Mitigating the psychological impacts of COVID-19 restrictions on older people: The UK Behavioural Activation in Social Isolation (BASIL+) COVID-19 Urgent Public Health (UPH) trial and living systematic review (preprint)

Background Older adults were more likely to be socially isolated during the COVID-19 pandemic, with risk of depression and loneliness. Behavioural Activation (BA) could feasibly maintain mental health in the face of COVID isolation. Methods We undertook a multicentre randomised controlled trial [BASIL+ ISRCTN63034289] of BA to mitigate depression and loneliness among older people. BA was offered by telephone to intervention participants (n=218). Control participants received usual care, with existing COVID wellbeing resources (n=217). Findings Participants engaged with 5.2 (SD 2.9) of 8 remote BA sessions. Adjusted mean difference (AMD) for depression (PHQ-9) at 3 months [primary outcome] was -1.65 (95% CI -2.54 to -0.75, p<0.001). There was an effect for BA on emotional loneliness at 3 months (AMD -0.37, 95% CI -0.68 to -0.06, p=0.02), but not social loneliness (AMD -0.05, 95% CI -0.33 to 0.23, p=0.72). Other secondary outcomes at 3 months were anxiety (GAD-7: AMD -0.67, 95% CI -1.43 to 0.09, p=0.08) and quality of life (SF12 mental component: AMD 1.99, 95% CI 0.22 to 3.76, p=0.03; physical component: AMD -0.50, 95% CI -2.14 to 1.10, p=0.53). BASIL+ trial results were incorporated into a living systematic review [PROSPERO CRD42021298788], and we found strong evidence of an impact of behavioural and/or cognitive strategies on depression [random effects pooled standardised mean difference -0.32, 95% CI -0.48 to -0.16, 10 studies, n=1,210 participants] and loneliness [random effects pooled standardised mean difference -0.44, 95%CI -0.64 to -0.24, 13 studies, n=1,421 participants] in the short-term (<6 months). Interpretation BA is an effective intervention that reduces depression and some aspects of loneliness in the short term. This adds to the range of strategies to improve population mental health, particularly among older adults with multiple long-term conditions. These results will be helpful to policy makers in preventing depression and loneliness beyond the pandemic. Funding NIHR RP-PG-0217-20006

Evaluation of publication bias for 12 clinical trials of molnupiravir to treat SARS-CoV-2 infection in 13,694 patients (preprint)

Introduction: During the COVID-19 pandemic, Merck Sharp and Dohme (MSD) acquired the global licensing rights for molnupiravir. MSD allowed Indian manufacturers to produce the drug under voluntary license. Indian companies conducted local clinical trials to evaluate the efficacy and safety of molnupiravir.Methods Searches of the Clinical Trials Registry-India (CTRI) were conducted to find registered trials of molnupiravir in India. Subsequent investigations were performed to assess which clinical trials had been presented or published.Results According to the CTRI, 12 randomised trials of molnupiravir were conducted in India, in 13,694 patients, starting in late May 2021. By July 2022, none of the 12 trials has been published, one was presented at a medical conference, and two were announced in press releases suggesting failure of treatment. Results from three trials were shared with the World Health Organisation. One of these three trials had many unexplained results, with effects of treatment significantly different from the MSD MOVE-OUT trial in a similar population.Discussion The lack of results runs counter to established practices and leaves a situation where approximately 90% of the global data on molnupiravir has not been published in any form. Access to patient-level databases is required to investigate risks of bias or medical fraud.

Supporting Weight Management during COVID-19 (SWiM-C): Twelve-month follow-up of a randomised controlled trial of a web-based, ACT-based, guided self-help intervention (preprint)

Objectives: We developed a guided self-help intervention (Supporting Weight Management during COVID-19, “SWiM-C”) to support adults with overweight or obesity in their weight management during the COVID-19 pandemic. This study evaluated the effect of SWiM-C on weight and determinants of weight management over twelve months.Methods: Participants (≥18 years, body-mass-index ≥25kg/m2) were randomised to the SWiM-C intervention or to a standard advice group. Participants completed online questionnaires at baseline, four months, and twelve months. The primary outcome was change in self-reported weight from baseline to twelve months; secondary outcomes were eating behaviour (uncontrolled eating, emotional eating, cognitive restraint of food intake), experiential avoidance/psychological flexibility, mental health (depression, anxiety, stress), wellbeing and physical activity. Interventions: SWiM-C is based on acceptance and commitment therapy (ACT). Participants had access to an online web platform with 12 weekly modules and limited email and telephone contact with a trained, non-specialist coach. Standard advice was a leaflet on managing weight and mood during the COVID-19 pandemic. Results: 388 participants were randomised (SWiM-C: n=192, standard advice: n=196). The baseline-adjusted difference in weight change between SWiM-C and standard advice participants was -0.81kg (95% CI: -2.24 to 0.61kg). SWiM-C participants reported a greater reduction in experiential avoidance (-2.45, 95% CI: -4.75 to -0.15), uncontrolled eating (-3.36, 95% CI: -5.66 to -1.06), and emotional eating (-4.14, 95% CI: -7.25 to -1.02) and an increase in physical activity (8.96, 95% CI: 0.29 to 17.62) compared to standard advice participants.Conclusions: Whilst the effect of the SWiM-C intervention on weight was inconclusive, SWiM-C improved eating behaviours, psychological flexibility and physical activity. These factors have been previously identified as determinants of successful weight management. Further refinement of the SWiM-C intervention is necessary to ensure meaningful effects on weight prior to implementation in practice.

Can we mitigate the psychological impacts of social isolation using behavioural activation? Long-term results of the UK BASIL Urgent Public Health COVID-19 pilot randomised controlled trial and living systematic review (preprint)

BackgroundBehavioural and cognitive interventions remain a credible approach in preventing loneliness and depression. There was a need to rapidly generate and assimilate trial-based data during COVID-19. ObjectivesWe undertook a COVID-19 parallel pilot RCT of behavioural activation for depression and loneliness [the BASIL-C19 trial ISRCTN94091479]. We also assimilate these data in a COVID-19 living systematic review [PROSPERO CRD42021298788]. MethodsPrimary care participants (>=65 years) with long-term conditions were computer randomised to Behavioural Activation (n=47) versus care-as-usual (n=49). The single blinded primary outcome was the PHQ-9. Secondary outcomes included loneliness (De Jong Gierveld Scale). Data from the BASIL-C19 trial were included in a random effects meta-analysis of depression and loneliness. FindingsThe 12 months adjusted mean difference for PHQ-9 was -0.70 (95% CI -2.61 to 1.20) and for loneliness was -0.39 (95% CI -1.43 to 0.65). Secondary 12-month trial outcomes suggested evidence of benefit for behavioural activation. The BASIL-C19 meta-analysis (13 trials) found short-term reductions in depression (standardised mean difference [SMD]=-0.31, 95%CI -0.51 to -0.11) and loneliness (SMD=-0.48, 95%CI -0.70 to -0.27). There were few long-term trials, but there was evidence of some benefit (loneliness SMD=-0.20, 95%CI -0.40 to -0.01; depression SMD=-0.20, 95%CI -0.47 to 0.07). DiscussionWe found a signal of effect in reducing loneliness and depression in the BASIL trial. Living meta-analysis provides strong evidence of short-term benefit for loneliness and depression. Clinical implicationsScalable behavioural and cognitive approaches should be considered as population-level strategies for depression and loneliness on the basis of the living systematic review. FundingThis study was funded by National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research (PGfAR) RP-PG-0217-20006. Author summaryO_ST_ABSWhy was this study done?C_ST_ABS Older people with long-term conditions have been impacted by COVID-19 pandemic restrictions and have experienced social isolation. In turn, this puts them at risk for depression and loneliness, and these are bad for health and wellbeing. Psychosocial approaches, such as behavioural activation, could be helpful. Trial-based evidence is needed to demonstrate if it is possible to prevent the onset, or mitigate the impact, of loneliness and depression. There are few studies of brief psychosocial interventions to mitigate depression and loneliness, and it is important to know how emerging trial-based data adds to existing evidence. What did the researchers do and find? There was preliminary evidence that levels of loneliness were reduced at 3 months when behavioural activation was offered. At longer term (12-month) follow-up there were signals of ongoing positive impact. When BASIL-C19 data were assimilated into a living systematic review there is clear evidence of impact of brief psychological interventions on depression and loneliness in the short-term. More research into the longer-term impact is needed. What does all this mean? Behavioural activation now shows evidence of benefit which will be useful for policy makers in offering support to people who are socially isolated. This research knowledge will be useful once the COVID-19 pandemic has passed, since loneliness is common in older populations and effective scalable solutions will be needed to tackle this problem. As new trial-based data emerges, our living systematic review and meta-analysis will be updated since this is an area of active research.

Estimated global cost of treating COVID-19, HIV, Hepatitis B and Hepatitis C with approved effective oral medications (preprint)

Background High drug prices can limit treatment access. Patented drugs can be sold for prices far higher than the costs of production. This analysis aimed to determine prices currently feasible to treat COVID-19, HIV, and Hepatitis B or C, with WHO/FDA/NICE approved oral medications assuming competitive generic manufacture.Methods Data on Active Pharmaceutical Ingredients (API) exported from India were collected from the Panjiva database ( www.panjiva.com ) – an online database of global exports – and were used to calculate current weighted mean cost/kg of API. Target prices were calculated based on the per-pill cost of API, plus costs of manufacture ($0.01/pill), 10% profit margin, and assumed 27% tax on profit. We selected a range of the most commonly used oral treatments based on WHO guidelines for treatment of COVID-19, HIV, HBV and HCV. Current lowest global prices were obtained from public reports and the Pan American Health Organization Antiretroviral Report. Our target prices were compared with national pricing data from a range of low, middle, and high-income countries.Results The main results table shows current prices of antiretrovirals for SARS-CoV-2 (5–14-day course), HIV or HBV (per 365-day course), and HCV treatments (per 12-week course). COVID-19 can be treated with molnupiravir for $12.40, baricitinib for $0.60, or dexamethasone for $0.19 per course. HIV can be treated with DRV/r for $286 per year, ATV/r for $140 per year, TDF/3TC/DTG for $74 per year, TAF/FTC/DTG for $89 and TDF/FTC for $59. HBV can be treated with TDF for $23 per year and TAF for $38 per year. HCV could be cured with sofosbuvir/daclatasvir for $35 per patient and sofosbuvir/velpatasvir for $79 per patient. Maximum list prices (typically from US) were up to 600 times higher than costs of production (e.g. for TDF).Conclusions Key viral infections can be treated or cured with generic drugs at prices far below those of branded equivalents. Use of branded drugs at high prices can limit the potential for countries to achieve the UNAIDS 95-95-95 targets.

Dual spatially resolved transcriptomics for SARS-CoV-2 host-pathogen colocalization studies in humans (preprint)

To advance our understanding of cellular host-pathogen interactions, technologies that facilitate the co-capture of both host and pathogen spatial transcriptome information are needed. Here, we present an approach to simultaneously capture host and pathogen spatial gene expression information from the same formalin-fixed paraffin embedded (FFPE) tissue section using the spatial transcriptomics technology. We applied the method to COVID-19 patient lung samples and enabled the dual detection of human and SARS-CoV-2 transcriptomes at 55 m resolution. We validated our spatial detection of SARS-CoV-2 and identified an average specificity of 94.92% in comparison to RNAScope and 82.20% in comparison to in situ sequencing (ISS). COVID-19 tissues showed an upregulation of host immune response, such as increased expression of inflammatory cytokines, lymphocyte and fibroblast markers. Our colocalization analysis revealed that SARS-CoV-2 + spots presented shifts in host RNA metabolism, autophagy, NF{kappa}B, and interferon response pathways. Future applications of our approach will enable new insights into host response to pathogen infection through the simultaneous, unbiased detection of two transcriptomes.

Prices versus costs of production for molnupiravir as a COVID-19 treatment (preprint)

Background: Molnupiravir has been recently approved in the United Kingdom for the treatment of COVID-19 for showing promising survival benefits in clinical trials. This analysis will estimate and compare potential generic minimum costs of molnupiravir as well as observe countries eligible for pricing discounts as agreed by Merck and The Medicines Patent Pool (MPP). Methods Drug prices were searched for molnupiravir using active pharmaceutical ingredients (API) data extracted from global shipping records. This was compared with national pricing data from a range of low, medium, and high-income countries. Annual API export volumes from India were used to estimate the current availability. Trends of molnupiravir drugs prices were also evaluated for the last 6-month period. Mean daily COVID-19 diagnosis rates were calculated for the countries eligible for voluntary licensing. Results Molnupiravir can be generically manufactured at the very low per-course cost of $9.00. Over the past 6 months, prices of molnupiravir have fallen significantly, and when comparing reported international prices, we found wide variations between countries. Only 9% of diagnosed patients worldwide were in the countries eligible for voluntary licensing. Conclusions Prices of molnupiravir range from $20 to $750 per course. Only 9% of worldwide COVID-19 diagnoses are made in countries covered by voluntary licenses. Middle income countries not eligible for voluntary licensing may need to issue compulsory licenses to secure access to molnupiravir at affordable prices.

Ivermectin for the prevention of COVID-19: addressing potential bias and medical fraud (preprint)

Background: Ivermectin is an antiparasitic drug being investigated in clinical trials for the prevention of COVID-19. However, there are concerns about the quality of some of these trials. Objectives To conduct a meta-analysis with randomised controlled trials of ivermectin for the prevention of COVID-19, while controlling for the quality of data. Methods We conducted a sub-group analysis based on the quality of randomised controlled trials evaluating ivermectin for the prevention of COVID-19. Quality was assessed using the Cochrane Risk of Bias measures (RoB 2) and additional checks on raw data, where possible. Results Four studies were included in the meta-analysis. One was rated as being potentially fraudulent, two as having a high risk of bias and one as having some concerns for bias. Ivermectin did not have a significant effect on preventing RT-PCR confirmed COVID-19 infection. Ivermectin had a significant effect on preventing symptomatic COVID-19 infection in one trial with some concerns of bias, but this result was based on post-hoc analysis of a multi-arm study. Conclusions This meta-analysis demonstrates that the currently available randomised trials evaluating ivermectin for the prevention of COVID-19 are insufficient and of poor quality.

Ivermectin for COVID-19: addressing potential bias and medical fraud (preprint)

Ivermectin has become a controversial potential medicine for COVID-19. Some early studies suggested clinical benefits in treatment and prevention of infection. However, the body of evidence includes studies of varying quality. Furthermore, some trials have now been identified as potentially fraudulent. We present a sub-group analysis, to assess the effects of stratifying by trial quality on the overall results. The stratification is based on the Cochrane Risk of Bias measures (RoB 2) and analysis of raw data where possible. The results suggest that the significant effect of ivermectin on survival was dependent on largely poor quality and potentially fraudulent studies. This highlights the need for rigorous quality assessments, the need for authors to share patient level data and efforts to continue to avoid publication bias for registered studies. These steps are vital to facilitate accurate conclusions on any clinical treatment.

Evaluation of Different Types of Face Masks To Limit The Spread of SARS-CoV-2 – A Modeling Study (preprint)

We updated a published mathematical model of SARS-CoV-2 transmission with laboratory-derived source and wearer protection efficacy estimates for a variety of face masks to estimate their impact on COVID-19 incidence and related mortality in the United States. When used at 25 already-observed population rates of 80% for those ≥65 years and 60% for those <65 years, face masks are associated with 69% (cloth) to 78% (medical procedure mask) reductions in cumulative COVID-19 infections and 82% (cloth) to 87% (medical procedure mask) reductions in related deaths over a 6-month timeline in the model, assuming a basic reproductive number of 2.5. If cloth or medical procedure masks’ source control and wearer protection efficacies are boosted about 30% each to 84% and 60% by cloth over medical procedure masking, fitters, or braces, the COVID-19 basic reproductive number of 2.5 could be reduced to an effective reproductive number ≤ 1.0, and from 6.0 to 2.3 for a variant of concern similar to delta (B.1.617.2).

Minimum manufacturing costs, national prices and estimated global availability of new repurposed therapies for COVID-19. (preprint)

Background Currently, only dexamethasone, tocilizumab and sarilumab have conclusively been shown to reduce mortality of COVID-19. No drug for prevention or treatment in earlier stages of COVID-19 are yet found; although several new candidates including ivermectin, dutasteride, baricitinib, budesonide and colchicine are being studied with some early promising results. Safe and effective treatments will need to be both affordable and widely available globally. Objectives This analysis will estimate and compare potential generic production costs of a selection of COVID-19 drug candidates with international list prices. Methods Costs of production for new and potential COVID-19 drugs (dexamethasone, ivermectin, dutasteride, budesonide, baricitinib, tocilizumab, sarilumab and colchicine) were estimated using active pharmaceutical ingredients (API) data extracted from global shipping records. This was compared with national pricing data from low, medium, and high-income countries. Annual API export volumes from India were used to estimate the current availability of each drug. Results Repurposed therapies can be generically manufactured at very low per-course costs: ranging from $2.58 for IV dexamethasone (or $0.19 orally) to $0.12 for ivermectin. No export price data was available for baricitinib, tocilizumab or sarilumab. When compared against international list prices, we found wide variations between countries. Drug API availability was generally good, with colchicine being the most available with sufficient annual API exported for 59.8 million treatment courses. Conclusions Successful management of COVID-19 will require equitable access to treatment for all populations, not just those able to pay high prices. Analysed drugs are widely available and affordable, whilst IV treatment courses are more expensive.

Evaluation of the Effect of Sofosbuvir and Daclatasvir in Hospitalised COVID-19 Patients: A Randomized Double-Blind Clinical Trial (DISCOVER) (preprint)

Background: The combination of sofosbuvir (SOF) and daclatasvir (DCV) has shown preliminary efficacy for patients with COVID-19 in five open-label studies with small sample sizes. This larger trial aimed to assess if the addition of sofosbuvir and daclatasvir to standard care improved clinical endpoints in hospitalized patients with moderate or severe COVID-19. Methods: This was a placebo-controlled, randomized clinical trial in adults with moderate or severe COVID-19 admitted to 19 hospitals in Iran. Patients were randomized to SOF/DCV 400/60mg once-daily or placebo in addition to standard of care. Patients were included if they had positive PCR or diagnostic chest CT, O 2 saturation <95%, and compatible symptoms. The primary endpoint was discharge from hospital within 10 days of first treatment. The trial is registered on Iran Registry of Clinical Trials under IRCT20200624047908N1 available at https://www.irct.ir/trial/49198.Results: Between July and October 2020, 1083 patients were allocated to either the SOF/DCV treatment arm (n=541) or matching placebo (n=542). The primary endpoint was achieved by 358 / 541 (66%) in the SOF/DCV arm and 370 /542 (68%) in controls (relative risk = 0.97, 95% CI = 0.89-1.05). The in-hospital death rates were 58/541 (11%) in the SOF/DCV group versus 53/542 (10%) in the placebo group (relative risk = 1.1, 95% CI = 0.77 to 1.56). Conclusions: We observed no significant effect of SOF/DCV versus placebo on the rate of hospital discharge or survival in hospitalized COVID-19 patients. However, the patient population was generally severe cases that may have been too advanced for antiviral drugs to be effective. Trial Registration: Iran Registry of Clinical Trials under IRCT20200624047908N1 available at https://www.irct.ir/trial/49198.Funding: This trial was sponsored by Abadan University of Medical Sciences and funded by the International Treatment Preparedness Coalition (grant number ITPC-2020)Declaration of Interests: S.Merat has received travel grants from and is a stockholder of Fanavaran Rojan Mohaghegh Daru Co. ANB and HNB are stockholders of Fanavaran Rojan Mohaghegh Daru Co. All other authors: none to declare.Ethics Approval Statement: The study protocol has been approved by the Abadan Faculty of Medicine Sciences Institutional Review Board and the Iranian Registry of Clinical Trials (IRCT) registry team.

Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection (preprint)

Ivermectin is an antiparasitic drug being investigated for repurposing to SARS-CoV-2. In-vitro, ivermectin showed limited antiviral activity and a COVID-19 animal model demonstrated pathological benefits but no effect on viral RNA. This meta-analysis investigated ivermectin in 18 randomized clinical trials (2282 patients) identified through systematic searches of PUBMED, EMBASE, MedRxiv and trial registries. Ivermectin was associated with reduced inflammatory markers (C-Reactive Protein, d-dimer and ferritin) and faster viral clearance by PCR. Viral clearance was treatment dose- and duration-dependent. In six randomized trials of moderate or severe infection, there was a 75% reduction in mortality (Relative Risk=0.25 [95%CI 0.12-0.52]; p=0.0002); 14/650 (2.1%) deaths on ivermectin; 57/597 (9.5%) deaths in controls) with favorable clinical recovery and reduced hospitalization. Many studies included were not peer reviewed and meta-analyses are prone to confounding issues. Ivermectin should be validated in larger, appropriately controlled randomized trials before the results are sufficient for review by regulatory authorities.

Efficacy and Safety of Sofosbuvir/Daclatasvir in the Treatment of COVID-19: A Randomized, Controlled Study (preprint)

BACKGROUND: Data from molecular docking, in-vitro experiments and 2 published small clinical studies suggested a potential therapeutic benefit for the anti-hepatitis C drugs, sofosbuvir (SOF) and daclatasvir (DCV), to repurpose for the treatment of COVID-19. We planned this study to evaluate efficacy and safety of dual SOF/DCV as add-on treatment to the standard of care (SOC) in patients with COVID-19, initially hospitalized to a non-intensive care setting.METHODS: Eighty nine consecutive eligible patients presenting to a single center in Cairo were included in the study and randomly assigned to two treatment groups. The experimental group was treated with the SOC therapy (as per the Egyptian ministry of health protocol) in addition to one 400 mg tablet SOF and one 60 mg DCV daily for 10 days; while the control group was treated with the SOC therapy alone. Baseline clinical, laboratory and imaging data were measured and followed up for 21 days. Data were compared between the two treatment groups.FINDINGS: The proportion of cumulative clinical recovery in the experimental group at day 21 was numerically greater than the control group (40/44 (91%; CI: 78.8-96.4%) versus 35/45 (77.8%; 63.7-87.5%)). The Hazard Ratio (HR) for time to clinical recovery adjusted for baseline severity by a Cox-regression model was statistically significant: HR: 1.59 (CI: 1.001-2.5), signifying nearly 1.6 times higher probability of clinical recovery in the experimental group than the control at any time point during the study. Concordantly, the experimental group also showed trends to greater numerical improvement in other efficacy endpoints including the mean 8 points ordinal scale score, the mean severity of lung lesions score and the case fatality rate (4.5% versus 11.1%) than the control group. All these effects, though did not reach statistical significance at the study sample size, but being all concordant with the HR, they support the study concept. No serious or severe adverse events were reported in both groups and the treatment was well tolerated.INTERPRETATION: This study provides support to the potential benefits and safety of sofosbuvir combined with daclatasvir in the treatment of COVID-19. It is hoped to encourage further large sized multinational studies to confirm these encouraging results.Trial Registration: The study protocol was registered in the German clinical trial database repository (DRKS00022203) before the study initiation.Funding Statement: This study was funded by Pharco Corporate.Declaration of Interests: SH and OE are employees of Pharco, SH holds stock in Pharco. MY, AH conducted clinical studies and provided consultations for Pharco. Others have nothing to declare. Ethics Approval Statement: The study protocol was reviewed and approved by the Research Ethics Committee of Faculty of Medicine, Alexandria University (IRB00007555) and the Central Egyptian Ministry of Health and People Research Ethics Committee according to the Declaration of Helsinki. All subjects gave written informed consent before any treatment interventions were performed.

Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis (preprint)

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic by the World Health Organisation and urgent treatment and prevention strategies are needed. Many clinical trials have been initiated with existing medications, but assessments of the expected plasma and lung exposures at the selected doses have not featured in the prioritisation process. Although no antiviral data is currently available for the major phenolic circulating metabolite of nitazoxanide (known as tizoxanide), the parent ester drug has been shown to exhibit in vitro activity against SARS-CoV-2. Nitazoxanide is an anthelmintic drug and its metabolite tizoxanide has been described to have broad antiviral activity against influenza and other coronaviruses. The present study used physiologically-based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported nitazoxanide 90% effective concentration (EC90) against SARS-CoV-2. MethodsA whole-body PBPK model was constructed for oral administration of nitazoxanide and validated against available tizoxanide pharmacokinetic data for healthy individuals receiving single doses between 500 mg - 4000 mg with and without food. Additional validation against multiple-dose pharmacokinetic data when given with food was conducted. The validated model was then used to predict alternative doses expected to maintain tizoxanide plasma and lung concentrations over the reported nitazoxanide EC90 in >90% of the simulated population. Optimal design software PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials. ResultsThe PBPK model was validated with AAFE values between 1.01 - 1.58 and a difference less than 2-fold between observed and simulated values for all the reported clinical doses. The model predicted optimal doses of 1200 mg QID, 1600 mg TID, 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food, to provide tizoxanide plasma and lung concentrations over the reported in vitro EC90 of nitazoxanide against SARS-CoV-2. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12h post dose was estimated. ConclusionThe PBPK model predicted that it was possible to achieve plasma and lung tizoxanide concentrations, using proven safe doses of nitazoxanide, that exceed the EC90 for SARS-CoV-2. The PBPK model describing tizoxanide plasma pharmacokinetics after oral administration of nitazoxanide was successfully validated against clinical data. This dose prediction assumes that the tizoxanide metabolite has activity against SARS-CoV-2 similar to that reported for nitazoxanide, as has been reported for other viruses. The model and the reported dosing strategies provide a rational basis for the design (optimising plasma and lung exposures) of future clinical trials of nitazoxanide in the treatment or prevention of SARS-CoV-2 infection.