Trials In Older People Research Articles

A multicomponent personalized prevention program in the primary care setting: a randomized clinical trial in older people with noncommunicable chronic diseases (Primacare_P3 study)

BackgroundMulticomponent interventions based on a comprehensive geriatric assessment (CGA) could promote active aging and improve health status in older people with Noncommunicable Chronic Diseases (NCDs), but conflicting evidences are available.AimTo evaluate the efficacy of a CGA-based multicomponent personalized preventive program (PPP) in reducing unplanned hospitalization rates during 12-month follow-up in community-dwelling older people with NCDs.Materials and methodsIn this randomized clinical trial (RCT), 1216 older adults recruited by 33 general practitioners (GPs) will be randomly allocated to intervention group (IG) or usual care control group (CG). The IG will receive a multicomponent PPP developed on the findings of the CGA-based Multidimensional Prognostic Index short-form (Brief-MPI), including structured interventions to improve functional, physical, cognitive, and nutritional status, to monitor NCDs and vaccinations, and to prevent social isolation. Participants in the CG will receive usual care. Brief-MPI, resilience, and health-related quality of life will be assessed after 6 and 12 months. Moreover, saliva samples will be collected at baseline in IG to measure biomarkers of oxidative stress, inflammatory cytokines, and oral microbiome.Expected resultsThe CGA-based PPP might reduce unplanned hospitalization rates and potentially institutionalization rates, emergency department (ED) and unplanned GP visits, and mortality. Further outcomes explored in the IG will be the adherence to PPP, resilience, health-related quality of life, and multidimensional frailty as assessed by the Brief-MPI.ConclusionsResults will suggest whether the CGA-based multicomponent PPP is able to improve specific outcomes in a primary care setting.Trial registrationClinicalTrials.gov; identifier: NCT06224556; Registered January 25, 2024.

Биомедицинские исследования с участием пожилых людей: этические аспекты

Due to the aging of the population and growing proportion of the elderly, medicine requires a more active and purposeful approach not only to study theoretical aspects of gerontology, but also to search for new drugs designed specifically for this category of the population. Clinical trials in older people are more in demand than ever. However, researchers must ensure that they conduct their studies ethically. Key ethical issues include prevention of discrimination and violations of the autonomy of older people, as well as special requirements for informing and obtaining voluntary informed consent. When preparing voluntary informed consent for older people, especially for those with cognitive decline, special attention should be paid not only to the information itself, but also to the form of its presentation. The documents should be concise, clear and contain all the key information. In addition, the use of modern multimedia technologies can help the subjects make an informed decision about their participation in the study. For patients with cognitive impairment, it is important to adhere to the principle that the higher the risk for the study participants, the more the patient’s cognitive functions and decision-making ability should be preserved. Excluding patients from studies with potential benefit due to age or cognitive impairment is considered unethical and discriminatory. This is taken as an unfair restriction of their access to the achievements of scientific and technological progress in the field of medicine.

Frailty in clinical drug trials: Frailty assessments, subgroup analyses and outcomes.

With population ageing, drug trials are increasingly turning their attention to including older, frailer people. This review aimed to provide an overview of how frailty was assessed in published studies related to clinical pharmacological trials, and on the interaction of frailty on the efficacy of the treatments. We searched MEDLINE, EMBASE and Cochrane for clinical drug trials in older people. A total of 4031 abstracts were screened and 17 relevant studies were included in this review. We summarized the findings of these 17 trials into five main clinical areas: cardiovascular (eight studies), cognition (one study), vaccination (two studies), cancer (four studies) and other (two studies). Frailty was assessed retrospectively in most of the studies. Frailty was treated as an ordinal variable (with different levels of frailty) or binary variable (frail/non-frail) using cut-offs in some studies, and as a continuous in some other studies. The effect of frailty on the treatment efficacy was not consistent among the studies. While several trials, such as the Action in Diabetes and Vascular Disease-Preterax and Diamicron Modified Release Controlled Evaluation trials, the Systolic Blood Pressure Intervention Trial and the Aspirin in Reducing Events in the Elderly trial, showed some reduced effects of the treatment in frail patients, most of the trials showed that the benefits of the treatment are not affected by frailty. Some trials even showed that the benefits of the treatment were more significant in frailer patients (the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure and the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure trials). The results of this review suggest that routine measurement of frailty in participants in clinical drug trials would improve our knowledge of the effect of treatment in the frail and identify those who have more or least to gain from treatment.

Novel 3-arm wait-list controlled trial designs together with mixed-effects analysis improve precision of treatment effect estimators

ABSTRACT Clinical trialists have long been searching for approaches to increase statistical power without increasing sample size. Conventional wait-list controlled (WLC) trials are limited to two trial arms and two or three repeated measurements per person. These features limit statistical power. Furthermore, their analysis is usually based on analysis of covariance or mixed effects modelling, with a focus on estimating treatment effect at one time-period after initiation of therapy. We propose two 3-arm WLC trial designs together with a mixed-effects analysis framework. The designs require three or four repeated measurements per person. The analytic framework defines up to three treatment effect estimands, representing the effects at one to three time-periods after initiation of therapy. The precision (inverse of variance) of the treatment effect estimators in the new and conventional trial designs are analytically derived and evaluated in simulations. The results are interpreted in the context of a cognitive training trial in older people. The proposed designs and analysis methods increase the precision level of treatment effect estimators as compared to conventional designs and analyses. Given a target level of statistical power, the proposed methods require a smaller number of participants per trial than the conventional methods, without necessarily increasing the number of measurements per trial. Furthermore, the proposed analytic framework sheds light on the treatment effects at different times after initiation of therapy, which is not usually considered in conventional WLC trial analysis. In situations that a WLC trial is appropriate, the 3-arm designs are useful alternatives to existing 2-arm designs.

Temporal changes in characteristics and external validity of randomized controlled trials in older people from 2012 to 2019

BackgroundOlder individuals are often underrepresented in clinical trials. In 2012 only 7% of RCT’s specifically studied older people and their geriatric characteristics were poorly reported. The aim of this review was to investigate temporal changes in characteristics and external validity of randomized controlled trials in older people from 2012 to 2019.MethodsPubMed was searched for randomized clinical trials (RCTs) published in 2019. Firstly, the proportion of RCTs specially designed for older people were determined by the following criteria: a reported mean age of ≥ 70 years or a lower age cutoff of ≥ 55. Secondly, the trials with a majority of older people, defined by a reported mean age of ≥ 60 years, were screened for reporting of geriatric assessments. Both parts were compared with identical reviews performed in 2012.ResultsFrom a 10% random sample, 1446 RCTs were included in this systematic review. First, 8% of trials were specifically designed for older people in 2019 compared to 7% in 2012. Secondly, 25% of the trials included a majority of older people in 2019, compared to 22% in 2012. Thirdly, in 52% of these trials in 2019 one or more of the geriatric assessments were reported compared to 34% in 2012.ConclusionsAlthough in 2019 the proportion of published RCTs specifically designed for older people remains low, more characteristics on geriatric assessments were reported compared to 2012. Continued efforts should be paid to increase both the number and the validity of trials for older people.

Clinical trials in older people.

Randomised controlled trials (RCTs) usually provide the best evidence for treatments and management. Historically, older people have often been excluded from clinical medication trials due to age, multimorbidity and disabilities. The situation is improving, but still the external validity of many trials may be questioned. Individuals participating in trials are generally less complex than many patients seen in geriatric clinics.Recruitment and retention of older participants are particular challenges in clinical trials. Multiple channels are needed for successful recruitment, and especially individuals experiencing frailty, multimorbidity and disabilities require support to participate. Cognitive decline is common, and often proxies are needed to sign informed consent forms. Older people may fall ill or become tired during the trial, and therefore, special support and empathic study personnel are necessary for the successful retention of participants.Besides the risk of participants dropping out, several other pitfalls may result in underestimating or overestimating the intervention effects. In nonpharmacological trials, imperfect blinding is often unavoidable. Interventions must be designed intensively and be long enough to reveal differences between the intervention and control groups, as control participants must still receive the best normal care available. Outcome measures should be relevant to older people, sensitive to change and targeted to the specific population in the trial. Missing values in measurements are common and should be accounted for when designing the trial.Despite the obstacles, RCTs in geriatrics must be promoted. Reliable evidence is needed for the successful treatment, management and care of older people.

ASSERT (Acute Sacral inSufficiEncy fractuRe augmenTation): randomised controlled, feasibility trial in older people

ObjectiveTo determine the feasibility of designing and conducting a definitive trial to evaluate the effectiveness of sacral fracture fixation compared with non-surgical management among older people admitted with a lateral...

Challenges of a Statin Trial in Older People

See the Reply by Singh et al.

A Proposal for the Retrospective Identification and Categorization of Older People With Functional Impairments in Scientific Studies—Recommendations of the Medication and Quality of Life in Frail Older Persons (MedQoL) Research Group

When treating older adults, a main factor to consider is physical frailty. Because specific assessments in clinical trials are frequently lacking, critical appraisal of treatment evidence with respect to functional status is challenging. Our aim was to identify and categorize assessments for functional status given in clinical trials in older adults to allow for a retrospective characterization and indirect comparison of treatment evidence from these cohorts. We conducted 4 separate systematic reviews of randomized and nonrandomized controlled clinical trials in older people with hypertension, diabetes, depression, and dementia. All assessments identified that reflected functional status were analyzed. Assessments were categorized across 4 different functional status levels. These levels span from functionally not impaired, slightly impaired, significantly impaired, to severely impaired/disabled. If available from the literature, cut-offs for these 4 functioning levels were extracted. If not, or if the existing cut-offs did not match the predefined functional levels, cut-off points were defined by an expert group composed of geriatricians, pharmacists, pharmacologists, neurologists, psychiatrists, and epidemiologists using a patient-centered approach. We identified 51 instruments that included measures of functional status. Although some of the assessments had clearly defined cut-offs across our predefined categories, many others did not. In most cases, no cut-offs existed for slightly impaired or severely impaired older adults. Missing cut-offs or values to adjust were determined by the expert group and are presented as described. The functional status assessments that were identified and operationalized across 4 functional levels could now be used for a retrospective characterization of functional status in randomized controlled trials and observational studies. Allocated categories only serve as approximations and should be validated head-to-head in future studies. Moreover, as general standard, upcoming studies involving older adults should include and explicitly report functional impairment as a baseline characteristic of all participants enrolled.

Serum high-density lipoprotein cholesterol is a protective predictor of executive function in older patients with diabetes mellitus.

Aims/IntroductionOlder people with diabetes mellitus are at high risk for cognitive impairment or dementia. The clinical predictors for cognitive decline in older people with diabetes mellitus were elucidated.Materials and MethodsThis was a secondary analysis of a vitamin B12 intervention trial in older people with diabetes mellitus. A total of 271 non‐demented individuals were followed up at 9‐month intervals for 27 months. We explored the association between baseline clinical features with changes in cognitive measures (Clinical Dementia Rating scale, Neuropsychological Test Battery including executive function z‐scores, psychomotor speed z‐scores and memory z‐scores).ResultsA total of 152 participants had normal cognition (Clinical Dementia Rating 0) and 119 had cognitive impairment (Clinical Dementia Rating 0.5) at baseline. After 27 months, 41 participants had cognitive decline, 36 of whom were cognitively normal at baseline. Multiple logistic regression showed no significant clinical predictor of global cognitive decline. Higher high‐density lipoprotein cholesterol (HDL‐C) was associated with better executive performance at month 27 (β = 0.359, P < 0.001). Multilevel modeling showed that the highest tertile of HDL‐C was associated with better executive function z‐scores than the lowest tertile of HDL‐C at all time‐points.ConclusionsAmong older people with diabetes mellitus, higher serum HDL‐C was associated with better executive function.

Effect of dietary omega-3 fatty acid supplementation on frailty-related phenotypes in older adults: a systematic review and meta-analysis protocol

IntroductionThe beneficial effect of dietary omega-3 supplementation in younger adults or older people with acute or chronic disease is established. Knowledge is now needed about the effect in medically stable...

The role of dose administration aids in medication management for older people

AbstractWhile medicine use in the older population is high, adherence to prescribed regimens is often suboptimal. Older people may be unintentionally non‐adherent due to difficulties managing and manipulating medicines. Dose administration aids are medicine packaging systems designed to reduce unintentional non‐adherence by simplifying management of oral medicines and enabling people to see if they have taken their medicines. Evidence suggests dose administration aids can improve medicine adherence but the size of this benefit is unclear and there is little evidence from controlled trials in older people or people taking multiple medicines. There is no conclusive evidence that they improve health outcomes. Use of an aid is limited to medicines suitable and stable for repackaging. Other limitations include reduced user medicine knowledge and autonomy, risk of filling discrepancies and incorrect use, and increased complexity at transitions of care. Upon consideration of a dose administration aid, a comprehensive assessment of the patient's medication management and a review of their medicines is required. Dose administration aids are best combined with other medication management strategies, such as medicine lists and education, and are most effective in people who are motivated to take their medicines and who have the required physical and cognitive capacity to use an aid.

Mechanisms, Efficacy, and Safety ofBacopa monnieri(Brahmi) for Cognitive and Brain Enhancement

The plant Bacopa monnieri (water hyssop, Brahmi, thyme-leaved Gratiola, herb of grace, and Indian pennywort) is a perennial, creeping herb native to the wet lands of India, particularly northeast and southern regions. Bacopa is an important plant of Ayurveda, where it is named as Brahmi, after Lord Brahma, the mythological creator of the world and originator of the science of Ayurveda. Bacopa is frequently mentioned in the religious, social, and medical treatises of India since the time of Vedic civilization. Its antiquity can be traced to the time of Athar Ved (the science of well-being) written in 800 BC where Bacopa finds a mention in the very first verse of the third chapter of Athar Samhita (compilation on the factors promoting well-being). More recently researchers have turned their attention to better understanding the mechanisms and efficacy of various extracts of Bacopa monnieri on human conditions. Although extracts of Bacopa have been studied and used to treat various disorders for centuries (pain, epilepsy, and inflammation, amongst many) perhaps the chief therapeutic claim concerning its benefits has been in improving memory. The Indian government has invested significant resources and conducted hundreds of studies examining the mechanisms of action on the brain and at a cellular level. Interestingly this research has uncovered a myriad of possible mechanisms relating to anti-inflammatory, antioxidant, metal chelation, amyloid, and cholinergic effects amongst many others. Although it is not unusual for plant based medicines to have multiple effects on cellular processes, Bacopa monnieri is perhaps one of the most scientifically studied in terms of mechanisms of action. Interestingly these mechanisms seem to comprehensively map on to the biological mechanisms that many researchers have argued underpin cognitive and memory processes. In 1996 a special extract of Bacopa monnieri was launched by the Indian Government's Central Drug Research Institute, Lucknow, termed CDRI 08. It was thought at the time that this particular standardised extract had been subjected to the most research and was the most promising extract for medical conditions. In 2010 the three editors for this special issue attended CDRI's 60th research anniversary where a special one-day symposium on research on CDRI 08 was held. It is this extract of Bacopa monnieri that is the focus of most of the papers in this special issue which reports studies relating to the safety, mechanisms, and efficacy of specific extracts of Bacopa monnieri. Over the last ten years there have been growing scientific studies on this interesting terrestrial herb. As can be seen in Figure 1 the number of publications concerning Bacopa monnieri is steadily growing reflecting increasing scientific interest in this plant for human conditions. Most of these studies reflect scientific endeavours relating to cellular mechanisms. As such these studies are an excellent base to launch larger clinical trials in humans. Although much is known about the mechanisms of Bacopa extracts on the brain there are still significant gaps in our knowledge. For instance, long-term chronic trials in older people are now required to understand whether Bacopa extracts such as CDRI 08 can prevent age-related cognitive decline or even more insidious diseases such as Alzheimer's dementia. We note that a number of studies are also currently examining the effect of Bacopa extracts on improving cognitive and behavioural function in younger people. Clearly the next decade will focus on larger clinical trials in humans and expand upon the excellent animal and preclinical work mainly conducted in India. Figure 1 Con Stough Hemant Singh Andrea Zangara

Does a complex intervention by primary care nurses increase walking in older people? Outcomes at 3 and 12 months in the PACE-Lift (Pedometer Accelerometer Consultation Evaluation-Lift) cluster-randomised controlled trial

BackgroundWalking is the commonest physical activity done by older people. Intensity can be light if strolling, and moderate if brisker. We assessed whether a primary care nurse-delivered complex intervention increased walking. MethodsOur study was a parallel two-arm cluster-randomised trial, randomised by household, by researcher using an internet randomisation service. 988 people aged 60–75 years, with no contraindications to increasing their walking, randomly selected from three UK general practices, were invited to participate. 298 people from 250 households were randomised to intervention (150 individuals) or usual care control group (148 individuals). During 3 months, intervention participants received four consultations from their own practice nurse about their physical activity, incorporating behaviour change techniques, feedback on step-counts as measured by pedometer and intensity of physical activity as measured by accelerometer, and an individual physical activity diary and plan. Outcomes were accelerometer-assessed change in average daily step counts over 7 days (primary outcome) and average time spent in physical activity of moderate-to-vigorous intensity weekly (secondary outcome) between baseline, 3 months, and 12 months. Adverse events were recorded by self-administered questionnaire. Assessors were not masked to group allocation. Analysis was by intention to treat, controlling for household clustering (intraclass correlation coefficient=0·004 at 3 months, 0·16 at 12 months). This trial is registered with Current Controlled Trials, ISRCTN42122561. FindingsOutcome data were available for 280 (94%) individuals. Mean baseline average daily step-count was 7388 (SD 2218) in the intervention group and 7453 (2463) in the control group. At 3 months both average daily step-counts and average weekly moderate-to-vigorous physical activity increased significantly more in the intervention than in the control group by 1037 steps per day (95% CI 513–1560) and 66 min per week (36–96), respectively. At 12 months the corresponding differences were 609 (104–1115) and 40 (10–70). Differences in adverse events between intervention and control groups were not significant at either 3 months or 12 months (−4% [95% CI −15 to 7] vs −1% [–13 to 11], respectively). InterpretationIn the PACE-Lift trial, both step-counts and moderate-to-vigorous physical activity increased in people aged 60–75 years at 3 and 12 months. To our knowledge, this is the first trial in older people to show objective increases in moderate-to-vigorous physical activity, and it highlights the value of both accelerometry physical activity assessment and primary care as a setting for phyisical activity interventions. If these differences in physical activity are sustained they should lead to important differences in health outcomes. FundingNational Institute for Health Research Research for Patient Benefit Programme.

The A4 Study: Stopping AD Before Symptoms Begin?

A new secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer's disease dementia should provide insights into whether anti-amyloid therapy can delay cognitive decline.

Pharmacist-led interventions to reduce unplanned admissions for older people: a systematic review and meta-analysis of randomised controlled trials

medication problems are thought to cause between 10 and 30% of all hospital admissions in older people. This systematic review aimed to evaluate the effectiveness of interventions led by hospital or community pharmacists in reducing unplanned hospital admissions for older people. eighteen databases were searched with a customised search strategy. Relevant websites and reference lists of included trials were checked. Randomised controlled trials were included that evaluated pharmacist-led interventions compared with usual care, with unplanned admissions or readmissions as an outcome. Two authors independently extracted data and assessed methodological quality. twenty-seven randomised controlled trials (RCTs) were identified; seven trials were excluded. The 20 included trials comprised 16 for older people and 4 for older people with heart failure. Interventions led by hospital pharmacists (seven trials) or community pharmacists (nine trials) did not reduce unplanned admissions in the older population (risk ratios 0.97 95% CI: 0.88, 1.07; 1.07 95% CI: 0.96, 1.20). Three trials in older people with heart failure showed that interventions delivered by a hospital pharmacist reduced the relative risk of admissions. However, these trials were heterogeneous in intensity and duration of follow-up. One trial had a high risk of bias. evidence from three randomised controlled trials suggests that interventions led by hospital pharmacists reduce unplanned hospital admissions in older patients with heart failure, although these trials were heterogeneous. Data from 16 trials do not support the concept that interventions led by hospital or community pharmacists for the general older population reduces unplanned admissions.

Clinical trials in older people: are we being ageist?

The next few decades will witness a large increase in the number of older people in the population, principally those aged 80 and over. This age group also has the highest prevalence of disease and disability. Therefore, one might expect that the evidence base on how best to treat this group would be well established, but this is not the case. Older people, especially those with physical and mental health comorbidities, continue to be unjustifiably excluded from clinical trials [1,2]. This raises the question as to whether the exclusion of older people from such investigations can be considered as ageist and whether, as a consequence, older people suffer from age discrimination

Design considerations in long-term intervention studies for the prevention of cognitive decline or dementia

The results of randomized controlled trials of nutritional interventions aimed at preventing cognitive decline or dementia in older people have been largely disappointing. A reasonable argument can be made that this is at least in part because the design of primary prevention trials in older people is not straightforward and that the complexities of such trials are not readily apparent and commonly remain not fully recognized. This article analyzes some of the difficulties associated with identifying and enrolling study participants in long-term prevention trials, with available data from three large, recently published trials used as examples. This analysis also serves to identify examples of good practice and areas for further research. Randomized controlled trials remain the single most important tool in the epidemiological arsenal for identifying the effects of specific interventions, but consideration of critically important design features is essential.

Neurology in the elderly: more trials urgently needed

The rapidly increasing elderly population poses a major challenge for future health-care systems. Many of the diseases of old age are neurological disorders, so neurological practice is likely to be disproportionately affected by an ageing society. However, as highlighted in two Reviews in this issue of The Lancet Neurology, there is a dearth of clinical trials among older people—indeed, very elderly patients are systematically excluded from many clinical trials. If we are to meet the challenge of caring for the rising numbers of elderly patients in the future, more good-quality trials in older people are needed to inform clinical practice.

Vitamin D supplementation and type 2 diabetes: a substudy of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438)

Vitamin D supplementation and type 2 diabetes: a substudy of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438)