Critical illness can have a significant psychological impact on patients and their families. To inform the design of a larger trial, we assessed feasibility of ICU diaries and psychoeducation to ...prevent posttraumatic stress disorder, depression, and anxiety following ICU stays.
Four-arm pilot randomized controlled trial.
A 10-bed tertiary ICU in Winnipeg, MB, Canada.
Critically ill patients greater than 17 years old with predicted ICU stays greater than 72 hours and mechanical ventilation duration greater than 24 hours.
Patients were randomized to usual care, ICU diary, psychoeducation, or both ICU diary and psychoeducation.
Our primary objective was to determine feasibility measured by enrollment/mo. Secondary outcomes included acceptability of the ICU diary intervention and psychological distress, including patients' memories 1 week post ICU using the ICU Memory Tool, posttraumatic stress disorder (Impact of Events Scale-Revised), depression, and anxiety symptoms (Hospital Anxiety and Depression Scale) 30 and 90 days post ICU. Over 3.5 years, we enrolled 58 patients, an average of 1.9 participants/mo. Families and healthcare providers wrote a mean of 3.2 diary entries/d (SD, 2.9) and indicated positive attitudes and low perceived burden toward ICU diary participation. A majority of patients reported distressing memories of their ICU stay. Those who received the diary intervention had significantly lower median Hospital Anxiety and Depression Scale anxiety (3.0 interquartile range, 2-6.25 vs 8.0 interquartile range, 7-10; p = 0.01) and depression (3.0 interquartile range, 1.75-5.25 vs 5.0 interquartile range, 4-9; p = 0.04) symptom scores at 90 days than patients who did not receive a diary.
ICU diaries are a feasible intervention in a tertiary Canadian ICU context. Preliminary evidence supports the efficacy of ICU diaries to reduce psychological morbidity following discharge.
Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and ...quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown.
We conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days.
We enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 11.8%) and those receiving placebo (58 of 407 14.3%); the absolute difference was -2.4 percentage points (95% confidence interval, -7.0 to 2.2; P = 0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.
After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki and Jan Ellison Baszucki and others; ClinicalTrials.gov number, NCT04308668.).
Background
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 causing the coronavirus disease (COVID-19) pandemic. Currently, there is a lack of evidence-based ...therapies to prevent COVID-19 following exposure to the virus, or to prevent worsening of symptoms following confirmed infection. We describe the design of a clinical trial of hydroxychloroquine for post-exposure prophylaxis (PEP) and pre-emptive therapy (PET) for COVID-19.
Methods
We will conduct two nested multicentre international double-blind randomized placebo-controlled clinical trials of hydroxychloroquine for: 1) PEP of asymptomatic household contacts or healthcare workers exposed to COVID-19 within the past four days, and 2) PET for symptomatic outpatients with COVID-19 showing symptoms for less than four days. We will recruit 1,500 patients each for the PEP and PET trials. Participants will be randomized 1:1 to receive five days of hydroxychloroquine or placebo. The primary PEP trial outcome will be the incidence of symptomatic COVID-19. 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-controlled trials are innovatively designed and adequately powered to rapidly answer urgent questions regarding the effectiveness of hydroxychloroquine to reduce virus transmission and disease severity of COVID-19 during a pandemic. In-person participant follow-up will not be conducted 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); registered 16 March, 2020.
Abstract
Background
Use of hydroxychloroquine in hospitalized patients with coronavirus disease 2019 (COVID-19), especially in combination with azithromycin, has raised safety concerns. Here, we ...report safety data from 3 outpatient randomized clinical trials.
Methods
We conducted 3 randomized, double-blind, placebo-controlled trials investigating hydroxychloroquine as pre-exposure prophylaxis, postexposure prophylaxis, and early treatment for COVID-19 using an internet-based design. We excluded individuals with contraindications to hydroxychloroquine. We collected side effects and serious adverse events. We report descriptive analyses of our findings.
Results
We enrolled 2795 participants. The median age of research participants (interquartile range) was 40 (34–49) years, and 59% (1633/2767) reported no chronic medical conditions. Overall 2544 (91%) participants reported side effect data, and 748 (29%) reported at least 1 medication side effect. Side effects were reported in 40% with once-daily, 36% with twice-weekly, 31% with once-weekly hydroxychloroquine, compared with 19% with placebo. The most common side effects were upset stomach or nausea (25% with once-daily, 19% with twice-weekly, and 18% with once-weekly hydroxychloroquine, vs 11% for placebo), followed by diarrhea, vomiting, or abdominal pain (23% for once-daily, 17% twice-weekly, and 13% once-weekly hydroxychloroquine, vs 7% for placebo). Two individuals were hospitalized for atrial arrhythmias, 1 on placebo and 1 on twice-weekly hydroxychloroquine. No sudden deaths occurred.
Conclusions
Data from 3 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, in cohorts of healthy outpatients, can safely investigate whether hydroxychloroquine is efficacious for COVID-19.
ClinicalTrials.gov Identifier
NCT04308668 for postexposure prophylaxis and early treatment trials; NCT04328467 for pre-exposure prophylaxis trial.
Abstract Purpose Observational research focused upon emerging infectious diseases such as Ebola virus, Middle East Respiratory Syndrome (MERS-CoV) and Zika virus has been challenging to quickly ...initiate. We aimed to determine the duration of start-up procedures and barriers encountered for an observational study focused upon such infectious outbreaks. Materials and methods At 1 pediatric and 5 adult ICUs, we measured durations from protocol receipt to a variety of outbreak research milestones, including research ethics board (REB) approval, data sharing agreement (DSA) execution, and patient study screening initiation. Results The median (IQR) time from site receipt of the protocol to REB submission was 73 (30126) days; to REB approval 158 (42188) days; to DSA completion 276 (186312) days; and to study screening initiation 293 (269391) days. The median time from REB submission to REB approval was 43 (13,85) days. The median time for all start-up procedures was 335 (188335) days. Conclusions There is a lengthy start-up period required for outbreak-focussed research. Completing data sharing agreements was the most time consuming step. A reactive approach to newly emerging threats such as Ebola virus, MERS-CoV and Zika virus will likely not allow sufficient time to initiate research before most outbreaks are advanced.
Avian influenza, Ebola virus, Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome coronaviruses are but a few recent examples. Sincerely, Conflicts of interests None. 1 The ...ISARIC-WHO Clinical Characterization Protocol for Severe Emerging Infections, Available from:, (Accessed March 26, 2017) 2 Short PeRiod IncideNce sTudy of Severe Acute Respiratory Infection, Available from:, (Accessed March 26, 2017)
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