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

2020 ◽  
Vol 7 (11) ◽  
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.

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

2020 ◽  
Author(s):  
SARAH M LOFGREN ◽  
Melanie R Nicol ◽  
Ananta S Bangdiwala ◽  
Katelyn A Pastick ◽  
Elizabeth C Okafor ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Side Effect ◽  
Randomized Clinical Trials ◽  
Safety Data ◽  
Post Exposure Prophylaxis ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Gastrointestinal Side Effects ◽  
Exposure Prophylaxis

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.

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

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.

scholarly journals Vaccines to prevent COVID-19: a protocol for a living systematic review with network meta-analysis including individual patient data (The LIVING VACCINE Project)

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Steven Kwasi Korang ◽  
Sophie Juul ◽  
Emil Eik Nielsen ◽  
Joshua Feinberg ◽  
Faiza Siddiqui ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Individual Patient Data ◽  
Viral Vector ◽  
Meta Analysis ◽  
Risk Of Bias ◽  
Serious Adverse Events ◽  
Meta Analyses ◽  
Harmful Effects

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) which has rapidly spread worldwide. Several human randomized clinical trials assessing potential vaccines are currently underway. There is an urgent need for a living systematic review that continuously assesses the beneficial and harmful effects of all available vaccines for COVID-19. Methods/design We will conduct a living systematic review based on searches of major medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify relevant randomized clinical trials. We will update the literature search once a week to continuously assess if new evidence is available. Two review authors will independently extract data and conduct risk of bias assessments. We will include randomized clinical trials comparing any vaccine aiming to prevent COVID-19 (including but not limited to messenger RNA; DNA; non-replicating viral vector; replicating viral vector; inactivated virus; protein subunit; dendritic cell; other vaccines) with any comparator (placebo; “active placebo;” no intervention; standard care; an “active” intervention; another vaccine for COVID-19) for participants in all age groups. Primary outcomes will be all-cause mortality; a diagnosis of COVID-19; and serious adverse events. Secondary outcomes will be quality of life and non-serious adverse events. The living systematic review will include aggregate data meta-analyses, trial sequential analyses, network meta-analyses, and individual patient data meta-analyses. Within-study bias will be assessed using Cochrane risk of bias tool. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) and Confidence in Network Meta-Analysis (CINeMA) approaches will be used to assess certainty of evidence. Observational studies describing harms identified during the search for trials will also be included and described and analyzed separately. Discussion COVID-19 has become a pandemic with substantial mortality. A living systematic review assessing the beneficial and harmful effects of different vaccines is urgently needed. This living systematic review will regularly inform best practice in vaccine prevention and clinical research of this highly prevalent disease. Systematic review registration PROSPERO CRD42020196492

Autoimmunity associated with immunotherapy of cancer

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 499-509 ◽  
Author(s):  
Sally M. Amos ◽  
Connie P. M. Duong ◽  
Jennifer A. Westwood ◽  
David S. Ritchie ◽  
Richard P. Junghans ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Side Effects ◽  
Cell Transfer ◽  
Serious Adverse Events ◽  
Normal Tissues ◽  
Immune Mediated ◽  
Organ Systems ◽  
Immunotherapy Of Cancer ◽  
Future Potential

Abstract In this age of promise of new therapies for cancer, immunotherapy is emerging as an exciting treatment option for patients. Vaccines and cytokines are being tested extensively in clinical trials, and strategies using monoclonal antibodies and cell transfer are mediating dramatic regression of tumors in patients with certain malignancies. However, although initially advocated as being more specific for cancer and having fewer side effects than conventional therapies, it is becoming increasingly clear that many immunotherapies can lead to immune reactions against normal tissues. Immunotoxicities resulting from treatment can range from relatively minor conditions, such as skin depigmentation, to severe toxicities against crucial organ systems, such as liver, bowel, and lung. Treatment-related toxicity has correlated with better responses in some cases, and it is probable that serious adverse events from immune-mediated reactions will increase in frequency and severity as immunotherapeutic approaches become more effective. This review introduces immunotherapeutic approaches to cancer treatment, provides details of toxicities arising from therapy, and discusses future potential ways to avoid or circumvent these side effects.

Placebo and nocebo effects in randomized double-blind clinical trials for fatigue in advanced cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9640-9640
Author(s):  
M. de la Cruz ◽  
D. Hui ◽  
H. A. Parsons ◽  
P. Lynn ◽  
C. Parker ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Cancer Patients ◽  
Advanced Cancer ◽  
Randomized Clinical Trials ◽  
Placebo Response ◽  
Well Being ◽  
Advanced Cancer Patients ◽  
Edmonton Symptom Assessment Scale ◽  
Nocebo Effects

9640 Background: We have previously reported significant placebo response in randomized controlled treatment trials for cancer related fatigue (CRF). We conducted a retrospective study to determine the frequency and predictors of response to placebo and nocebo effect in patients with CRF. Methods: We reviewed patients that received placebo in two previous randomized clinical trials conducted by our group and determined the proportion of patients who demonstrated clinical response to fatigue using an increase (ΔFACIT-F score) > 7 from baseline to day 8, and those with nocebo response as those who reported side effects. Baseline patient characteristics and symptoms recorded from the Edmonton Symptom Assessment Scale (ESAS) were analyzed to determine their association with placebo and nocebo effects. Results: A total of 105 advanced cancer patients received placebo. 59 (56%) patients responded to placebo (median Δ FACIT-F score of 22). Worse baseline anxiety and well-being subscale score (univariate) and well-being (multivariate, MR) were significantly associated with placebo response. Common side effects reported were insomnia (79%), anorexia (53%), nausea (38%) and restlessness (34%). MR analysis showed that worse baseline (ESAS) sleep, appetite, nausea, and restless are associated with increased reporting of these side effects ( Table ). Conclusions: Nearly half of advanced cancer patients enrolled in the fatigue trials responded to placebo. Worse physical well-being score was associated with placebo response. Patients experiencing specific symptoms at baseline were more likely to report these as side effects of the medication. These findings should be considered in fatigue clinical trial design. [Table: see text] No significant financial relationships to disclose.

Safety profile of poxviral vaccines: NCI experience.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 85-85
Author(s):  
Joseph W. Kim ◽  
Jennifer L. Marte ◽  
Marijo Bilusic ◽  
Nishith K. Singh ◽  
Christopher Ryan Heery ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Safety Profile ◽  
Specific Antigen ◽  
Safety Data ◽  
Treatment Modalities ◽  
Mucin 1 ◽  
Serious Adverse Events ◽  
Scientific Review ◽  
Gm Csf

85 Background: Recombinant poxviruses have been developed as therapeutic cancer vaccines. Here, we report the safety data from NCI clinical trials with poxviral vaccines. Methods: We evaluated all vaccine injections from 215 patients in 8 clinical trials involving poxviral viral vaccines. The Office of Biotechnology Activities, National Cancer Institute (NCI) Institutional Review Board, and NCI Scientific Review Committee approved all of these trials. Vaccines were consisted of recombinant vaccinia and recombinant fowlpox encoded with 3 human costimulatory molecules (TRICOM), and prostate specific antigen (PSA), or carcinoembryonic antigen, and/or mucin-1. Vaccines were administered at doses between 1.2x108 to 2x109 pfu, subcutaneously, in all patients. Twenty-one patients were also vaccinated intra-tumorally. 84 patients also received other concurrent treatment modalities, such as radiation, celecoxib, ipilimumab, samarium-153, or flutamide on 4 of these trials. All 8 clinical trials involved granulocyte-macrophage colony-stimulating factor (GM-CSF) 100mcg, or recombinant fowlpox encoding GM-CSF at 1x 108pfu as an immune adjuvant. Here, we report here the grade 2 or higher adverse events given at least a possible attribution to vaccine. Results: A total of 1,348 poxviral injections were given in 215 patients. No contact transmission, inadvertent inoculation, or any serious adverse events (AEs) related to vaccinia was observed. Below is the summary of proportion of vaccine administrations associated with specific AEs. Conclusions: These data demonstrate a favorable safety profile of the poxviral vaccines at a broad range of doses, routes of administration, in combination with other treatments, and in various tumor types. Clinical trial information: NCT00060528, NCT00096551, NCT00088413, NCT00081848, NCT00113984, NCT00450619, NCT00450463. [Table: see text]

scholarly journals ACROSTUDY: the first 5 years

2009 ◽  
Vol 161 (suppl_1) ◽  
pp. S19-S24 ◽  
Author(s):  
Peter J Trainer
Keyword(s):  
Tumour Size ◽  
Safety Data ◽  
Liver Function Tests ◽  
Dose Titration ◽  
Serious Adverse Events ◽  
Once Daily ◽  
Injection Site Reactions ◽  
The Mean ◽  
Magnetic Resonance Imaging Mri

ACROSTUDY is an observational registry intended to collect safety and efficacy data on pegvisomant therapy. A total of 792 patients have been enrolled, of whom 83% had commenced pegvisomant prior to recruitment. The mean follow-up is 1.66 years with the mean duration of pegvisomant therapy 3.31 years representing 2625 patient years of treatment. About 90% of patients were on once daily pegvisomant, and 67% were on monotherapy. Disappointingly, IGF1 was normalised in <70% of patients; furthermore, in 80% of patients with an elevated IGF1, the daily dose of pegvisomant was 20 mg or less. A total of 56 serious adverse events (AEs) were reported, of which 13 were related to pegvisomant. A total of 276 AEs were reported, of which 56 were considered related to pegvisomant. The AEs most frequently attributed to pegvisomant were disturbed liver function tests and injection site reactions. Magnetic resonance imaging (MRI) was available in 684 patients. A total of 411 patients had at least one MRI on pegvisomant compared with a baseline. In 31 patients, a decrease in tumour size has been reported, of whom 20 had previously received radiotherapy. An increase in tumour size has been reported and confirmed in 22 patients. In 11 patients, there was contradictory data on tumour size, while, in six patients, central review of the films failed to confirm increase in tumour size. In conclusion, the safety data are generally reassuring, while the IGF1 normalisation rate is disappointing, which probably reflects a failure of dose titration. Further effort is needed to understand the reasons for the failure of dose titration.

scholarly journals Outcome Measures for Clinical Drug Trials in Autism

CNS Spectrums ◽  
2004 ◽  
Vol 9 (1) ◽  
pp. 36-47 ◽  
Author(s):  
Michael G. Aman ◽  
Sherie Novotny ◽  
Carole Samango-Sprouse ◽  
Luc Lecavalier ◽  
Elizabeth Leonard ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Randomized Clinical Trials ◽  
Vital Signs ◽  
Autism Spectrum ◽  
Spectrum Disorders ◽  
Age Range ◽  
Clinical Drug ◽  
Cognitive Data ◽  
Core Features

ABSTRACTThis paper identifies instruments and measures that may be appropriate for randomized clinical trials in participants with autism spectrum disorders (ASDs). The Clinical Global Impressions scale was recommended for all randomized clinical trials. At this point, however, there is no “perfect” choice of outcome measure for core features of autism, although we will discuss five measures of potential utility. Several communication instruments are recommended, based in part on suitability across the age range. In trials where the intention is to alter core features of ASDs, adaptive behavior scales are also worthy of consideration. Several “behavior complexes” common to ASDs are identified, and instruments are recommended for assessment of these. Given the prevalence of cognitive impairment in ASDs, it is important to assess any cognitive effects, although cognitive data from ASD randomized clinical trials, thus far, are minimal. Guidance from trials in related pharmacologic areas and behavioral pharmacology may be helpful. We recommend routine elicitation of side effects, height and weight, vital signs, and (in the case of antipsychotics) extrapyramidal side-effects assessment. It is often appropriate to include laboratory tests and assessments for continence and sleep pattern.

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