and Aß positivity is useful to enrich tau‐targeting trials using tau positron emission tomography (PET) as outcome. Here, we investigated the implications of considering APOEe4 carriership for population enrichment in trials testing drug effects on tau tangle deposition in cognitively impaired (CI) individuals across the AD continuum.MethodWe studied 29 Aß positive CI individuals (16 with mild cognitive impairment [MCI] and 13 with AD dementia) from the McGill Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Study participants underwent clinical assessments, APOE genotyping, magnetic resonance imaging, PET for Aß ([18F]AZD4694) and tau ([18F]MK6240) at baseline, as well as a follow‐up tau‐PET scan (mean follow‐up, 2.2 years). Aß positivity was determined as global [18F]AZD4694 SUVR = 1.55.ResultNo demographic differences were observed between APOEe4 carriers and noncarriers (Table 1). Regression analysis revealed that APOEe4 carriers had higher tau‐PET SUVR increase in temporal regions compared to APOEe4 noncarriers (Figure 1). The use of Aß positivity alone for population enrichment of a clinical trial focusing on CI individuals would require a sample size of 436 individuals per study arm to test a 25% drug effect on tau‐PET accumulation (Figure 2). A similar clinical trial with a population enrichment strategy using Aß positivity plus APOEe4 carriership would require a sample size of as few as 158 individuals per study arm (reduction of 64% in relation to using only Aß positivity) to test the same drug effect (Figure 2).ConclusionOur results reveal that APOEe4 carriership is associated with increased tau tangle accumulation in CI individuals who are Aß positive. Clinical trials testing drug effects on tangle deposition may benefit from assessing both APOEe4 carriership and Aß positivity statuses as enrollment criteria to select individuals at higher risk of fast tau accumulation, resulting in a more cost‐effective trial.

Potential utility of using both APOEε4 and Aβ positivity to enrich clinical trials of tau‐targeting therapies

AbstractBackgroundThe use of enrichment strategies is crucial for selecting individuals with the highest probability of Alzheimer’s disease (AD)‐related progression in typical clinical trial time frames. Although both amyloid‐β (Aβ) pathology and the apolipoprotein E ε4 (APOEε4) genotype have been shown to accelerate tau accumulation, it is still not clear whether assessing both APOEε4 genotype and Aβ positivity is useful to enrich tau‐targeting trials using tau positron emission tomography (PET) as outcome. Here, we investigated the implications of considering APOEε4 carriership for population enrichment in trials testing drug effects on tau tangle deposition in cognitively impaired (CI) individuals across the AD continuum.MethodWe studied 29 Aβ positive CI individuals (16 with mild cognitive impairment [MCI] and 13 with AD dementia) from the McGill Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Study participants underwent clinical assessments, APOE genotyping, magnetic resonance imaging, PET for Aβ ([18F]AZD4694) and tau ([18F]MK6240) at baseline, as well as a follow‐up tau‐PET scan (mean follow‐up, 2.2 years). Aβ positivity was determined as global [18F]AZD4694 SUVR ≥ 1.55.ResultNo demographic differences were observed between APOEε4 carriers and noncarriers (Table 1). Regression analysis revealed that APOEε4 carriers had higher tau‐PET SUVR increase in temporal regions compared to APOEε4 noncarriers (Figure 1). The use of Aβ positivity alone for population enrichment of a clinical trial focusing on CI individuals would require a sample size of 436 individuals per study arm to test a 25% drug effect on tau‐PET accumulation (Figure 2). A similar clinical trial with a population enrichment strategy using Aβ positivity plus APOEε4 carriership would require a sample size of as few as 158 individuals per study arm (reduction of 64% in relation to using only Aβ positivity) to test the same drug effect (Figure 2).ConclusionOur results reveal that APOEε4 carriership is associated with increased tau tangle accumulation in CI individuals who are Aβ positive. Clinical trials testing drug effects on tangle deposition may benefit from assessing both APOEε4 carriership and Aβ positivity statuses as enrollment criteria to select individuals at higher risk of fast tau accumulation, resulting in a more cost‐effective trial.

The natural history of ALS: Baseline characteristics from a multicenter clinical cohort

Background Amyotrophic lateral sclerosis (ALS) is a rare disease with urgent need for improved treatment. Despite the acceleration of research in recent years, there is a need to understand the full natural history of the disease. As only 40% of people living with ALS are eligible for typical clinical trials, clinical trial datasets may not generalize to the full ALS population. While biomarker and cohort studies have more generous inclusion criteria, these too may not represent the full range of phenotypes, particularly if the burden for participation is high. To permit a complete understanding of the heterogeneity of ALS, comprehensive data on the full range of people with ALS is needed. Methods The ALS Natural History Consortium (ALS NHC) consists of nine ALS clinics and was created to build a comprehensive dataset reflective of the ALS population. At each clinic, most patients are asked to participate and about 95% do. After obtaining consent, a minimum dataset is abstracted from each participant’s electronic health record. Participant burden is therefore minimal. Results Data on 1925 ALS patients were submitted as of 9 December 2022. ALS NHC participants were more heterogeneous relative to anonymized clinical trial data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The ALS NHC includes ALS patients of older age of onset and a broader distribution of El Escorial categories, than the PRO-ACT database. Conclusions ALS NHC participants had a higher diversity of diagnostic and demographic data compared to ALS clinical trial participants. Key Messages What is already known on this topic: Current knowledge of the natural history of ALS derives largely from regional and national registries that have broad representation of the population of people living with ALS but do not always collect covariates and clinical outcomes. Clinical studies with rich datasets of participant characteristics and validated clinical outcomes have stricter inclusion and exclusion criteria that may not be generalizable to the full ALS population. What this study adds: To bridge this gap, we collected baseline characteristics for a sample of the population of people living with ALS seen at a consortium of ALS clinics that collect extensive, pre-specified participant-level data, including validated outcome measures. How this study might affect research, practice, or policy: A clinic-based longitudinal dataset can improve our understanding of the natural history of ALS and can be used to inform the design and analysis of clinical trials and health economics studies, to help the prediction of clinical course, to find matched controls for open label extension trials and expanded access protocols, and to document real-world evidence of the impact of novel treatments and changes in care practice.

Roger’s syndrome presenting with stroke

Rogers syndrome (Thiamine responsive megaloblastic anaemia-TRMA) occurs due to defect in the SLC19A2 gene. SLC19A2 and SLC19A3 genes encode THTR1 and 2 respectively, which are thiamine transporter proteins. The SLC19A2 gene is expressed in the inner ear cells, β-islet cells, and hematopoietic stem cells; consequently, the typical clinical trial of TRMA is diabetes, TRMA, and sensorineural hearing loss. This syndrome, eponymously called Roger’s syndrome is rare. Mode of inheritance of TRMA is autosomal recessive. Clinical presentation as recurrent stroke is extremely rare. We present a case of a five-year-old boy who had recurrent large artery territory cerebral infarcts, with no other identifiable underlying cause of stroke. During current admission, no underlying etiology could be identified for cerebral infarct. On workup, a preliminary diagnosis of TRMA was made and thiamine supplementation was instituted. Gene analysis confirmed the diagnosis. The child was a product of non-consanguineous marriage. There was history of early childhood demise of two older siblings within five years of age due to diabetic ketoacidosis (DKA). TRMA is a rare autosomal recessive syndrome that manifests as a typical triad with diabetes, hearing loss and megaloblastic anaemia. The treatment is with high dose thiamine supplementation that can alleviate symptoms of diabetes and megaloblastic anaemia. Onset and progression of hearing loss may be delayed with treatment. Some cases may present with recurrent stroke as in the proband.

LBSUN320 Building The Evidence To Address Disparities In Type 1 Diabetes (BEAD-T1D): Recruitment Practices To Engage Underrepresented Youth And Their Families

Abstract Underrepresented youth have less access to diabetes technology research and usage. The BEAD-T1D study aims to build an evidence-based intervention to reduce disparities in diabetes technology uptake in youth with public insurance and type 1 diabetes (T1D). Here, we present our strategies to optimize recruitment of underrepresented groups. | Our recruitment strategy started with hiring a bilingual and bicultural Latino research assistant (RA) to facilitate culturally competent recruitment. Youth with public insurance aged &amp;lt;12 years with T1D were screened in advance of their clinic visits. The RA coordinated with the clinic team to facilitate contact with potential participants. Parent/guardian preferred language and times of contact were always solicited and honored by the RA. The RA introduced the study to the parent/guardian and answered any questions, including personal concerns around research in the family's preferred language. If interested, they were given the option of consenting in clinic, in person, or virtually (video or phone call). Consents were conducted at a pace set by the parent/guardian to ensure understanding. | A total of 56 families (64% Hispanic, 25% Non-Hispanic White [NHW], 2% Non-Hispanic Black [NHB], and 9% other) were eligible. We approached 42 families (14 not approached: 6 no showed, 2 provider preference, and 6 dismissed from clinic before RA contact). Of the 42 approached, 23 consented (age 39±9 years; 78% female; 65% Hispanic, 26% NHW, and 9% Other). Of the 19 who did not consent, 2 declined (1 NHW and 1 NHB), 13 did not answer phone calls, and 4 plan to consent in a few months. The preferred times of contact were 8am-7pm and families were contacted 2 times (range 1-4) before a definitive response was received. In-clinic approach was important to successful consent: 78% consenters versus 31% non-consenters were approached in-clinic. Barriers to in-clinic approach for the RA included late or no response from providers or care team ending the clinic visit as well as bandwidth/connectivity issues. | We demonstrated that culturally congruent staff and flexible recruitment practices prioritizing participants’ availability is beneficial in recruiting individuals from historically underrepresented groups. Our study population is 65% Hispanic, which is significantly higher than typical T1D clinical trials. Culturally and linguistically congruent RA with wide availability in times of contact and communication methods was key. We formed a culturally competent interpersonal relationship with our families, addressing barriers to research participation underrepresented families face within and outside of the medical system. In-clinic recruitment to introduce the study and build rapport with the family appears to encourage consenting. Researchers can modify their hiring practices and recruitment protocols to support recruitment of historically excluded families. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

P.019 Interictal burden of migraine: correlations with other measures of migraine burden and effects of galcanezumab migraine-preventive treatment

Background: Typical migraine clinical trial endpoints assess only ictal burden. Methods: Adults (N=462) with episodic or chronic migraine with previous failure of 2-4 preventive medication categories were randomized 1:1 to 3-month double-blind treatment with placebo or galcanezumab 120mg. Primary endpoint was mean change from baseline in monthly migraine headache days. Migraine Interictal Burden Scale-4 (MIBS-4) measured migraine-related burden on non-headache days for past 4 weeks (0=no burden, 1-2=mild, 3-4=moderate, 5-12=severe). Migraine Disability Assessment (MIDAS), Migraine-Specific Quality of Life Questionnaire (MSQ), Patient Global Impression-Severity (PGI-S), depression (Patient Health Questionaire-9 [PHQ-9]), and anxiety (Generalized Anxiety Disorder Scale [GAD-7]) were assessed. Relationships among measures were assessed at baseline using Spearman’s rank correlation coefficient. Results: MIBS-4 was moderately correlated with PHQ-9 (r=.55) and MSQ total (r=−.53). Other correlations with MIBS-4 were low (GAD-7, r=0.42; MIDAS, r=0.41; PGI-S, r=0.32) or negligible (migraine headache days, r=0.22). After 3 months, from a mean baseline of 13.2 monthly migraine headache days, galcanezumab patients improved by 4.4 vs 1.3 days for placebo (p&lt;.0001). From mean MIBS-4 baseline of 5.5, galcanezumab patients improved by 1.8 vs 0.8 points for placebo (p&lt;.0001). Conclusions: Galcanezumab significantly reduced ictal and interictal burden of migraine. Results suggest interictal burden is a distinct effect of the disease.

A Bayesian model with application for adaptive platform trials having temporal changes.

Temporal changes exist in clinical trials. Over time, shifts in patients' characteristics, trial conduct, and other features of a clinical trial may occur. In typical randomized clinical trials, temporal effects, that is, the impact of temporal changes on clinical outcomes and study analysis, are largely mitigated by randomization and usually need not be explicitly addressed. However, temporal effects can be a serious obstacle for conducting clinical trials with complex designs, including the adaptive platform trials that are gaining popularity in recent medical product development. In this paper, we introduce a Bayesian robust prior for mitigating temporal effects based on a hidden Markov model, and propose a particle filtering algorithm for computation. We conduct simulation studies to evaluate the performance of the proposed method and provide illustration examples based on trials of Ebola virus disease therapeutics and hemostat in vascularsurgery.

Analyzing longitudinal binary data in clinical studies

In clinical studies, it is common to have binary outcomes collected over time as repeated measures. This manuscript reviews and evaluates two popular classes of statistical methods for analyzing binary response data with repeated measures: likelihood-based Generalized Linear Mixed Model (GLMM), and semiparametric Generalized Estimating Equation (GEE). Recommendations for choice of analysis model and points to consider for implementation in clinical studies in the presence of missing data are provided based on a comprehensive literature review, as well as, a simulation study evaluating the performance of both GLMM and GEE under scenarios representative of typical clinical trial settings. Under Missing at Random (MAR) assumption, GLMM is preferred over GEE, and the SAS PROC GLIMMIX marginal model is recommended for implementing GLMM in analyzing clinical trial data. When there is an underlying continuous variable used to define the binary response, and the missing proportion is high and/or unbalanced between treatment groups, a two-step approach combining Multiple Imputation (MI) and GEE (MI-GEE) is recommended.

Retinal Implantation of Electronic Vision Prostheses to Treat Retinitis Pigmentosa: A Systematic Review.

PurposeRetinitis pigmentosa (RP) is a hereditary disease causing photoreceptor degeneration and permanent vision loss. Retinal implantation of a stimulating electrode array is a new treatment for RP, but quantification of its efficacy is the subject of ongoing work. This review evaluates vision-related outcomes resulting from retinal implantation in participants with RP.MethodsWe searched MEDLINE and Embase for journal articles published since January 1, 2015. We selected articles describing studies of implanted participants that reported the postimplantation measurement of vision. We extracted study information including design, participants’ residual vision, comparators, and assessed outcomes. To assess the risk of bias, we used signaling questions and a target trial.ResultsOur search returned 425 abstracts. We reviewed the full text of 34 articles. We judged all studies to be at high risk of bias owing to the study design or experimental conduct. Regarding design, studies lacked the measures that typical clinical trials take to protect against bias (e.g., control groups and masking). Regarding experimental conduct, outcome measures were rarely comparable before and after implantation, and psychophysical methods were prone to bias (subjective, not forced choice, methods). The most common comparison found was between postimplantation visual function with the device powered off versus on. This comparison is at high risk of bias.ConclusionsThere is a need for high-quality evidence of efficacy of retinal implantation to treat RP.Translational RelevanceFor patients and clinicians to make informed choices about RP treatment, visual function restored by retinal implantation must be properly quantified and reported.

MO516A STRUCTURED EXPERT ELICITATION TO INFORM AND VALIDATE MORTALITY EXTRAPOLATIONS FOR A COST-EFFECTIVENESS ANALYSIS OF DAPAGLIFLOZIN

Abstract Background and Aims Elevated albuminuria in patients with chronic kidney disease (CKD) is associated with increased risks of CKD progression, cardiovascular events and all-cause death. In the DAPA-CKD study, dapagliflozin significantly reduced the risk of all-cause death in patients with elevated albuminuria compared with placebo (hazard ratio: 0.69; 95% confidence interval 0.53–0.88). To assess the cost-effectiveness of new treatments, decision makers require survival estimates over a longer period than that of a typical clinical trial, usually over a lifetime time horizon. A formal elicitation process is currently underway to obtain estimates of long-term survival of patients with albuminuric CKD from clinical experts. Their responses will be used to validate extrapolations of all-cause mortality data from DAPA-CKD, which could inform cost-effectiveness analyses for dapagliflozin. Method Targeted literature searches were conducted to collate data on all-cause mortality in patients with CKD and elevated albuminuria. Clinical trials and observational studies were included if they involved non-dialysis-dependent patients with CKD aged 18 years and over, had more than 500 participants per study arm and reported incidence of all-cause death and/or all-cause mortality/survival Kaplan–Meier (KM) curves. To estimate long-term survival, KM curves were extrapolated to 20 years by calculating standard mortality ratios (SMRs) using age- and sex-adjusted general-population lifetable data. Study and patient characteristics and mortality data from relevant studies were provided to clinical experts to inform their judgements in a formal elicitation process. After receiving training on the elicitation process, six leading disease area experts were invited to complete the elicitation survey using an Excel-based tool, which consisted of 10 calibration questions, and three questions regarding the survival of patients in the placebo arm of the DAPA-CKD study at 10 and 20 years. The elicited estimates will be weighted and aggregated using Cooke’s method. Results Literature searches identified 13 relevant articles (seven clinical trials and six observational studies), with a range of 1094 to 5674 participants. Mean age varied across studies (range: 55–70 years). Where reported, median follow-up was 9–144 months, and mean estimated glomerular filtration rate (eGFR) at baseline was 22.4–56.3 mL/min/1.73 m2. Five studies exclusively included patients with type 2 diabetes (T2D). The incidence of all-cause death was reported in nine studies and was 1.5–9.4 deaths per 100 patient-years, with the highest incidence observed in a study reporting data for patients with CKD stage 4 and 5 (8.0 and 9.4 deaths per 100 patient-years, respectively). Nine studies provided KM curves; from these, estimated survival at 2 years ranged from 86% (study population mean age 67 years, eGFR &amp;lt; 15 mL/min/1.73 m2) to 98% (study population mean age 58 years, mean eGFR 46.2 mL/min/1.73 m2). The SMR-extrapolated survival at 10 and 20 years was 36–80% and 2–69%, respectively. The ranges defined by the expert judgements collected to date for survival at 10 and 20 years are in line with the variability of the extrapolated KM survival curves. The elicitation process is ongoing and therefore, to avoid biasing the judgements that remain to be collected, preliminary results are not reported here. Results of the expert elicitation will be presented in full at the congress. Conclusion Initial results from the survey calibration questions suggest that the expert elicitation process provides expert judgements that are both informative and precise. The elicitation of survival estimates for patients with CKD and elevated albuminuria at 10 and 20 years will provide greater insight than extrapolated data alone, and will increase the validity of long-term survival projections for dapagliflozin cost-effectiveness analyses.

Parental perspectives long term after neonatal clinical trial participation: a survey

BackgroundAlthough recruiting newborns is ethically challenging, clinical trials remain essential to improve neonatal care. There is a lack of empirical data on the parental perspectives following participation of their neonate in a clinical trial, especially at long term. The objective of this study is to assess experiences and emotions of parents, long term after trial participation in an interventional drug trial.MethodsParents of former participants of five neonatal interventional drug trials were surveyed at long term (3–13 years ago) after participation. The survey assessed parental contentment with trial participation, perceived influence of the trial on care and health, emotional consequences of participation, and awareness of typical clinical trial characteristics on 6-point Likert scales.ResultsComplete responses were received from 123 parents (52% of involved families). Twenty percent of parents did not remember participation. Those who remembered participation reported high contentment with overall trial participation (median 5.00), but not with follow-up (median 3.00). Most parents did not perceive any influence of the trial on care (median 2.00) and health (median 2.43). Almost all parents reported satisfaction and pride (median 4.40), while a minority of parents reported anxiety and stress (median 1.44) or guilt (median 1.33) related to trial participation. A relevant minority was unaware of typical trial characteristics (median 4.20; 27% being unaware).ConclusionsOverall, parents reported positive experiences and little emotional distress long term after participation. Future efforts to improve the practice of neonatal clinical trials should focus on ensuring effective communication about the concept and characteristics of a clinical trial during consent discussions and on the follow-up after the trial.

Same-Day Consent for Regional Anesthesia Clinical Research Trials: It's About Time.

Same-Day Consent for Regional Anesthesia Clinical Research Trials: It's About Time.

A hierarchical testing approach for detecting safety signals in clinical trials.

Detecting safety signals in clinical trial safety data is known to be challenging due to high dimensionality, rare occurrence, weak signal, and complex dependence. We propose a new hierarchical testing approach for analyzing safety data from a typical randomized clinical trial. This approach accounts for the hierarchical structure of adverse events (AEs), that is, AEs are categorized by system organ class (SOC). Our approach contains two steps: the first step tests, for each SOC, whether any AEs within this SOC are differently distributed between treatment arms; and the second step identifies signal AEs from SOCs passing the first step tests. We show the superiority, in terms of power of detecting safety signals given controlled false discovery rate, of the new approach comparing with currently available approaches through simulation studies. We also demonstrate this approach with two real data examples.

Method for Estimating Non-study Cigarette Use among Switchers to Low Nicotine Content Cigarettes in Ambulatory Clinical Studies

Background: FDA is considering to establish a product standard to reduce nicotine in cigarettes to make them “minimally addictive or non addictive.” FDA has funded many clinical studies where smokers are switched to smoking low nicotine cigarettes to determine a nicotine ceiling that is appropriate for the protection of the public health. Unlike typical clinical trials involving pharmaceuticals or medical devices, ambulatory studies with low nicotine cigarettes face a unique challenge in that conventional nicotine nonstudy cigarettes are readily available to participants when protocols require them to exclusively use study cigarettes. As a consequence, protocol deviation in non-study product use is a major limitation common in such ambulatory studies, with up to 80 percent of participants using non-study cigarettes during the study. There is no published method for estimating the magnitude of such protocol deviation, i.e., the number of non-study cigarettes smoked by participants, in such studies. Methods: We present a method for estimating the magnitude of noncompliance based on the proposition that the level of biomarker of exposure to a smoke constituent is proportional to the amount of the constituent per cigarette and the number of cigarettes smoked by participants. The method estimates the number of non-study cigarettes smoked by participants based on the discrepancies between the yield of smoke constituents (e.g., nicotine) and the level of the corresponding biomarkers measured in a study. Results: Data from a confined study confirmed the validity of this method. Under-reporting on the magnitude of non-study cigarette use is widespread across studies using different low nicotine cigarettes. Participants in one of the largest published studies under-reported the number of non-study cigarette used by 79-90%. Conclusions: Controlling and accurately estimating non-study cigarette use is critical for ambulatory low nicotine cigarette switching studies to ensure the resulting data can be appropriately evaluated to support science-based regulatory decision-making. In planning future studies, researchers should consider incorporating specific biomarkers that would enable objective assessment of both the prevalence and the magnitude of non-study cigarette use.

Reliable Data Collection in Participatory Trials to Assess Digital Healthcare Applications

The number of digital healthcare mobile applications in the market is exponentially increasing owing to the development of mobile networks and widespread usage of smartphones. However, only few of these applications have been adequately validated. Like many mobile applications, in general, the use of healthcare applications is considered safe; thus, developers and end users can easily exchange them in the marketplace. However, existing platforms are unsuitable for collecting reliable data for evaluating the effectiveness of the applications. Moreover, these platforms reflect only the perspectives of developers and experts, and not of end users. For instance, typical clinical trial data collection methods are not appropriate for participant-driven assessment of healthcare applications because of their complexity and high cost. Thus, we identified the need for a participant-driven data collection platform for end users that is interpretable, systematic, and sustainable, as a first step to validate the effectiveness of the applications. To collect reliable data in the participatory trial format, we defined distinct stages for data preparation, storage, and sharing. The interpretable data preparation consists of a protocol database system and semantic feature retrieval method that allow a person without professional knowledge to create a protocol. The systematic data storage stage includes calculation of the collected data reliability weight. For sustainable data collection, we integrated a weight method and a future reward distribution function. We validated the methods through statistical tests involving 718 human participants. The results of a validation experiment demonstrate that the compared methods differ significantly and prove that the choice of an appropriate method is essential for reliable data collection, to facilitate effectiveness validation of digital healthcare applications. Furthermore, we created a Web-based system for our pilot platform to collect reliable data in an integrated pipeline. We compared the platform features using existing clinical and pragmatic trial data collection platforms.