Abstracts for References 68, 69, 70, 71, 72, 73 of 'COVID-19: Management of adults with acute illness in the outpatient setting'
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Hydroxychloroquine for Early Treatment of Adults With Mild Coronavirus Disease 2019: A Randomized, Controlled Trial.
AU
MitjàO, Corbacho-MonnéM, Ubals M, TebéC, Peñafiel J, Tobias A, Ballana E, Alemany A, Riera-MartíN, Pérez CA, Suñer C, Laporte P, Admella P, MitjàJ, Clua M, Bertran L, Sarquella M, Gavilán S, Ara J, Argimon JM, Casabona J, Cuatrecasas G, Cañadas P, Elizalde-Torrent A, Fabregat R, FarréM, Forcada A, Flores-Mateo G, Muntada E, Nadal N, Narejos S, Nieto A, Prat N, Puig J, Quiñones C, Reyes-Ureña J, Ramírez-Viaplana F, Ruiz L, Riveira-Muñoz E, Sierra A, Velasco C, Vivanco-Hidalgo RM, Sentís A, G-Beiras C, Clotet B, Vall-Mayans M
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Clin Infect Dis. 2021;73(11):e4073.
BACKGROUND: No effective treatments for coronavirus disease 2019 (COVID-19) exist. We aimed to determine whether early treatment with hydroxychloroquine (HCQ) would be efficacious for outpatients with COVID-19.
METHODS: Multicenter open-label, randomized, controlled trial conducted in Catalonia, Spain, between 17 March and 26 May 2020. Patients recently diagnosed with<5-day of symptom onset were assigned to receive HCQ (800 mg on day 1 followed by 400 mg once daily for 6 days) or usual care. Outcomes were reduction of viral load in nasopharyngeal swabs up to 7 days after treatment start, disease progression up to 28 days, and time to complete resolution of symptoms. Adverse events were assessed up to 28 days.
RESULTS: A total of 293 patients were eligible for intention-to-treat analysis: 157 in the control arm and 136 in the intervention arm. The mean age was 41.6 years (SD, 12.6), mean viral load at baseline was 7.90 log10 copies/mL (SD, 1.82), and median time from symptom onset to randomization was 3 days. No differences were found in the mean reduction of viral load at day 3 (-1.41 vs -1.41 log10 copies/mL in the control and intervention arm, respectively) or at day 7 (-3.37 vs -3.44). Treatment did not reduce risk of hospitalization (7.1% control vs 5.9% intervention) nor shorten the time to complete resolution of symptoms (12 days, control vs 10 days, intervention). No relevant adverse events were reported.
CONCLUSIONS: In patients with mild COVID-19, no benefit was observed with HCQ beyond the usual care.
AD
PMID
32674126
69
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Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial.
AU
Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, Williams DA, Okafor EC, Pullen MF, Nicol MR, Nascene AA, Hullsiek KH, Cheng MP, Luke D, Lother SA, MacKenzie LJ, Drobot G, Kelly LE, Schwartz IS, Zarychanski R, McDonald EG, Lee TC, Rajasingham R, Boulware DR
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Ann Intern Med. 2020;173(8):623. Epub 2020 Jul 16.
BACKGROUND: No effective oral therapy exists for early coronavirus disease 2019 (COVID-19).
OBJECTIVE: To investigate whether hydroxychloroquine could reduce COVID-19 severity in adult outpatients.
DESIGN: Randomized, double-blind, placebo-controlled trial conducted from 22 March through 20 May 2020. (ClinicalTrials.gov: NCT04308668).
SETTING: Internet-based trial across the United States and Canada (40 states and 3 provinces).
PARTICIPANTS: Symptomatic, nonhospitalized adults with laboratory-confirmed COVID-19 or probable COVID-19 and high-risk exposure within 4 days of symptom onset.
INTERVENTION: Oral hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours,then 600 mg daily for 4 more days) or masked placebo.
MEASUREMENTS: Symptoms and severity at baseline and then at days 3, 5, 10, and 14 using a 10-point visual analogue scale. The primary end point was change in overall symptom severity over 14 days.
RESULTS: Of 491 patients randomly assigned to a group, 423 contributed primary end point data. Of these, 341 (81%) had laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or epidemiologically linked exposure to a person with laboratory-confirmed infection; 56% (236 of 423) were enrolled within 1 day of symptoms starting. Change in symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups (difference in symptom severity: relative, 12%; absolute, -0.27 point [95% CI, -0.61 to 0.07 point]; P = 0.117). At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receiving placebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine versus 22% (46 of 211) receiving placebo (P <0.001). With placebo, 10 hospitalizations occurred (2 non-COVID-19-related), including 1 hospitalized death. With hydroxychloroquine, 4 hospitalizations occurred plus 1 nonhospitalized death (P = 0.29).
LIMITATION: Only 58% of participants received SARS-CoV-2 testing because of severe U.S. testing shortages.
CONCLUSION: Hydroxychloroquine did not substantially reduce symptom severity inoutpatients with early, mild COVID-19.
PRIMARY FUNDING SOURCE: Private donors.
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PMID
32673060
70
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Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
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PRINCIPLE Trial Collaborative Group
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Lancet. 2021;397(10279):1063. Epub 2021 Mar 4.
BACKGROUND: Azithromycin, an antibiotic with potential antiviral and anti-inflammatory properties, has been used to treat COVID-19, but evidence from community randomised trials is lacking. We aimed to assess the effectiveness of azithromycin to treat suspected COVID-19 among people in the community who had an increased risk of complications.
METHODS: In this UK-based, primary care, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in people at increased risk of an adverse clinical course (PRINCIPLE), we randomly assigned people aged 65 years and older, or 50 years and older with at least one comorbidity, who had been unwell for 14 days or less with suspected COVID-19, to usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone. The trial had two coprimary endpoints measured within 28 days from randomisation: time to first self-reported recovery, analysed using a Bayesian piecewise exponential, and hospital admission or death related to COVID-19, analysed using a Bayesian logistic regression model. Eligible participants with outcome data were included in the primary analysis, and those who received the allocated treatment were included in the safety analysis. The trial is registered with ISRCTN, ISRCTN86534580.
FINDINGS: The first participant was recruited to PRINCIPLE on April 2, 2020. The azithromycin group enrolled participants between May 22 and Nov 30, 2020, by which time 2265 participants had been randomly assigned, 540 to azithromycin plus usual care, 875 to usual care alone, and 850 to other interventions. 2120 (94%) of 2265 participants provided follow-up data and were included in the Bayesian primary analysis, 500 participants in the azithromycin plus usual care group, 823 in the usual care alone group, and 797 in other intervention groups. 402 (80%) of 500 participants in the azithromycin plus usual care group and 631 (77%) of 823 participants in the usual care alone group reported feeling recovered within 28 days. We found little evidence of a meaningful benefit in the azithromycin plus usual care group in time to first reported recovery versus usual care alone (hazard ratio 1·08, 95% Bayesian credibility interval [BCI]0·95 to 1·23), equating to an estimated benefit in median time to first recovery of 0·94 days (95% BCI -0·56 to 2·43). The probability that there was a clinically meaningful benefit of at least 1·5 days in time to recovery was 0·23. 16 (3%) of 500 participants in the azithromycin plus usual care group and 28 (3%) of 823 participants in the usual care alone group were hospitalised (absolute benefit in percentage 0·3%, 95% BCI -1·7 to 2·2). There were no deaths in either study group. Safety outcomes were similar in both groups. Two (1%) of 455 participants in the azothromycin plus usual care group and four (1%) of 668 participants in the usual care alone group reported admission to hospital during the trial, not related to COVID-19.
INTERPRETATION: Our findings do not justifythe routine use of azithromycin for reducing time to recovery or risk of hospitalisation for people with suspected COVID-19 in the community. These findings have important antibiotic stewardship implications during this pandemic, as inappropriate use of antibiotics leads to increased antimicrobial resistance, and there is evidence that azithromycin use increased during the pandemic in the UK.
FUNDING: UK Research and Innovation and UK Department of Health and Social Care.
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PMID
33676597
71
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Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.
AU
Reis G, Moreira Silva EADS, Medeiros Silva DC, Thabane L, Singh G, Park JJH, Forrest JI, Harari O, Quirino Dos Santos CV, Guimarães de Almeida APF, Figueiredo Neto AD, Savassi LCM, Milagres AC, Teixeira MM, Simplicio MIC, Ribeiro LB, Oliveira R, Mills EJ, TOGETHER Investigators
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JAMA Netw Open. 2021;4(4):e216468. Epub 2021 Apr 1.
Importance: Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed.
Objective: To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting.
Design, Setting, and Participants: This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020.
Interventions: Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo.
Main Outcomes and Measures: The primary outcomes were COVID-19-associated hospitalization and death assessed at 90 days after randomization. COVID-19-associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events.
Results: Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavir-ritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56]as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1in the placebo group and 2 in the lopinavir-ritonavir intervention group.
Conclusions and Relevance: In this randomized clinical trial, neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19-associated hospitalization or other secondary clinical outcomes. This trial suggests that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic.
Trial Registration: ClinicalTrials.gov Identifier: NCT04403100.
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PMID
33885775
72
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Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial.
AU
Schwartz I, Boesen ME, Cerchiaro G, Doram C, Edwards BD, Ganesh A, Greenfield J, Jamieson S, Karnik V, Kenney C, Lim R, Menon BK, Mponponsuo K, Rathwell S, Ryckborst KJ, Stewart B, Yaskina M, Metz L, Richer L, Hill MD, ALBERTA HOPE COVID-19 Collaborators
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CMAJ Open. 2021;9(2):E693. Epub 2021 Jun 18.
BACKGROUND: Identification of therapies to prevent severe COVID-19 remains a priority. We sought to determine whether hydroxychloroquine treatment for outpatients with SARS-CoV-2 infection could prevent hospitalization, mechanical ventilation or death.
METHODS: This randomized controlled trial was conducted in Alberta during the first wave of the COVID-19 pandemic without direct contact with participants. Community-dwelling individuals with confirmed SARS-CoV-2 infection (by reverse transcription polymerase chain reaction [RT-PCR]viral ribonucleic acid test) within the previous 4 days, and symptom onset within the previous 12 days, were randomly assigned to oral hydroxychloroquine or matching placebo for 5 days. Enrolment began Apr. 15, 2020. The primary outcome was the composite of hospitalization, invasive mechanical ventilation or death within 30 days. Secondary outcomes included symptom duration and disposition at 30 days. Safety outcomes, such as serious adverse events and mortality, were also ascertained. Outcomes were determined by telephone follow-up and administrative data.
RESULTS: Among 4919 individuals with a positive RT-PCR test, 148 (10.2% of a planned 1446 patients) were randomly assigned, 111 to hydroxychloroquine and 37 to placebo. Of the 148 participants, 24 (16.2%) did not start the study drug. Four participants in the hydroxychloroquine group met the primary outcome (4 hospitalizations, 0 mechanical ventilation, 4 survived to 30 days) and none in the placebo group. Hydroxychloroquine did not reduce symptom duration (hazard ratio 0.77, 95% confidence interval 0.49-1.21). Recruitment was paused on May 22, 2020, when a since-retracted publication raised concerns about the safety of hydroxychloroquine for hospitalized patients with COVID-19. Although we had not identified concerns in a safety review, enrolment was slower than expected among those eligible for the study, and cases within the community were decreasing. Recruitment goals were deemed to be unattainable and the trial was not resumed, resulting in a study underpowered to assess the effect of treatment with hydroxychloroquine and safety.
INTERPRETATION: There was no evidence that hydroxychloroquine reduced symptom duration or prevented severe outcomes among outpatients with proven COVID-19, but the early termination of our study meant that it was underpowered.
TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT04329611.
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PMID
34145052
73
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Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection: A Randomized Clinical Trial.
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Oldenburg CE, Pinsky BA, Brogdon J, Chen C, Ruder K, Zhong L, Nyatigo F, Cook CA, Hinterwirth A, Lebas E, Redd T, Porco TC, Lietman TM, Arnold BF, Doan T
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JAMA. 2021;326(6):490.
Importance: Azithromycin has been hypothesized to have activity against SARS-CoV-2.
Objective: To determine whether oral azithromycin in outpatients with SARS-CoV-2 infection leads to absence of self-reported COVID-19 symptoms at day 14.
Design, Setting, and Participants: Randomized clinical trial of azithromycin vs matching placebo conducted from May 2020 through March 2021. Outpatients from the US were enrolled remotely via internet-based surveys and followed up for 21 days. Eligible participants had a positive SARS-CoV-2 diagnostic test result (nucleic acid amplification or antigen) within 7 days prior to enrollment, were aged 18 years or older, and were not hospitalized at the time of enrollment. Among 604 individuals screened, 297 were ineligible, 44 refused participation, and 263 were enrolled. Participants, investigators, and study staff were masked to treatment randomization.
Interventions: Participants were randomized in a 2:1 fashion to a single oral 1.2-g dose of azithromycin (n = 171) or matching placebo (n = 92).
Main Outcomes and Measures: The primary outcome was absence of self-reported COVID-19 symptoms at day 14. There were 23 secondary clinical end points, including all-cause hospitalization at day 21.
Results: Among 263 participants who were randomized (median age, 43 years; 174 [66%]women; 57% non-Hispanic White and 29% Latinx/Hispanic), 76% completed the trial. The trial was terminated by the data and safety monitoring committee for futility after the interim analysis. At day 14, there was no significant difference in proportion of participants who were symptom free (azithromycin: 50%; placebo: 50%; prevalence difference, 0%; 95% CI, -14% to 15%; P > .99). Of 23 prespecified secondary clinical end points, 18 showed no significant difference. By day 21, 5 participants in the azithromycin group had been hospitalized compared with 0 in the placebo group (prevalence difference, 4%; 95% CI, -1% to 9%; P = .16).
Conclusions and Relevance: Among outpatients with SARS-CoV-2 infection, treatment with a single dose of azithromycin compared with placebo did not result in greater likelihood of being symptom free at day 14. These findings do not support the routine use of azithromycin for outpatient SARS-CoV-2 infection.
Trial Registration: ClinicalTrials.gov Identifier: NCT04332107.
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PMID
34269813