Astodrimer Sodium Nasal Spray versus Placebo in Non-Hospitalised Patients with COVID-19: A Randomised, Double-Blinded, Placebo-Controlled Trial.

BACKGROUND/OBJECTIVES: Dendrimer-based astodrimer sodium nasal spray was assessed for its ability to reduce SARS-CoV-2 load in outpatients with COVID-19, which remains a severe illness for vulnerable groups. METHODS: This was a randomised, double-blind, placebo-controlled clinical investigation evaluating the efficacy of astodrimer nasal spray in reducing SARS-CoV-2 viral burden in the nasopharynx of outpatients with COVID-19. Non-hospitalised adults with SARS-CoV-2 infection were randomised 1:1 to astodrimer or placebo four times daily from Day 1 to Day 7. Nasopharyngeal swabs for SARS-CoV-2 load determination were self-obtained daily from Day 1 to Day 8. The primary endpoint was an area under the curve of SARS-CoV-2 RNA copies/mL through Day 8 (vAUCd1-8). The primary analysis population was the modified intent-to-treat population (mITT: all randomised participants exposed to the study treatment who had at least one post-baseline viral load determination). Safety analyses included all randomised participants exposed to the study treatment. STUDY REGISTRATION: ISRCTN70449927; Results: 231 participants were recruited between 9 January and 20 September 2023. The safety population comprised 109 and 113 participants randomised to astodrimer and placebo, respectively, with 96 and 101 participants in the mITT. Astodrimer sodium nasal spray reduced the SARS-CoV-2 burden (vAUCd1-8) vs. placebo in non-hospitalised COVID-19 patients aged 16 years and over (-1.2 log10 copies/mL × Day). The reduction in SARS-CoV-2 load was statistically significant in those aged 45 years and older (-3.7, p = 0.017) and the effect increased in older age groups, including in those aged 65 years and older (-7.3, p = 0.005). Astodrimer sodium nasal spray increased the rate of viral clearance and helped alleviate some COVID-19 symptoms, especially loss of sense of smell. Overall, 31 participants (14%) had ≥1 adverse event (AE). Four AEs were deemed possibly related to treatment. Most AEs were of mild severity and occurred at similar rates in both treatment arms. CONCLUSIONS: Astodrimer nasal spray reduces viral burden and accelerates viral clearance, especially in older populations, and is well tolerated.

Leflunomide treatment for patients hospitalised with COVID-19: DEFEAT-COVID randomised controlled trial.

OBJECTIVE: To evaluate the clinical efficacy and safety of leflunomide (L) added to the standard-of-care (SOC) treatment in COVID-19 patients hospitalised with moderate/critical clinical symptoms. DESIGN: Prospective, open-label, multicentre, stratified, randomised clinical trial. SETTING: Five hospitals in UK and India, from September 2020 to May 2021. PARTICIPANTS: Adults with PCR confirmed COVID-19 infection with moderate/critical symptoms within 15 days of onset. INTERVENTION: Leflunomide 100 mg/day (3 days) followed by 10-20 mg/day (7 days) added to standard care. PRIMARY OUTCOMES: The time to clinical improvement (TTCI) defined as two-point reduction on a clinical status scale or live discharge prior to 28 days; safety profile measured by the incidence of adverse events (AEs) within 28 days. RESULTS: Eligible patients (n=214; age 56.3±14.9 years; 33% female) were randomised to SOC+L (n=104) and SOC group (n=110), stratified according to their clinical risk profile. TTCI was 7 vs 8 days in SOC+L vs SOC group (HR 1.317; 95% CI 0.980 to 1.768; p=0.070). Incidence of serious AEs was similar between the groups and none was attributed to leflunomide. In sensitivity analyses, excluding 10 patients not fulfilling the inclusion criteria and 3 who withdrew consent before leflunomide treatment, TTCI was 7 vs 8 days (HR 1.416, 95% CI 1.041 to 1.935; p=0.028), indicating a trend in favour of the intervention group. All-cause mortality rate was similar between groups, 9/104 vs 10/110. Duration of oxygen dependence was shorter in the SOC+L group being a median 6 days (IQR 4-8) compared with 7 days (IQR 5-10) in SOC group (p=0.047). CONCLUSION: Leflunomide, added to the SOC treatment for COVID-19, was safe and well tolerated but had no major impact on clinical outcomes. It may shorten the time of oxygen dependence by 1 day and thereby improve TTCI/hospital discharge in moderately affected COVID-19 patients. TRIAL REGISTRATION NUMBERS: EudraCT Number: 2020-002952-18, NCT05007678.

Stigma towards mental illness in Asian nations and low-and-middle-income countries, and comparison with high-income countries: A literature review and practice implications.

Background: Stigma related to mental illness (and its treatment) is prevalent worldwide. This stigma could be at the structural or organizational level, societal level (interpersonal stigma), and the individual level (internalized stigma). Vulnerable populations, for example, gender minorities, children, adolescents, and geriatric populations, are more prone to stigma. The magnitude of stigma and its negative influence is determined by socio-cultural factors and macro (mental health policies, programs) or micro-level factors (societal views, health sectors, or individuals' attitudes towards mentally ill persons). Mental health stigma is associated with more serious psychological problems among the victims, reduced access to mental health care, poor adherence to treatment, and unfavorable outcomes. Although various nationwide and well-established anti-stigma interventions/campaigns exist in high-income countries (HICs) with favorable outcomes, a comprehensive synthesis of literature from the Low- and Middle-Income Countries (LMICs), more so from the Asian continent is lacking. The lack of such literature impedes growth in stigma-related research, including developing anti-stigma interventions. Aim: To synthesize the available mental health stigma literature from Asia and LMICs and compare them on the mental health stigma, anti-stigma interventions, and the effectiveness of such interventions from HICs. Materials and Methods: PubMed and Google Scholar databases were screened using the following search terms: stigma, prejudice, discrimination, stereotype, perceived stigma, associate stigma (for Stigma), mental health, mental illness, mental disorder psychiatric* (for mental health), and low-and-middle-income countries, LMICs, High-income countries, and Asia, South Asian Association for Regional Cooperation/SAARC (for countries of interest). Bibliographic and grey literature were also performed to obtain the relevant records. Results: The anti-stigma interventions in Asia nations and LMICs are generalized (vs. disorder specific), population-based (vs. specific groups, such as patients, caregivers, and health professionals), mostly educative (vs. contact-based or attitude and behavioral-based programs), and lacking in long-term effectiveness data. Government, international/national bodies, professional organizations, and mental health professionals can play a crucial in addressing mental health stigma. Conclusion: There is a need for a multi-modal intervention and multi-sectoral coordination to mitigate the mental health stigma. Greater research (nationwide surveys, cultural determinants of stigma, culture-specific anti-stigma interventions) in this area is required.