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

Introduction: Use 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. Methods: We 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. Results: We 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. Conclusion: Data 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.

Download Full-text

Safety of Hydroxychloroquine Among Outpatient Clinical Trial Participants for COVID-19

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa500 ◽

2020 ◽

Vol 7 (11) ◽

Cited By ~ 3

Author(s):

Sarah M Lofgren ◽

Melanie R Nicol ◽

Ananta S Bangdiwala ◽

Katelyn A Pastick ◽

Elizabeth C Okafor ◽

...

Keyword(s):

Clinical Trials ◽

Side Effects ◽

Early Treatment ◽

Side Effect ◽

Randomized Clinical Trials ◽

Safety Data ◽

Postexposure Prophylaxis ◽

Serious Adverse Events ◽

Once Daily ◽

Exposure Prophylaxis

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.

Download Full-text

Hydroxyzine Use and Mortality in Patients Hospitalized for COVID-19: A Multicenter Observational Study

Journal of Clinical Medicine ◽

10.3390/jcm10245891 ◽

2021 ◽

Vol 10 (24) ◽

pp. 5891

Author(s):

Marina Sánchez-Rico ◽

Frédéric Limosin ◽

Raphaël Vernet ◽

Nathanaël Beeker ◽

Antoine Neuraz ◽

...

Keyword(s):

Observational Study ◽

Randomized Clinical Trials ◽

Acid Sphingomyelinase ◽

Potential Usefulness ◽

Sensitivity Analyses ◽

Post Exposure Prophylaxis ◽

Multivariable Logistic Regression Model ◽

Double Blind ◽

Multicenter Observational Study ◽

Exposure Prophylaxis

(1) Background: Based on its antiviral activity, anti-inflammatory properties, and functional inhibition effects on the acid sphingomyelinase/ceramide system (FIASMA), we sought to examine the potential usefulness of the H1 antihistamine hydroxyzine in patients hospitalized for COVID-19. (2) Methods: In a multicenter observational study, we included 15,103 adults hospitalized for COVID-19, of which 164 (1.1%) received hydroxyzine within the first 48 h of hospitalization, administered orally at a median daily dose of 25.0 mg (SD = 29.5). We compared mortality rates between patients who received hydroxyzine at hospital admission and those who did not, using a multivariable logistic regression model adjusting for patients’ characteristics, medical conditions, and use of other medications. (3) Results: This analysis showed a significant association between hydroxyzine use and reduced mortality (AOR, 0.51; 95%CI, 0.29–0.88, p = 0.016). This association was similar in multiple sensitivity analyses. (4) Conclusions: In this retrospective observational multicenter study, the use of the FIASMA hydroxyzine was associated with reduced mortality in patients hospitalized for COVID-19. Double-blind placebo-controlled randomized clinical trials of hydroxyzine for COVID-19 are needed to confirm these results, as are studies to examine the potential usefulness of this medication for outpatients and as post-exposure prophylaxis for individuals at high risk for severe COVID-19.

Download Full-text

Existing and Emerging Approaches to Treating Chronic Inflammatory Demyelinating Polyneuropathy

US Neurology ◽

10.17925/usn.2019.15.1.33 ◽

2019 ◽

Vol 15 (1) ◽

pp. 33

Author(s):

Brannagan III Thomas H ◽

Khosro Farhad ◽

Inna Kleyman ◽

Megan Leitch ◽

Rebecca Traub ◽

...

Keyword(s):

Clinical Trials ◽

Side Effects ◽

Randomized Clinical Trials ◽

Chronic Inflammatory Demyelinating Polyneuropathy ◽

Neurological Diseases ◽

Demyelinating Polyneuropathy ◽

Double Blind ◽

Double Blind Placebo ◽

Inflammatory Demyelinating Polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare disabling disease with an incompletely understood autoimmune etiology. Differentiating the condition from other neurological diseases can be challenging and appropriate treatment is often delayed. Intravenous immunoglobulin (IVIg), plasmapheresis, corticosteroids and subcutaneous immunoglobulin (SCIg) have all been demonstrated to be beneficial in placebo-controlled, randomized clinical trials. Corticosteroids, including methylprednisolone and dexamethasone are effective and frequently used in CIDP but their long-term use is limited by side effects. One of the most commonly prescribed treatments for CIDP is IVIg which diminishes inflammatory processes and prevents disease progression. Treatment with IVIg has proven effective in randomized, double blind, placebo controlled, clinical trials and the results support its use in CIDP. For some patients, the benefit of IVIg, is limited by the frequency of infusions and systemic side effects such as flu-like symptoms, headache, and nausea. Other effective treatments for CIDP include corticosteroids that are associated with serious side effects in long-term use and plasmapheresis which requires specialized facilities. More recently, SCIg has been demonstrated in double blind, placebo-controlled studies to be effective for maintenance use in CIDP in patients whose disease has been controlled by IVIg. In a large clinical trial, 0.2 g/kg and 0.4 g/kg body weight doses of 20% SCIg equivalent to 1 mL/kg or 2 mL/kg, respectively, administered weekly, demonstrated efficacy in CIDP and were well tolerated. Immunomodulating treatments such as cyclophosphamide, mycophenolate mofetil and rituximab have also shown efficacy in select populations with CIDP.

Download Full-text

Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death: Meta-Analysis

10.1101/2020.09.30.20204693 ◽

2020 ◽

Author(s):

Joseph A. Ladapo ◽

John E. McKinnon ◽

Peter A. McCullough ◽

Harvey Risch

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Side Effects ◽

Fixed Effects ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Controlled Trials ◽

Cochrane Central Register ◽

Randomized Controlled ◽

Exposure Prophylaxis

Objective--To determine if hydroxychloroquine (HCQ) reduces the incidence of new illness, hospitalization or death among outpatients at risk for or infected with SARS-CoV-2 (COVID-19). Design--Systematic review and meta-analysis of randomized clinical trials. Data sources--Search of MEDLINE, EMBASE, PubMed, medRxiv, PROSPERO, and the Cochrane Central Register of Controlled Trials. Also review of reference lists from recent meta-analyses. Study selection--Randomized clinical trials in which participants were treated with HCQ or placebo/standard-of-care for pre-exposure prophylaxis, post-exposure prophylaxis, or outpatient therapy for COVID-19. Methods--Two investigators independently extracted data on trial design and outcomes. Medication side effects and adverse reactions were also assessed. The primary outcome was COVID-19 hospitalization or death. When unavailable, new COVID-19 infection was used. We calculated random effects meta-analysis according to the method of DerSimonian and Laird. Heterogeneity between the studies was evaluated by calculation of Cochran Q and I2 parameters. An Egger funnel plot was drawn to investigate publication bias. We also calculated the fixed effects meta-analysis summary of the five studies. All calculations were done in Excel, and results were considered to be statistically significant at a two-sided threshold of P=.05. Results--Five randomized controlled clinical trials enrolling 5,577 patients were included. HCQ was associated with a 24% reduction in COVID-19 infection, hospitalization or death, P=.025 (RR, 0.76 [95% CI, 0.59 to 0.97]). No serious adverse cardiac events were reported. The most common side effects were gastrointestinal. Conclusion--Hydroxychloroquine use in outpatients reduces the incidence of the composite outcome of COVID-19 infection, hospitalization, and death. Serious adverse events were not reported and cardiac arrhythmia was rare. Systematic review registration--This review was not registered.

Download Full-text

Network meta‐analysis of post‐exposure prophylaxis randomized clinical trials

HIV Medicine ◽

10.1111/hiv.12964 ◽

2020 ◽

Author(s):

I Fernández ◽

E. Lazzari ◽

A. Inciarte ◽

V. Diaz‐Brito ◽

A. Milinkovic ◽

...

Keyword(s):

Clinical Trials ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Post Exposure Prophylaxis ◽

Post Exposure ◽

Exposure Prophylaxis

Download Full-text

Efficacy and safety of hydroxychloroquine as pre-and post-exposure prophylaxis and treatment of COVID-19: A systematic review and meta-analysis of blinded, placebo-controlled, randomized clinical trials.

The Lancet Regional Health - Americas ◽

10.1016/j.lana.2021.100062 ◽

2021 ◽

pp. 100062

Author(s):

Paulo Ricardo Martins-Filho ◽

Lis Campos Ferreira ◽

Luana Heimfarth ◽

Adriano Antunes de Souza Araújo ◽

Lucindo José Quintans-Júnior

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Post Exposure Prophylaxis ◽

Efficacy And Safety ◽

Post Exposure ◽

Exposure Prophylaxis

Download Full-text

Repeat Subcutaneous Administration of REGEN-COV® in Adults is Well-Tolerated and Prevents the Occurrence of COVID-19

10.1101/2021.11.10.21265889 ◽

2021 ◽

Author(s):

Flonza Isa ◽

Eduardo Forleo-Neto ◽

Jonathan Meyer ◽

Wenjun Zheng ◽

Scott Rasmussen ◽

...

Keyword(s):

Risk Reduction ◽

Odds Ratio ◽

Controlled Trial ◽

Phase 1 ◽

Subcutaneous Administration ◽

Post Exposure Prophylaxis ◽

Serious Adverse Events ◽

Double Blind ◽

Grade 3 ◽

Exposure Prophylaxis

Background: Data show that a single dose of casirivimab and imdevimab (REGEN-COV®) is effective in treating hospitalized individuals and outpatients with COVID-19 and in post-exposure prophylaxis. We present results from a phase 1, double-blind, placebo-controlled trial evaluating the safety, tolerability, and efficacy of repeat monthly doses of subcutaneous (SC) REGEN-COV in uninfected adult volunteers who were healthy or had chronic stable medical conditions. Methods: Subjects were randomized (3:1) to SC REGEN-COV 1200 mg or placebo dosed every 4 weeks for up to 6 doses. The primary and secondary endpoints evaluated the safety, pharmacokinetics, and immunogenicity of multiple-dose administration of REGEN-COV. Efficacy was evaluated by the incidence of COVID-19 or SARS-CoV-2 seroconversion. Results: In total, 969 subjects were treated. Repeat monthly dosing of SC REGEN-COV led to a 92.4% relative risk reduction in clinically-defined COVID-19 compared to placebo (3/729 [0.4%] vs 13/240 [5.4%]; odds ratio: 0.07 [95% CI, 0.01–0.27]), and a 100% reduction in laboratory-confirmed COVID-19 (0/729 vs 10/240 [4.2%]; odds ratio 0.00). Development of anti-drug antibodies was low (<5% subjects). No grade ≥3 injection-site reactions (ISRs) or hypersensitivity reactions were reported. A slightly higher percentage of subjects reported TEAEs with REGEN-COV (54.9%) than placebo (48.3%), due to ISRs (all grade 1-2). Serious adverse events were rare and occurred at similar percentages in the REGEN-COV and placebo groups. No deaths were reported in the 6-month treatment period. Conclusions: Repeated monthly administration of 1200 mg SC REGEN-COV was well-tolerated with low immunogenicity, and showed a substantial risk reduction in COVID-19 occurrence. (ClinicalTrials.gov identifier, NCT04519437)

Download Full-text

Efficacy and safety of hydroxychloroquine as pre-and post-exposure prophylaxis and treatment of COVID-19. Systematic review and meta-analysis of blinded, placebo-controlled, randomized clinical trials

10.1101/2021.06.12.21258831 ◽

2021 ◽

Author(s):

Paulo Ricardo Martins-Filho ◽

Lis Campos Ferreira ◽

Luana Heimfarth ◽

Adriano Antunes de Souza Araujo ◽

Lucindo Jose Quintans-Junior

Keyword(s):

Clinical Trials ◽

Adverse Events ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Hospitalized Patients ◽

Post Exposure Prophylaxis ◽

Potential Candidate ◽

Efficacy And Safety ◽

Post Exposure ◽

Exposure Prophylaxis

BACKGROUND Hydroxychloroquine (HCQ) is an anti-malarial and immunomodulatory drug considered a potential candidate for drug repurposing in COVID-19 due to their in vitro antiviral activity against SARS-CoV-2. Despite the potential antiviral effects and anti-inflammatory profile, the results based on clinical studies are contradictory and the quality of the decision-making process from meta-analyses summarizing the available evidence selecting studies with different designs and unblinded trials is limited. The aim of this study was to synthesize the best evidence on the efficacy and safety of HCQ as pre-and post-exposure prophylaxis and treatment of non-hospitalized and hospitalized patients with COVID-19. METHODS Searches for studies were performed in PubMed, Web of Science, Embase, Lilacs, the website ClinicalTrials.gov and the preprint server medRxiv from January 1, 2020 to May 17, 2021. The following elements were used to define eligibility criteria: (1) Population, individuals at high-risk of exposure to SARS-CoV-2 (pre-exposure), individuals who had close contact with a positive or probable case of COVID-19 (post-exposure), non-hospitalized patients with COVID-19 and hospitalized patients with COVID-19; (2) Intervention, HCQ; (3) Comparison, placebo; (4) Outcomes: incidence of SARS-CoV-2 infection, need for hospitalization, length of hospital stay, need for invasive mechanical ventilation (MV), death, and adverse events; and (5) Study type, blinded, placebo-controlled, randomized clinical trials (RCTs). Risk of bias was judged according to the Cochrane guidelines for RCTs. Treatment effects were reported as relative risk (RR) for dichotomous variables and mean difference (MD) for continuous variables with 95% confidence intervals (CI). We used either a fixed or random-effects model to pool the results of individual studies depending on the presence of heterogeneity. The GRADE system was used to evaluate the strength of evidence between use of HCQ and the outcomes of interest. RESULTS Fourteen blinded, placebo-controlled RCTs were included in the meta-analysis. Four trials used HCQ as a prophylactic medication pre-exposure to COVID-19, two as a prophylactic medication post-exposure to COVID-19, three as treatment for non-hospitalized patients, and five as treatment for hospitalized patients with COVID-19. We found no decreased risk of SARS-CoV-2 infection among individuals receiving HCQ as pre-exposure (RR = 0.90; 95% CI 0.46 to 1.77) or post-exposure (RR = 0.96; 95% CI 0.72 to 1.29) prophylaxis to prevent COVID-19. There is no decreased risk of hospitalization for outpatients with SARS-CoV-2 infection (RR = 0.64; 95% CI 0.33 to 1.23) and no decreased risk of MV (RR = 0.81; 95% CI 0.49 to 1.34) and death (RR = 1.05; 95% CI 0.62 to 1.78) among hospitalized patients with COVID-19 receiving HCQ. The certainty of the results on the lack of clinical benefit for HCQ was rated as moderate. Moreover, our results demonstrated an increased risk for any adverse events and gastrointestinal symptoms among those using HCQ. CONCLUSION Available evidence based on the results of blinded, placebo-controlled RCTs showed no clinical benefits of HCQ as pre-and post-exposure prophylaxis and treatment of non-hospitalized and hospitalized patients with COVID-19.

Download Full-text