Democratising the design and delivery of large-scale randomised, controlled clinical trials in primary care: A personal view.

BACKGROUND: Rapid identification of effective treatments for use in the community during a pandemic is vital for the well-being of individuals and the sustainability of healthcare systems and society. Furthermore, identifying treatments that do not work reduces research wastage, spares people unnecessary side effects, rationalises the cost of purchasing and stockpiling medication, and reduces inappropriate medication use. Nevertheless, only a small minority of therapeutic trials for SARS-CoV-2 infections have been in primary care: most opened too late, struggled to recruit, and few produced actionable results. Participation in research is often limited by where one lives or receives health care, and trial participants may not represent those for whom the treatments are intended. INNOVATIVE TRIALS: The ALIC4E, PRINCIPLE and the ongoing PANORAMIC trial have randomised over 40,500 people with COVID-19. This personal view describes how these trials have innovated in: trial design (by using novel adaptive platform designs); trial delivery (by complementing traditional site-based recruitment ('the patient comes to the research') with mechanisms to enable sick, infectious people to participate without having to leave home ('taking research to the people'), and by addressing the 'inverse research participation law,' which highlights disproportionate barriers faced by those who have the most to contribute, and benefit from, research, and; in transforming the evidence base by evaluating nine medicines to support guidelines and care decisions world-wide for COVID-19 and contribute to antimicrobial stewardship. CONCLUSION: The PRINCIPLE and PANORAMIC trials represent models of innovation and inclusivity, and exemplify the potential of primary care to lead the way in addressing pressing global health challenges.

Adaptive platform trials can efficiently evaluate several treatments in parallel and sequentially'Taking research to people' can democratise participation by enabling sick, contagious people to contribute from home, country-wideThe PRINCIPLE and PANORAMIC Trials innovated in trial design and delivery to produce evidence on nine treatments for COVID-19 in the community.

Assessing acutely ill children in general practice using the National PEWS and LqSOFA clinical scores: a retrospective cohort study.

BACKGROUND: Clinical tools are needed in general practice to help identify seriously ill children. The Liverpool quick Sequential Organ Failure Assessment (LqSOFA) was validated in an Emergency Department and performed well. The National Paediatric Early Warning score (PEWS) has been introduced in hospitals throughout England with hopes for implementation in general practice. AIM: To validate the LqSOFA and National PEWS in general practice. DESIGN/SETTING: Secondary analysis of 6,703 children <5 years presenting to 225 general practices in England and Wales with acute illnesses, linked to hospital data. METHOD: Variables from the LqSOFA and National PEWS were mapped onto study data to calculate score totals. A primary outcome of admission within two days of GP consultation was used to calculate sensitivity, specificity, negative predictive values (NPV), positive predictive values (PPV) and area-under-the-curve (AUC). RESULTS: 104/6,703 children were hospitalised within two days (pre-test probability 1.6%). The sensitivity of the LqSOFA was 30.6% (95% confidence interval 21.8% - 41.0%), with a specificity of 84.7% (83.7% - 85.6%), PPV of 3.0% (2.1% - 4.4%), NPV of 98.7% (98.4% - 99.0%), and AUC of 0.58 (0.53 - 0.63). The sensitivity of the National PEWS was 81.0% (71.0% - 88.1%), with a specificity of 32.5% (31.2% - 33.8%); PPV of 1.9% (1.5% - 2.5%); NPV of 99.1% (98.4% - 99.4%) and AUC of 0.66 (0.59 - 0.72). CONCLUSION: Although the NPVs appear useful, due to low pre-test probabilities rather than discriminative ability, neither tool accurately identified hospitalisations. Unconsidered use by GPs could result in unsustainable referrals.

Long-term consequences of urinary tract infection in childhood: an electronic population-based cohort study in Welsh primary and secondary care.

BACKGROUND: Childhood urinary tract infection (UTI) can cause renal scarring, and possibly hypertension, chronic kidney disease (CKD), and end-stage renal failure (ESRF). Previous studies have focused on selected populations, with severe illness or underlying risk factors. The risk for most children with UTI is unclear. AIM: To examine the association between childhood UTI and outcomes in an unselected population of children. DESIGN AND SETTING: A retrospective population-based cohort study using linked GP, hospital, and microbiology records in Wales, UK. METHOD: Participants were all children born in 2005-2009, with follow-up until 31 December 2017. The exposure was microbiologically confirmed UTI before the age of 5 years. The key outcome measures were renal scarring, hypertension, CKD, and ESRF. RESULTS: In total, 159 201 children were included; 77 524 (48.7%) were female and 7% (n = 11 099) had UTI before the age of 5 years. A total of 0.16% (n = 245) were diagnosed with renal scarring by the age of 7 years. Odds of renal scarring were higher in children by age 7 years with UTI (1.24%; adjusted odds ratio 4.60 [95% confidence interval [CI] = 3.33 to 6.35]). Mean follow-up was 9.53 years. Adjusted hazard ratios were: 1.44 (95% CI = 0.84 to 2.46) for hypertension; 1.67 (95% CI = 0.85 to 3.31) for CKD; and 1.16 (95% CI = 0.56 to 2.37) for ESRF. CONCLUSION: The prevalence of renal scarring in an unselected population of children with UTI is low. Without underlying risk factors, UTI is not associated with CKD, hypertension, or ESRF by the age of 10 years. Further research with systematic scanning of children's kidneys, including those with less severe UTI and without UTI, is needed to increase the certainty of these results, as most children are not scanned. Longer follow-up is needed to establish if UTI, without additional risk factors, is associated with hypertension, CKD, or ESRF later in life.

Urine tenofovir and dried blood spot tenofovir diphosphate concentrations and viraemia in people taking efavirenz and dolutegravir-based antiretroviral therapy.

OBJECTIVE: We aimed to determine whether urine tenofovir (TFV) and dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations are associated with concurrent HIV viraemia. DESIGN: Cross-sectional study among people with HIV (PWH) receiving tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART). METHODS: We used dual tandem liquid chromatography and mass spectrometry to measure urine TFV and DBS TFV-DP concentrations, and evaluated their associations with concurrent viraemia at least 1000 copies/ml using logistic regression models. In exploratory analyses, we used receiver operating curves (ROCs) to estimate optimal urine TFV and DBS TFV-DP thresholds to predict concurrent viraemia. RESULTS: Among 124 participants, 68 (54.8%) were women, median age was 39 years [interquartile range (IQR) 34-45] and 74 (59.7%) were receiving efavirenz versus 50 (40.3%) receiving dolutegravir. Higher concentrations of urine TFV [1000 ng/ml increase, odds ratio (OR) 0.97 95% CI 0.94-0.99, P  = 0.005] and DBS TFV-DP (100 fmol/punch increase, OR 0.76, 95% CI 0.67-0.86, P  < 0.001) were associated with lower odds of viraemia. There was evidence that these associations were stronger among people receiving dolutegravir than among people receiving efavirenz (urine TFV, P  = 0.072; DBS TFV-DP, P  = 0.003). Nagelkerke pseudo- R2 for the DBS TFV-DP models was higher for the urine TFV models, demonstrating a stronger relationship between DBS TFV-DP and viraemia. Among people receiving dolutegravir, a DBS TFV-DP concentration of 483 fmol/punch had 88% sensitivity and 85% specificity to predict concurrent viraemia ≥1000 copies/ml. CONCLUSION: Among PWH receiving TDF-based ART, urine TFV concentrations, and in particular DBS TFV-DP concentrations, were strongly associated with concurrent viraemia, especially among people receiving dolutegravir.

d-Mannose for Prevention of Recurrent Urinary Tract Infection Among Women: A Randomized Clinical Trial.

Importance: Recurrent urinary tract infection (UTI) is a common debilitating condition in women, with limited prophylactic options. d-Mannose has shown promise in trials based in secondary care, but effectiveness in placebo-controlled studies and community settings has not been established. Objective: To determine whether d-mannose taken for 6 months reduces the proportion of women with recurrent UTI experiencing a medically attended UTI. Design, Setting, and Participants: This 2-group, double-blind randomized placebo-controlled trial took place across 99 primary care centers in the UK. Participants were recruited between March 28, 2019, and January 31, 2020, with 6 months of follow-up. Participants were female, 18 years or older, living in the community, and had evidence in their primary care record of consultations for at least 2 UTIs in the preceding 6 months or 3 UTIs in 12 months. Invitation to participate was made by their primary care center. A total of 7591 participants were approached, 830 responded, and 232 were ineligible or did not proceed to randomization. Statistical analysis was reported in December 2022. Intervention: Two grams daily of d-mannose powder or matched volume of placebo powder. Main Outcomes and Measures: The primary outcome measure was the proportion of women experiencing at least 1 further episode of clinically suspected UTI for which they contacted ambulatory care within 6 months of study entry. Secondary outcomes included symptom duration, antibiotic use, time to next medically attended UTI, number of suspected UTIs, and UTI-related hospital admissions. Results: Of 598 women eligible (mean [range] age, 58 [18-93] years), 303 were randomized to d-mannose (50.7%) and 295 to placebo (49.3%). Primary outcome data were available for 583 participants (97.5%). The proportion contacting ambulatory care with a clinically suspected UTI was 150 of 294 (51.0%) in the d-mannose group and 161 of 289 (55.7%) in the placebo group (risk difference, -5%; 95% CI, -13% to 3%; P = .26). Estimates were similar in per protocol analyses, imputation analyses, and preplanned subgroups. There were no statistically significant differences in any secondary outcome measures. Conclusions and Relevance: In this randomized clinical trial, daily d-mannose did not reduce the proportion of women with recurrent UTI in primary care who experienced a subsequent clinically suspected UTI. d-Mannose should not be recommended for prophylaxis in this patient group. Trial Registration: isrctn.org Identifier: ISRCTN13283516.

Did aetiology matter in illness duration and complications in patients presenting in primary care with acute respiratory tract infections early in the COVID-19 pandemic: An observational study in nine countries.

BACKGROUND: Despite considerable research into COVID-19 sequelae, little is known about differences in illness duration and complications in patients presenting in primary care with symptoms of acute respiratory tract infections (RTI) that are and are not attributed to SARS-CoV-2 infection. OBJECTIVE: To explore whether aetiology impacted course of illness and prediction of complications in patients presenting in primary care with symptoms of RTI early in the COVID-19 pandemic. METHODS: Between April 2020-March 2021 general practitioners from nine European countries recruited consecutively contacting patients with RTI symptoms. At baseline, an oropharyngeal-nasal swab was obtained for aetiology determination using PCR after follow-up of 28 days. Time to self-reported recovery was analysed with Kaplan-Meier curves. Predictors (baseline variables of demographics, patient and disease characteristics) of a complicated course (composite of hospital admission and persisting signs/symptoms at 28 days follow-up) were explored with logistic regression modelling. RESULTS: Of 855 patients with RTI symptoms, 237 (27.7%) tested SARS-CoV-2 positive. The proportion not feeling fully recovered (15.6% vs 18.1%, p = 0.39), reporting being extremely tired (9.7% vs 12.8%, p = 0.21), and not having returned to usual daily activities (18.1% vs 14.4%, p = 0.18) at day 28 were comparable between SARS-CoV-2 positive (n = 237) and negative (n = 618) groups. However, among those feeling fully recovered (SARS-CoV-2 positive: 200 patients, SARS-CoV-2 negative: 506 patients), time to full recovery was significantly longer in SARS-CoV-2 patients (10.6 vs 7.7 days, p < 0.001). We found no evidence that predictors of a complicated course differed between groups (p = 0.07). CONCLUSION: Early in the pandemic, the proportion of patients not feeling fully recovered by 28 days was similar between SARS-CoV-2 positive and negative patients presenting in primary care with RTI symptoms, but it took somewhat longer for SARS-CoV-2 patients to feel fully recovered. More research is needed on predictors of a complicated course in RTI.

Our primary care-based observational study found that recovery by 28 days was comparable between SARS-CoV-2 positive and negative RTI patients.Future research is needed to unravel which host- and pathogen-related profiles are associated with higher risk of complications and persisting symptoms among patients presenting in primary care with RTI symptoms.

Ivermectin for COVID-19 in adults in the community (PRINCIPLE): An open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.

BACKGROUND: The evidence for whether ivermectin impacts recovery, hospital admissions, and longer-term outcomes in COVID-19 is contested. The WHO recommends its use only in the context of clinical trials. METHODS: In this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial, we included participants aged ≥18 years in the community, with a positive SARS-CoV-2 test, and symptoms lasting ≤14 days. Participants were randomised to usual care, usual care plus ivermectin tablets (target 300-400 µg/kg per dose, once daily for 3 days), or usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery, and COVID-19 related hospitalisation/death within 28 days, analysed using Bayesian models. Recovery at 6 months was the primary, longer term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis included 8811 SARS-CoV-2 positive participants (median symptom duration 5 days), randomised to ivermectin (n = 2157), usual care (n = 3256), and other treatments (n = 3398) from June 23, 2021 to July 1, 2022. Time to self-reported recovery was shorter in the ivermectin group compared with usual care (hazard ratio 1·15 [95% Bayesian credible interval, 1·07 to 1·23], median decrease 2.06 days [1·00 to 3·06]), probability of meaningful effect (pre-specified hazard ratio ≥1.2) 0·192). COVID-19-related hospitalisations/deaths (odds ratio 1·02 [0·63 to 1·62]; estimated percentage difference 0% [-1% to 0·6%]), serious adverse events (three and five respectively), and the proportion feeling fully recovered were similar in both groups at 6 months (74·3% and 71·2% respectively (RR = 1·05, [1·02 to 1·08]) and also at 3 and 12 months. INTERPRETATION: Ivermectin for COVID-19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes. Further trials of ivermectin for SARS-Cov-2 infection in vaccinated community populations appear unwarranted. FUNDING: UKRI/National Institute of Health Research (MC_PC_19079).

Nasal sprays and behavioural interventions compared with usual care for acute respiratory illness in primary care: a randomised, controlled, open-label, parallel-group trial.

BACKGROUND: A small amount of evidence suggests that nasal sprays, or physical activity and stress management, could shorten the duration of respiratory infections. This study aimed to assess the effect of nasal sprays or a behavioural intervention promoting physical activity and stress management on respiratory illnesses, compared with usual care. METHODS: This randomised, controlled, open-label, parallel-group trial was done at 332 general practitioner practices in the UK. Eligible adults (aged ≥18 years) had at least one comorbidity or risk factor increasing their risk of adverse outcomes due to respiratory illness (eg, immune compromise due to serious illness or medication; heart disease; asthma or lung disease; diabetes; mild hepatic impairment; stroke or severe neurological problem; obesity [BMI ≥30 kg/m2]; or age ≥65 years) or at least three self-reported respiratory tract infections in a normal year (ie, any year before the COVID-19 pandemic). Participants were randomly assigned (1:1:1:1) using a computerised system to: usual care (brief advice about managing illness); gel-based spray (two sprays per nostril at the first sign of an infection or after potential exposure to infection, up to 6 times per day); saline spray (two sprays per nostril at the first sign of an infection or after potential exposure to infection, up to 6 times per day); or a brief behavioural intervention in which participants were given access to a website promoting physical activity and stress management. The study was partially masked: neither investigators nor medical staff were aware of treatment allocation, and investigators who did the statistical analysis were unaware of treatment allocation. The sprays were relabelled to maintain participant masking. Outcomes were assessed using data from participants' completed monthly surveys and a survey at 6 months. The primary outcome was total number of days of illness due to self-reported respiratory tract illnesses (coughs, colds, sore throat, sinus or ear infections, influenza, or COVID-19) in the previous 6 months, assessed in the modified intention-to-treat population, which included all randomly assigned participants who had primary outcome data available. Key secondary outcomes were possible harms, including headache or facial pain, and antibiotic use, assessed in all randomly assigned participants. This trial was registered with ISRCTN, 17936080, and is closed to recruitment. FINDINGS: Between Dec 12, 2020, and April 7, 2023, of 19 475 individuals screened for eligibility, 13 799 participants were randomly assigned to usual care (n=3451), gel-based nasal spray (n=3448), saline nasal spray (n=3450), or the digital intervention promoting physical activity and stress management (n=3450). 11 612 participants had complete data for the primary outcome and were included in the primary outcome analysis (usual care group, n=2983; gel-based spray group, n=2935; saline spray group, n=2967; behavioural website group, n=2727). Compared with participants in the usual care group, who had a mean of 8·2 (SD 16·1) days of illness, the number of days of illness was significantly lower in the gel-based spray group (mean 6·5 days [SD 12·8]; adjusted incidence rate ratio [IRR] 0·82 [99% CI 0·76-0·90]; p<0·0001) and the saline spray group (6·4 days [12·4]; 0·81 [0·74-0·88]; p<0·0001), but not in the group allocated to the behavioural website (7·4 days [14·7]; 0·97 [0·89-1·06]; p=0·46). The most common adverse event was headache or sinus pain in the gel-based group: 123 (4·8%) of 2556 participants in the usual care group; 199 (7·8%) of 2498 participants in the gel-based group (risk ratio 1·61 [95% CI 1·30-1·99]; p<0·0001); 101 (4·5%) of 2377 participants in the saline group (0·81 [0·63-1·05]; p=0·11); and 101 (4·5%) of 2091 participants in the behavioural intervention group (0·95 [0·74-1·22]; p=0·69). Compared with usual care, antibiotic use was lower for all interventions: IRR 0·65 (95% CI 0·50-0·84; p=0·001) for the gel-based spray group; 0·69 (0·45-0·88; p=0·003) for the saline spray group; and 0·74 (0·57-0·94; p=0·02) for the behavioural website group. INTERPRETATION: Advice to use either nasal spray reduced illness duration and both sprays and the behavioural website reduced antibiotic use. Future research should aim to address the impact of the widespread implementation of these simple interventions. FUNDING: National Institute for Health and Care Research.

Cost-utility analysis of molnupiravir for high-risk, community-based adults with COVID-19: an economic evaluation of the PANORAMIC trial.

BACKGROUND: The cost-effectiveness of molnupiravir, an oral antiviral for early treatment of SARS-CoV-2, has not been established in vaccinated populations. AIM: To evaluate the cost-effectiveness of molnupiravir relative to usual care alone among mainly vaccinated community-based people at higher risk of severe outcomes from COVID-19 over 6 months. DESIGN AND SETTING: An economic evaluation of the PANORAMIC trial in the UK. METHOD: A cost-utility analysis that adopted a UK NHS and personal social services perspective and a 6-month time horizon was performed using PANORAMIC trial data. Cost-effectiveness was expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. Sensitivity and subgroup analyses assessed the impacts of uncertainty and heterogeneity. Threshold analysis explored the price for molnupiravir consistent with likely reimbursement. RESULTS: In the base-case analysis, molnupiravir had higher mean costs of £449 (95% confidence interval [CI] = 445 to 453) and higher mean QALYs of 0.0055 (95% CI = 0.0044 to 0.0067) than usual care (mean incremental cost per QALY of £81 190). Sensitivity and subgroup analyses showed similar results, except for those aged ≥75 years, with a 55% probability of being cost-effective at a £30 000 per QALY threshold. Molnupiravir would have to be priced around £147 per course to be cost-effective at a £15 000 per QALY threshold. CONCLUSION: At the current cost of £513 per course, molnupiravir is unlikely to be cost-effective relative to usual care over a 6-month time horizon among mainly vaccinated patients with COVID-19 at increased risk of adverse outcomes, except those aged ≥75 years.

The impact of C-reactive protein testing on treatment-seeking behavior and patients' attitudes toward their care in Myanmar and Thailand.

C-reactive protein (CRP) point-of-care testing can reduce antibiotic prescribing in primary care patients with febrile and respiratory illness, yet little is known about its effects on treatment-seeking behavior. If patients go on to source antibiotics elsewhere, the impact of CRP testing will be limited. A randomized controlled trial assessed the impact of CRP testing on antibiotic prescriptions in Myanmar and Thai primary care patients with a febrile illness. Here we report patients' treatment-seeking behavior before and during the two-week study period. Self-reported antibiotic use is compared against urine antibacterial activity. Patients' opinions towards CRP testing were evaluated. Antibiotic use before study enrolment was reported by 5.4% while antimicrobial activity was detected in 20.8% of samples tested. During the study period, 14.8% of the patients sought additional healthcare, and 4.3% sourced their own antibiotics. Neither were affected by CRP testing. Overall, patients' satisfaction with their care and CRP testing was high. CRP testing did not affect patients' treatment-seeking behavior during the study period whilst modestly reducing antibiotic prescriptions. CRP testing appears to be acceptable to patients and their caregivers.