Analysis of start-up, retention, and adherence in ALS clinical trials.
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ABSTRACT: Objective
To investigate predictors of trial start-up times, high attrition, and poor protocol adherence in amyotrophic lateral sclerosis (ALS) trials.Methods
Retrospective analysis of start-up times, retention, and protocol adherence was performed on 5 clinical studies conducted by the Northeast ALS Consortium and 50 ALS clinical trials identified by PubMed search. Predictors of start-up times were estimated by accelerated failure time models with random effects. Predictors of retention and protocol deviations were estimated by mixed-model logistic regression.Results
Median times for contract execution and institutional review board (IRB) approval were 105 days and 125 days, respectively. Contract execution was faster at sites with more ongoing trials (p = 0.005), and more full-time (p = 0.006) and experienced (p < 0.001) coordinators. IRB approval was faster at sites with more ongoing trials (p = 0.010) and larger ALS clinics (p = 0.038). Site activation after IRB approval was faster at sites with more full-time (p = 0.038) and experienced (p < 0.001) coordinators. Twenty-two percent of surviving participants withdrew before completing the trial. Better participant functional score at baseline was an independent predictor of trial completion (odds ratio 1.29, p = 0.002) and fewer protocol deviations (odds ratio 0.86, p = 0.030).Conclusion
Delays in IRB review contribute the most to prolonged trial start-up times, and these timelines are faster in sites with more experienced staff. Strategies to improve protocol adherence and participants' retention may include enrolling people at early disease stages.
SUBMITTER: Atassi N
PROVIDER: S-EPMC3806927 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceRandomized clinical trials (RCTs) are critical in advancing patient care, yet conducting such large-scale trials requires tremendous resources and coordination. Clinical site start-up performance metrics can provide insight into opportunities for improved trial efficiency but have not been well described.ObjectiveTo measure the start-up time needed to reach prespecified milestones across sites in large cardiovascular RCTs in North America and to evaluate how these metrics vary by time and type of regulatory review process.Design, setting, and participantsThis cohort study evaluated cardiovascular RCTs conducted from July 13, 2004, to February 1, 2017. The RCTs were coordinated by a single academic research organization, the Duke Clinical Research Institute. Nine consecutive trials with completed enrollment and publication of results in their target journal were studied. Data were analyzed from December 4, 2019, to January 11, 2021.ExposuresYear of trial enrollment initiation (2004-2007 vs 2008-2012) and use of a central vs local institutional review board (IRB).Main outcomes and measuresThe primary outcome was the median start-up time (from study protocol delivery to first participant enrollment) as compared by trial year and type of IRB used. The median start-up time for the top 10% of sites was also reported. Secondary outcomes included time to site regulatory approval, time to contract execution, and time to site activation.ResultsFor the 9 RCTs included, the median site start-up time shortened only slightly over time from 267 days (interquartile range [IQR], 185-358 days) for 2004-2007 trials to 237 days (IQR, 162-343 days) for 2008-2012 trials (overall median, 255 days [IQR, 177-350 days]; P < .001). For the top 10% of sites, median start-up time was 107 days (IQR, 95-121 days) for 2004-2007 trials vs 104 days (IQR, 84-118 days) for 2008-2012 trials (overall median, 106 days [IQR, 90-120 days]; P = .04). The median start-up time was shorter among sites using a central IRB (199 days [IQR, 140-292 days]) than those using a local IRB (287 days [IQR, 205-390 days]; P < .001).Conclusions and relevanceThis cohort study of North American research sites in large cardiovascular RCTs found a duration of nearly 9 months from the time of study protocol delivery to the first participant enrollment; this metric was only slightly shortened during the study period but was reduced to less than 4 months for top-performing sites. These findings suggest that the use of central IRBs has the potential to improve RCT efficiency.
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Project description:ObjectiveTo study the attributes of quantitative strength testing using hand-held dynamometry (HHD) as an efficacy measure in 2 large phase 3 amyotrophic lateral sclerosis (ALS) trials.MethodsIn the phase 3 trials of ceftriaxone and dexpramipexole, 513 and 943 patients, respectively, were enrolled in double-blind, randomized, placebo-controlled trials with planned follow-up of at least 1 year. Patients were studied every 3 months in the ceftriaxone study and every 2 months in the dexpramipexole study. Evaluators of HHD were trained and had to show evidence of adequate performance of strength testing; the testing paradigm involved testing 9 muscle groups in the upper and lower extremity bilaterally. Neither drug significantly affected any outcome measure. Strength measurements were evaluated by individual muscle and by megascores, which averaged scaled strength measures to produce an overall measure of muscle strength.ResultsA measure combining rate of decline with both within- and between-patient variabilities of measurement, the coefficient of variation for rate of change, was calculated, and showed that HHD overall performed slightly less well than Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) but better than vital capacity. Individual muscles were highly correlated to the identical muscles on the contralateral side, as well as to other muscles in the same body region. Strength decline was correlated both with ALSFRS-R and vital capacity.ConclusionQuantitative strength testing using HHD is a reliable and reproducible measure of decline in ALS.
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Project description:Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.
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Project description:The past decade has seen a dramatic increase in the discovery of candidate biomarkers for ALS. These biomarkers typically can either differentiate ALS from control subjects or predict disease course (slow versus fast progression). At the same time, late-stage clinical trials for ALS have failed to generate improved drug treatments for ALS patients. Incorporation of biomarkers into the ALS drug development pipeline and the use of biologic and/or imaging biomarkers in early- and late-stage ALS clinical trials have been absent and only recently pursued in early-phase clinical trials. Further clinical research studies are needed to validate biomarkers for disease progression and develop biomarkers that can help determine that a drug has reached its target within the central nervous system. In this review we summarize recent progress in biomarkers across ALS model systems and patient population, and highlight continued research directions for biomarkers that stratify the patient population to enrich for patients that may best respond to a drug candidate, monitor disease progression and track drug responses in clinical trials. It is crucial that we further develop and validate ALS biomarkers and incorporate these biomarkers into the ALS drug development process. This article is part of a Special Issue entitled ALS complex pathogenesis.
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Project description:BackgroundThe failure to retain patients or collect primary-outcome data is a common challenge for trials and reduces the statistical power and potentially introduces bias into the analysis. Identifying strategies to minimise missing data was the second highest methodological research priority in a Delphi survey of the Directors of UK Clinical Trial Units (CTUs) and is important to minimise waste in research. Our aim was to assess the current retention practices within the UK and priorities for future research to evaluate the effectiveness of strategies to reduce attrition.MethodsSeventy-five chief investigators of NIHR Health Technology Assessment (HTA)-funded trials starting between 2009 and 2012 were surveyed to elicit their awareness about causes of missing data within their trial and recommended practices for improving retention. Forty-seven CTUs registered within the UKCRC network were surveyed separately to identify approaches and strategies being used to mitigate missing data across trials. Responses from the current practice surveys were used to inform a subsequent two-round Delphi survey with registered CTUs. A consensus list of retention research strategies was produced and ranked by priority.ResultsFifty out of seventy-five (67%) chief investigators and 33/47 (70%) registered CTUs completed the current practice surveys. Seventy-eight percent of trialists were aware of retention challenges and implemented strategies at trial design. Patient-initiated withdrawal was the most common cause of missing data. Registered CTUs routinely used newsletters, timeline of participant visits, and telephone reminders to mitigate missing data. Whilst 36 out of 59 strategies presented had been formally or informally evaluated, some frequently used strategies, such as site initiation training, have had no research to inform practice. Thirty-five registered CTUs (74%) participated in the Delphi survey. Research into the effectiveness of site initiation training, frequency of patient contact during a trial, the use of routinely collected data, the frequency and timing of reminders, triggered site training and the time needed to complete questionnaires was deemed critical. Research into the effectiveness of Christmas cards for site staff was not of critical importance.ConclusionThe surveys of current practices demonstrates that a variety of strategies are being used to mitigate missing data but with little evidence to support their use. Six retention strategies were deemed critically important within the Delphi survey and should be a primary focus of future retention research.
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Project description:Supporting Treatment Adherence Readiness through Training (START) is an HIV antiretroviral adherence intervention, based on the Information Motivation and Behavioral skills (IMB) model, that significantly improved adherence in our randomized controlled trial. To understand how and for whom START had its effects on adherence, we examined mediators and moderators. Ninety-nine HIV-patients (53 control, 46 intervention) who enrolled in the trial and provided month 6 electronic monitored adherence data. The intervention was associated with increased adherence-related knowledge and lower impulsive/careless problem solving, but had no effects on other IMB-related constructs. Neither of these variables mediated the adherence effects of the intervention (based on linear regression models with bootstraping for unbiased standard errors). Four variables interacted with the intervention to moderate its effects: the intervention group had consistent high adherence across the range of depression and time since HIV diagnosis, compared to lower adherence with higher values in the usual care control; those with unstable housing or frequent drug use had higher adherence if in the intervention group compared to the control group. These findings suggest that START provides support that enables its recipients to cope with and overcome challenges (e.g., depression, unstable housing, drug use) that would typically impede adherence.Trial registration: ClinicalTrials.gov identifier: NCT02329782.
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Project description:IntroductionVaginismus is mostly unknown among clinicians and women. Vaginismus causes women to have fear, anxiety, and pain with penetration attempts.AimTo present a large cohort of patients based on prior published studies approved by an institutional review board and the Food and Drug Administration using a comprehensive multimodal vaginismus treatment program to treat the physical and psychologic manifestations of women with vaginismus and to record successes, failures, and untoward effects of this treatment approach.MethodsAssessment of vaginismus included a comprehensive pretreatment questionnaire, the Female Sexual Function Index (FSFI), and consultation. All patients signed a detailed informed consent. Treatment consisted of a multimodal approach including intravaginal injections of onabotulinumtoxinA (Botox) and bupivacaine, progressive dilation under conscious sedation, indwelling dilator, follow-up and support with office visits, phone calls, e-mails, dilation logs, and FSFI reports.Main outcome measuresLogs noting dilation progression, pain and anxiety scores, time to achieve intercourse, setbacks, and untoward effects. Post-treatment FSFI scores were compared with preprocedure scores.ResultsOne hundred seventy-one patients (71%) reported having pain-free intercourse at a mean of 5.1 weeks (median = 2.5). Six patients (2.5%) were unable to achieve intercourse within a 1-year period after treatment and 64 patients (26.6%) were lost to follow-up. The change in the overall FSFI score measured at baseline, 3 months, 6 months, and 1 year was statistically significant at the 0.05 level. Three patients developed mild temporary stress incontinence, two patients developed a short period of temporary blurred vision, and one patient developed temporary excessive vaginal dryness. All adverse events resolved by approximately 4 months. One patient required retreatment followed by successful coitus.ConclusionA multimodal program that treated the physical and psychologic aspects of vaginismus enabled women to achieve pain-free intercourse as noted by patient communications and serial female sexual function studies. Further studies are indicated to better understand the individual components of this multimodal treatment program. Pacik PT, Geletta S. Vaginismus Treatment: Clinical Trials Follow Up 241 Patients. Sex Med 2017;5:e114-e123.
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