Cilostazol and isosorbide mononitrate for the prevention of progression of cerebral small vessel disease: baseline data and statistical analysis plan for the Lacunar Intervention Trial-2 (LACI-2) (ISRCTN14911850).

BACKGROUND: Cerebral small vessel disease (SVD) causes lacunar strokes (25% of all ischaemic strokes), physical frailty and cognitive impairment and vascular and mixed dementia. There is no specific treatment to prevent progression of SVD. METHODS: The LACunar Intervention Trial-2 is an investigator-initiated prospective randomised open-label blinded-endpoint phase II feasibility study assessing cilostazol and isosorbide mononitrate for preventing SVD progression. We aimed to recruit 400 patients with clinically evident lacunar ischaemic stroke and randomised to cilostazol, isosorbide mononitrate, both or neither, in addition to guideline secondary ischaemic stroke prevention, in a partial factorial design. The primary outcome is feasibility of recruitment and adherence to medication; key secondary outcomes include: drug tolerability; recurrent vascular events, cognition and function at 1 year after randomisation; and safety (bleeding, falls, death). Data are number (%) and median (IQR). RESULTS: The trial commenced on 5 February 2018 and ceased recruitment on 31 May 2021 with 363 patients randomised, with the following baseline characteristics: average age 64 (56.0, 72.0) years, female 112 (30.9%), stroke onset to randomisation 79.0 (27.0, 244.0) days, hypertension 267 (73.6%), median blood pressures 143.0 (130.0, 157.0)/83.0 (75.0, 90.0) mm Hg, current smokers 67 (18.5%), educationally achieved end of school examinations (A-level) or higher 118 (32.5%), modified Rankin scale 1.0 (0.0, 1.0), National Institutes Health stroke scale 1.0 (1.4), Montreal Cognitive Assessment 26.0 (23.0, 28.0) and total SVD score on brain imaging 1.0 (0.0, 2.0). This publication summarises the baseline data and presents the statistical analysis plan. SUMMARY: The trial is currently in follow-up which will complete on 31 May 2022 with results expected in October 2022. TRIAL REGISTRATION NUMBER: ISRCTN14911850.

Dietary nitrate supplementation for preventing and reducing the severity of winter infections, including COVID-19, in care homes (BEET-Winter): a randomised placebo-controlled feasibility trial.

PURPOSE: Infections cause considerable care home morbidity and mortality. Nitric oxide (NO) has broad-spectrum anti-viral, bacterial and yeast activity in vitro. We assessed the feasibility of supplementing dietary nitrate (NO substrate) intake in care home residents. METHODS: We performed a cluster-randomised placebo-controlled trial in UK residential and nursing care home residents and compared nitrate containing (400 mg) versus free (0 mg daily) beetroot juice given for 60 days. Outcomes comprised feasibility of recruitment, adherence, salivary and urinary nitrate, and ordinal infection/clinical events. RESULTS: Of 30 targeted care homes in late 2020, 16 expressed interest and only 6 participated. 49 residents were recruited (median 8 [interquartile range 7-12] per home), mean (standard deviation) age 82 (8) years, with proxy consent 41 (84%), advance directive for hospital non-admission 8 (16%) and ≥ 1 doses of COVID-19 vaccine 37 (82%). Background dietary nitrate was < 30% of acceptable daily intake. 34 (76%) residents received > 50% of juice. Residents randomised to nitrate vs placebo had higher urinary nitrate levels, median 50 [18-175] v 18 [10-50] mg/L, difference 25 [0-90]. Data paucity precluded clinical between-group comparisons; the outcome distribution was as follows: no infection 32 (67%), uncomplicated infection 0, infection requiring healthcare support 11 (23%), all-cause hospitalisation 5 (10%), all-cause mortality 0. Urinary tract infections were most common. CONCLUSIONS: Recruiting UK care homes during the COVID-19 pandemic was partially successful. Supplemented dietary nitrate was tolerated and elevated urinary nitrate. Together, infections, hospitalisations and deaths occurred in 33% of residents over 60 days. A larger trial is now required. TRIAL REGISTRATION: ISRCTN51124684. Application date 7/12/2020; assignment date 13/1/2021.

Development of a core outcome set for the evaluation of interventions to prevent COVID-19 in care homes (COS-COVID-PCARE Study).

BACKGROUND: People living in care homes have experienced devastating impact from COVID-19. As interventions to prevent the transmission of COVID-19 are developed and evaluated, there is an urgent need for researchers to agree on the outcomes used when evaluating their effectiveness. Having an agreed set of outcomes that are used in all relevant trials can ensure that study results can be compared. OBJECTIVE: The aim of the study was to develop a core outcome set (COS) for trials assessing the effectiveness of pharmacological and non-pharmacological interventions for preventing COVID-19 infection and transmission in care homes. METHODS: The study used established COS methodology. A list of candidate outcomes was identified by reviewing registered trials to evaluate interventions to prevent COVID-19 in care homes. Seventy key stakeholders participated in a Delphi survey, rating the candidate outcomes on a nine-point scale over two rounds, with the opportunity to propose additional outcomes. Stakeholders included care home representatives (n = 19), healthcare professionals (n = 20), people with personal experience of care homes (n = 7), researchers (n = 15) and others (n = 9). Outcomes were eligible for inclusion if they met an a priori threshold. A consensus meeting with stakeholders resulted in agreement of the final outcome set. RESULTS: Following the Delphi and consensus meeting, twenty-four outcomes were recommended for inclusion. These are grouped across four domains of infection, severity of illness, mortality, and 'other' (intervention specific or life impact). Due to the considerable heterogeneity between care homes, residents, and interventions, the relevance and importance of outcomes may differ between trial contexts. Intervention-specific outcomes would be included only where relevant to a given trial, thus reducing the measurement burden. CONCLUSION: Using a rapid response approach, a COS for COVID-19 prevention interventions in care homes has been developed. Future work should focus on identifying instruments for measuring these outcomes, and the interpretation and application of the COS across different trial contexts. Beyond COVID-19, the outcomes identified in this COS may have relevance to other infectious diseases in care homes, and the rapid response approach may be useful as preparation for future pandemics.

The COVID-19 pandemic has highlighted the need to invest in care home research infrastructure.

The COVID-19 pandemic resulted in catastrophic levels of morbidity and mortality for care home residents. Despite this, research platforms for COVID-19 in care homes arrived late in the pandemic compared with other care settings. The Prophylactic Therapy in Care Homes Trial (PROTECT-CH) was established to provide a platform to deliver multi-centre cluster-randomized clinical trials of investigational medicinal products for COVID-19 prophylaxis in UK care homes. Commencing set-up in January 2021, this involved the design and development of novel infrastructure for contracting and recruitment, remote consent, staff training, research insurance, eligibility screening, prescribing, dispensing and adverse event reporting; such infrastructure being previously absent. By the time this infrastructure was in place, the widespread uptake of vaccination in care homes had changed the epidemiology of COVID-19 rendering the trial unfeasible. While some of the resources developed through PROTECT-CH will enable the future establishment of care home platform research, the near absence of care home trial infrastructure and nationally linked databases involving the care home sector will continue to significantly hamper progress. These issues are replicated in most other countries. Beyond COVID-19, there are many other research questions that require addressing to provide better care to people living in care homes. PROTECT-CH has exposed a clear need for research funders to invest in, and legislate for, an effective care home research infrastructure as part of national pandemic preparedness planning. Doing so would also invigorate care home research in the interim, leading to improved healthcare delivery specific to those living in this sector.

Tackling challenges in care of Alzheimer's disease and other dementias amid the COVID-19 pandemic, now and in the future.

We have provided an overview on the profound impact of COVID-19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health-care settings, including hospital, out-patient, care homes, and the community during the COVID-19 pandemic. We have also proposed a conceptual framework and practical suggestions for health-care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health-care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD-19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term.