COVID-SAFER: Deprescribing Guidance for Nirmatrelvir-ritonavir Drug Interactions in Older Adults (preprint)

Importance: Older adults, at high-risk of developing complications from COVID-19, could benefit from nirmatrelvir-ritonavir, an oral antiviral treatment for outpatients at high risk of complications from COVID-19; however, due to its potent CYP3A4 inhibition, nirmatrelvir-ritonavir is associated with many drug-drug interactions (DDI). Objectives: Identify how common DDIs are between nirmatrelvir-ritonavir, common medications, and PIMs in older adults with polypharmacy. Craft anticipatory deprescribing guidance for PIMs that interact with nirmatrelvir-ritonavir to help prioritize deprescribing resources, and increase the proportion of older adults potentially benefitting from treatment. Design: In this secondary analysis, we retrospectively analyzed all patients in the MedSafer cluster randomized deprescribing trial (N=5698 participants) to investigate the proportion of older adults (age > 65) with polypharmacy ([≥] 5 usual home medications) who would be ineligible for treatment with nirmatrelvir-ritonavir due to pre-existing DDIs. Setting: The setting of the primary study was in medical inpatient units at 11 Canadian acute care hospitals. Participants: Hospitalized persons, age 65 years and older, on 5 or more daily home medications, with an expected survival of 3 months or longer were included in this secondary analysis. Main outcomes and measures: We identified the prevalence of (PIMs), as defined by the MedSafer software. We then developed deprescribing guidance, so clinicians could proactively deprescribe in an effort to increase the proportion of older adults eligible for safe treatment with nirmatrelvir-ritonavir in the event of a SARS-CoV-2 infection. Results: Of 5698 participants, a total of 3869 (68%) were taking a medication with a known nirmatrelvir-ritonavir DDI, and of these 823 (21%) had at least one PIM. Of 823 PIMs, 627 (76%) were medications with a known high risk DDI and 213 (26%) were considered moderate risk DDIs with nirmatrelvir-ritonavir. Many of the PIMs required "advanced deprescribing" and could not simply be stopped, held, or adjusted at the time of nirmatrelvir-ritonavir receipt. Conclusions and relevance: Older adults are at high risk of developing severe complications from COVID-19. Deprescribing PIMs in advance of a COVID-19 infection could increase the proportion of older adults who can safely receive nirmatrelvir-ritonavir, in addition to the usual benefits observed with medication management.

Remdesivir for the Treatment of COVID-19: An Updated Systematic Review and Meta-Analysis (preprint)

Background: The benefits of remdesivir in the treatment of hospitalized patients with Covid-19 remain debated with the National Institutes of Health and the World Health Organization providing contradictory recommendations for and against use. Methods: We performed a systematic review of randomized controlled trials (RCTs) of remdesivir for the treatment of hospitalized patients with COVID-19. The primary outcome was mortality, stratified by oxygen use (none, supplemental oxygen without mechanical ventilation, and mechanical ventilation). We conducted a frequentist random effects meta-analysis on the risk ratio (RR) scale and, to better contextualize the probabilistic benefits, we also performed a bayesian random effects meta-analysis on the risk difference scale. Results: We identified 8 randomized trials, totaling 9157 participants. The RR for mortality comparing remdesivir versus control was 0.71 (95% confidence interval [CI] 0.42-1.22; I2=0.0%) in the patients who did not require supplemental oxygen; 0.83 (95%CI 0.73-0.95; I2=0.0%) for nonventilated patients requiring oxygen; and 1.19 (95%CI 0.98-1.44 I2=0.0%) in the setting of mechanical ventilation. Using neutral priors, the probabilities that remdesivir reduces mortality were 74.7%, 96.9% and 8.9%, respectively. The probability that remdesivir reduced mortality by more than 1% was 88.1% for nonventilated patients requiring oxygen. Conclusion: Based on this meta-analysis, there is a high probability that remdesivir reduces mortality for nonventilated patients with COVID-19 requiring supplemental oxygen therapy.

Outpatient therapies for COVID-19: How do we choose? (preprint)

BackgroundSeveral outpatient COVID-19 therapies have reduced hospitalization in randomized controlled trials. The choice of therapy may depend on drug efficacy, toxicity, pricing, availability, and access to administration infrastructure. To facilitate comparative decision making, we evaluated the efficacy of each treatment in clinical trials and then estimated the associated cost per hospitalization prevented. MethodsWherever possible, we obtained relative risk for hospitalization from published randomized controlled trials. Otherwise, we extracted data from press releases, conference abstracts, government submissions, or preprints. If more than one study was published, the results were meta-analyzed. Using relative risk, we estimated the number needed to treat (NNT), assuming a baseline hospitalization risk of 5%. Drug pricing was based on Canadian formularies, government purchases, or manufacturer estimates. Administrative and societal costs were not included. Results will be updated online as new studies emerge or final publication numbers become available. ResultsAt a 5% risk of hospitalization the estimated NNTs were: 87 for colchicine, 80 for fluvoxamine, 72 for inhaled corticosteroids, 24 for nirmatrelvir/ritonavir, 25 for sotrovimab, 24 for remdesivir, 29 for casirivimab/imdevimab, 29 for bamlanivimab/etesevimab and 52 for molnupiravir. Colchicine, fluvoxamine, inhaled corticosteroids, and nirmatrelvir/ritonavir had cost per hospitalization prevented point estimates below the CIHI estimated cost of hospitalization ($23000). InterpretationCanada is fortunate to have access to several effective outpatient therapies to prevent COVID-19 hospitalization. Given differences in efficacy, toxicity, cost and administration complexities, this assessment serves as one tool to help guide policy makers and clinicians in their treatment selection.

Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial (preprint)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing Covid-19 pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS CoV-2 in healthcare workers at high-risk of exposure. Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with Covid-19, including those working in emergency departments, intensive care units, Covid-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine 400mg once weekly or twice weekly for 12 weeks. The primary endpoint was confirmed or probable Covid-19-compatible illness. We measured hydroxychloroquine whole blood concentrations. Results: We enrolled 1483 healthcare workers, of which 79% reported performing aerosol-generating procedures. The incidence of Covid-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events per person-year with once-weekly and 0.28 events per person-year with twice-weekly hydroxychloroquine compared with 0.38 events per person-year with placebo. For once weekly hydroxychloroquine prophylaxis, the hazard ratio was 0.72 (95%CI 0.44 to 1.16; P=0.18) and for twice weekly was 0.74 (95%CI 0.46 to 1.19; P=0.22) as compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82-120) with once-weekly and 200 ng/mL (IQR, 159-258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed Covid-19 (154 ng/mL) versus participants without Covid-19 (133 ng/mL; P=0.08). Conclusions: Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed Covid-19 or Covid-19-compatible illness among healthcare workers.

Safety of Hydroxychloroquine among Outpatient Clinical Trial Participants for COVID-19 (preprint)

IntroductionUse of hydroxychloroquine in hospitalized patients with COVID-19, especially in combination with azithromycin, has raised safety concerns. Here, we report safety data from three outpatient randomized clinical trials. MethodsWe conducted three randomized, double-blind, placebo-controlled trials investigating hydroxychloroquine as pre-exposure prophylaxis, post-exposure prophylaxis and early treatment for COVID-19. We excluded individuals with contraindications to hydroxychloroquine. We collected side effects and serious adverse events. We report descriptive analyses of our findings. ResultsWe enrolled 2,795 participants. The median age of research participants was 40 (IQR 34-49) years, and 59% (1633/2767) reported no chronic medical conditions. Overall 2,324 (84%) participants reported side effect data, and 638 (27%) reported at least one medication side effect. Side effects were reported in 29% with daily, 36% with twice weekly, 31% with once weekly hydroxychloroquine compared to 19% with placebo. The most common side effects were upset stomach or nausea (25% with daily, 18% with twice weekly, 16% with weekly, vs. 10% for placebo), followed by diarrhea, vomiting, or abdominal pain (23% for daily, 16% twice weekly, 12% weekly, vs. 6% for placebo). Two individuals were hospitalized for atrial arrhythmias, one on placebo and one on twice weekly hydroxychloroquine. No sudden deaths occurred. ConclusionData from three outpatient COVID-19 trials demonstrated that gastrointestinal side effects were common but mild with the use of hydroxychloroquine, while serious side effects were rare. No deaths occurred related to hydroxychloroquine. Randomized clinical trials can safely investigate whether hydroxychloroquine is efficacious for COVID-19. Short SummaryData from three randomized clinical trials using hydroxychloroquine for the prevention and treatment of COVID-19 did not suggest significant safety concerns. Gastrointestinal side effects were common but arrhythmias were rare. There were no sudden deaths in any trial.

Syndromic Surveillance for COVID-19 in Canada (preprint)

Background: Syndromic surveillance through web or phone-based polling has been used to track the course of infectious diseases worldwide. Our study objective was to describe the characteristics, symptoms, and self-reported testing rates of respondents in three different COVID-19 symptom surveys in Canada. Methods: Data sources consisted of two distinct Canada-wide web-based surveys, and phone polling in Ontario. All three sources contained self-reported information on COVID-19 symptoms and testing. In addition to describing respondent characteristics, we examined symptom frequency and the testing rate among the symptomatic, as well as rates of symptoms and testing across respondent groups. Results: We found that 1.6% of respondents experienced a symptom on the day of their survey, 15% of Ontario households had a symptom in the previous week, and 44% of Canada-wide respondents had a symptom in the previous month over March-April 2020. Across the three surveys, SARS-CoV-2-testing was reported in 2-9% of symptomatic responses. Women, younger and middle-aged adults (versus older adults) and Indigenous/First nations/Inuit/Metis were more likely to report at least one symptom, and visible minorities were more likely to report the combination of fever with cough or shortness of breath. Interpretation: The low rate of testing among those reporting symptoms suggests significant opportunity to expand testing among community-dwelling residents of Canada. Syndromic surveillance data can supplement public health reports and provide much-needed context to gauge the adequacy of current SARS-CoV-2 testing rates.

Post-exposure Prophylaxis or Preemptive Therapy for SARS-Coronavirus-2: Study Protocol for a Pragmatic Randomized Controlled Trial (preprint)

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 causing the coronavirus disease 2019 (COVID-19) pandemic. Currently, there are a lack of evidence-based therapies to prevent COVID-19 following exposure, or to prevent worsening of symptoms following confirmed infection. We describe the design of a clinical trial of hydroxychloroquine for post-exposure prophylaxis and pre-emptive therapy for COVID-19. Methods: We will conduct two nested multicenter international double-blind randomized placebo-controlled clinical trials of hydroxychloroquine for: 1) post-exposure prophylaxis (PEP) of asymptomatic household contacts or healthcare workers exposed to COVID-19 within the past four days, and 2) pre-emptive therapy (PET) for symptomatic outpatients with COVID-19 with a total symptom duration of less than 4 days. We will recruit 1500 patients for each the PEP and PET trials. Participants will be randomized 1:1 to receive 5 days of hydroxychloroquine or placebo. The primary PEP trial outcome will be the incidence of symptomatic COVID-19 disease. The primary PET trial outcome will be an ordinal scale of disease severity (not hospitalized; hospitalized without intensive care, hospitalization with intensive care, or death). Participant screening, informed consent, and follow up will be exclusively internet-based with appropriate regulatory and research ethics board approvals in Canada and the United States. Discussion: These complementary randomized control trials are innovatively designed and adequately powered to rapidly answer urgent questions regarding the effectiveness of hydroxychloroquine to reduce transmission and disease severity of COVID-19 during a pandemic. In-person participant follow-up will not be conducted in order to facilitate social distancing strategies and reduce risks of exposure to study personnel. Innovative trial approaches are needed to urgently assess therapeutic options to mitigate the global impact of this pandemic. Trials Registration: clinicaltrials.gov (NCT04308668); 16 March 2020.