Rate of Recovery and Symptomatic Efficacy of a Polyherbal AYUSH Formulation in the Treatment of SARS-CoV-2 Disease: A Single-arm Trial.

Background: The COVID-19 pandemic, caused by the human coronavirus, SARS-CoV-2, has led to the death of millions across the globe. The SARS-CoV-2 virus is highly infectious, and mutates rapidly. This creates additional challenges for the development of robust therapeutic solutions. Along with modern healthcare, there is a need to explore natural, plant-based antiviral compounds that can be used in the treatment of COVID-19. Objective: The present feasibility study investigates the efficacy of a 13-ingredient Ayurvedic polyherbal formulation, NOQ19, in the management of COVID-19. Methodology: A single-arm, open-label study design was adopted for this feasibility study. 161 RT-PCR-positive COVID-19 patients were enrolled. The enrolled participants were provided with the Ayurvedic intervention - two tablets of NOQ19 thrice daily along with the standard of care treatment. Follow-up COVID-19 RT-PCR tests were conducted on days 5, 10, and 14 or until the patient tested negative. The time taken to turn RT-PCR negative or become asymptomatic was noted. Setting: The study was conducted at Sri Sri Institute for Advanced Research from April 2021 to June 2021. Participants: A total of 161 COVID-19 patients isolating at home were assessed. Intervention: The NOQ19 preparation is a combination of 13 Ayurvedic herbs. Outcomes Measured: RT-PCR tests, the turnaround time to becoming asymptomatic, and regular symptoms assessment. Results: The analysis demonstrated that 74% of the patients tested negative on the RT-PCR within five days of taking NOQ19. Additionally, 98% of the subjects tested negative on the RT-PCR on day 10 after taking NOQ19 and standard of care treatment (as necessary). None of the participants reported any adverse events or side-effects due to NOQ19 medication. Conclusion: The NOQ19 Ayurvedic polyherbal formulation can be an effective and safe option for the symptomatic management of COVID-19.

Preliminary Study on Open Labelled Randomized Controlled Trial of the Safety and Efficacy of Hydroxychloroquine and Chloroquine Phosphate for the Treatment of Persons Infected with 2019 Coronavirus Disease in Nigeria.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of COVID-19 is a leading cause of ill-health and deaths worldwide. Currently, COVID-19 has no known widely approved therapeutics. Thus, the need for effective treatment. OBJECTIVES: We investigated the safety and efficacy of two (2) therapeutic agents; chloroquine phosphate (CQ), 2- hydroxychloroquine (HCQ) and a control (standard supportive therapy) among hospitalized adults with COVID-19. METHODS: The clinical trial was done in accordance to the World Health Organization master protocol for investigational therapeutics for COVID-19. Atotal of 40 participants with laboratory-confirmed positive COVID-19 were enrolled. Blood samples and oropharyngeal (OP) swabs were obtained on days 1,3,15 and 29 for safety and efficacy assessments. RESULTS: The baseline demographics showed that the median ages in years (range) were 45 (31-57) in CQ, 45 (36.5-60.5) in HCQ, 43 (39.5-67.0) and 44.5 (25.3-51.3) in the control (P<0.042).At randomization, seven (7) participants were asymptomatic, thirty-three (33) had mild symptoms, eight (8) had moderate symptoms while three (3) had severe symptoms. The average day of conversion to negative COVID-19 was 15.5 days for CQ, 16 days for HCQ and 18 days for the control(P=0.036). CONCLUSION: The safety assessment revealed no adverse effect of the drugs in COVID-19 patients after treatment. These findings proved that chloroquine and hydroxychloroquine are effective for the treatment of COVID-19 among hospitalized adults. It also confirmed that they are safe.

CONTEXTE: Le coronavirus du syndrome respiratoire aigu sévère 2 (SARS-CoV-2),agentcausaldelaCOVID-19, est l'unedes principales causes demaladie et de décès dans le monde. À l'heure actuelle, il n'existe aucun traitement largement approuvé pour la COVID-19. Ainsi, ilya un besoin de traitement efficace. OBJECTIFS: Nous avons étudié l'innocuité et l'efficacité de deux (2) agents thérapeutiques, le phosphate de chloroquine (CQ) et l'hydroxychloroquine (HCQ), ainsi qu'un groupe témoin (traitement de soutien standard) chez des adultes hospitalisés atteints de la COVID-19.MÉTHODES: L'essai clinique a été mené conformément au protocole maître de l'Organisation mondiale de la santé pour les thérapeutiques à l'étude de la COVID-19. Au total, 40 participants atteints de la COVID-19, confirmée en laboratoire, ont été in scrits. Des échantillons de sang et des prélèvements oropharyngés (PO) ont été effectuésauxjours1,3,15et29pourévaluerl'innocuitéetl'efficacité. RÉSULTATS: Les données démographiques initiales ont révélé que l'âge médian en années (plage) était de 45 (31-57) pour le groupe CQ, de 45 (36,5-60,5) pour le groupe HCQ, de 43 (39,5-67,0) et de 44,5 (25,3-51,3) pour le groupe témoin (P<0,042). À la randomisation, sept (7) participants étaient asymptomatiques, trente-trois (33) présentaient des symptômes bénins, huit(8) avaient des symptômes modérés, tandis que trois(3) avaient des symptômes graves. Le jour moyende conversionentest COVID-19 négatif était de 15,5 jours pour le groupe CQ, de 16 jours pour le groupe HCQ et de 18 jours pourle groupe témoin (P=0,036). CONCLUSION: L'évaluation de la sécurité n'a révélé aucun effet indésirable des médicaments chez les patients atteints de la COVID-19 après le traitement. Ces conclusions ont prouvé que la chloroquine et l'hydroxychloroquine sont efficaces pour le traitement de la COVID-19 chez les adultes hospitalisés. Cela a également confirmé qu' ilssont sûrs. Mots-clés: COVID-19, SARS-CoV-2, essai clinique, innocuité, efficacité, thérapeutiques.

Case Series of Patients with Coronavirus Disease 2019 Pneumonia Treated with Hydroxychloroquine.

The efficacy of hydroxychloroquine (HCQ) therapy, a previous candidate drug for coronavirus disease 2019 (COVID-19), was denied in the global guideline. The risk of severe cardiac events associated with HCQ was inconsistent in previous reports. In the present case series, we show the tolerability of HCQ therapy in patients treated in our hospital, and discuss the advantages and disadvantages of HCQ therapy for patients with COVID-19. A representative case was a 66-year-old woman who had become infected with severe acute respiratory syndrome coronavirus 2 and was diagnosed as having COVID-19 pneumonia via polymerase chain reaction. She was refractory to treatment with levofloxacin, lopinavir, and ritonavir, while her condition improved after beginning HCQ therapy without severe side effects. We show the tolerability of HCQ therapy for 27 patients treated in our hospital. In total, 21 adverse events occurred in 20 (74%) patients, namely, diarrhea in 11 (41%) patients, and elevated levels of both aspartate aminotransferase and alanine transaminase in 10 (37%) patients. All seven grade ≥ 4 adverse events were associated with the deterioration in COVID-19 status. No patients discontinued HCQ treatment because of HCQ-related adverse events. Two patients (7%) died of COVID-19 pneumonia. In conclusion, HCQ therapy that had been performed for COVID-19 was well-tolerated in our case series.

Comparison between leflunomide and sulfasalazine based triple therapy in methotrexate refractory rheumatoid arthritis: an open-label, non-inferiority randomized controlled trial.

To compare efficacy and safety of two different combination csDMARD therapy in Methotrexate-failed Rheumatoid arthritis patients. In this 24-week open-label, parallel-group non-inferiority, single-center clinical trial, Methotrexate-failed Rheumatoid arthritis patients with disease duration < 2 years, were randomized to either of the two treatment regimens-Methotrexate + Leflunomide + Hydroxychloroquine or Methotrexate + Sulfasalazine + Hydroxychloroquine. Primary endpoint was proportion of patients achieving EULAR good response at 12 weeks. Non-inferiority of Leflunomide based therapy was confirmed if the upper limit of the 2-sided 95% confidence interval of treatment difference between the 2 groups was lower than the selected non-inferiority margin of (- 20%) in primary endpoint at 12 weeks. Secondary endpoints were improvement in DAS28, functional outcome and adverse events at 24 weeks. 136 eligible patients were randomized to either Leflunomide or Sulfasalazine group (68 in each group).63 and 59 patients in Leflunomide and 66 and 61 patients in Sulfasalazine group completed 12 and 24 weeks of trial, respectively. In Intension-to-treat analysis, EULAR good response was achieved by 58.8% and 54.4% patients (p = 0.7) at the end of 12 weeks, and 61.7% and 64.7% patients (p = 0.8) at the end of 24 weeks-in Leflunomide and Sulfasalazine group respectively. At 12 weeks, the difference in EULAR good response with 2-sided 95% confidence interval between 2 groups was 4.4% (- 12%, 20%) in intention-to-treat and 5.8% (- 11%, 23%) in perprotocol analysis.15 and 21 adverse events were recorded in Leflunomide and Sulfasalazine group respectively. Parenteral Methotrexate was required more in Sulfasalazine group due to gastrointestinal intolerance. Leflunomide based csDMARD therapy is non-inferior to Sulfasalazine based csDMARD therapy in Methotrexate-failed Rheumatoid arthritis patients with comparable safety profile. Trial registered at clinicaltrials.gov (NCT02930343) dated 10.09.2016.

The cardiac effects of hydroxychloroquine in immune-mediated rheumatologic diseases.

ABSTRACT: Hydroxychloroquine, when used to treat patients with rheumatoid arthritis or systemic lupus erythematosus, has been found to reduce cardiovascular disease (CVD). The drug also has been associated with cardiac adverse reactions such as conduction abnormalities. This article reviews the reduction of CVD and the cardiac adverse reactions associated with hydroxychloroquine.

Hydroxychloroquine early in pregnancy and risk of birth defects.

BACKGROUND: Hydroxychloroquine is generally considered safe in pregnancy for the treatment of rheumatic conditions, but studies have been too small to evaluate teratogenicity. Quantifying the risk of congenital malformations associated with early pregnancy exposure to hydroxychloroquine is important in both the context of its ongoing use for rheumatological disorders and its potential future use for coronavirus disease 2019 prophylaxis, for which a number of clinical trials are ongoing despite initial trials for coronavirus disease 2019 treatment having been negative. OBJECTIVE: The study objective was to evaluate the risk of major congenital malformations associated with exposure to hydroxychloroquine during the first trimester of pregnancy, the period of organogenesis. STUDY DESIGN: We performed a population-based cohort study nested in the Medicaid Analytic eXtract (MAX, 2000-2014) and IBM MarketScan Research Database (MarketScan, 2003-2015). The source cohort included 2045 hydroxychloroquine-exposed pregnancies and 3,198,589 pregnancies not exposed to hydroxychloroquine continuously enrolled in their respective insurance program for 3 months before the last menstrual period through at least 1 month after delivery; infants were enrolled for at least 3 months after birth. We compared the risk of congenital malformations in women using hydroxychloroquine during the first trimester of pregnancy with that of those not using hydroxychloroquine, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (1867 hydroxychloroquine-exposed pregnancies and 19,080 pregnancies not exposed to hydroxychloroquine). The outcomes considered included major congenital malformations diagnosed during the first 90 days after delivery and specific malformation types for which there were at least 5 exposed events: oral cleft, cardiac, respiratory, gastrointestinal, genital, urinary, musculoskeletal, and limb defects. RESULTS: Overall, 54.8 per 1000 infants exposed to hydroxychloroquine were born with a major congenital malformation versus 35.3 per 1000 unexposed infants, corresponding to an unadjusted relative risk of 1.51 (95% confidence interval, 1.27-1.81). Patient characteristics were balanced in the restricted, propensity score-matched cohort. The adjusted relative risk was 1.26 (95% confidence interval, 1.04-1.54); it was 1.33 (95% confidence interval, 1.08-1.65) for a daily dose of ≥400 mg and 0.95 (95% confidence interval, 0.60-1.50) for a daily dose of <400 mg. Among the different malformation groups considered, more substantial increases in the risk of oral clefts, respiratory anomalies, and urinary defects were observed, although estimates were imprecise. No pattern of malformation was identified. CONCLUSION: Our findings suggest a small increase in the risk of malformations associated with first-trimester hydroxychloroquine use. For most patients with autoimmune rheumatic disorders, the benefits of treatment during pregnancy will likely outweigh this risk. If hydroxychloroquine were shown to be effective for coronavirus disease 2019 prophylaxis in ongoing trials, the risk of malformations would need to be balanced against such benefits.

Modelling sudden cardiac death risks factors in patients with coronavirus disease of 2019: the hydroxychloroquine and azithromycin case.

AIMS: Coronavirus disease of 2019 (COVID-19) has rapidly become a worldwide pandemic. Many clinical trials have been initiated to fight the disease. Among those, hydroxychloroquine and azithromycin had initially been suggested to improve clinical outcomes. Despite any demonstrated beneficial effects, they are still in use in some countries but have been reported to prolong the QT interval and induce life-threatening arrhythmia. Since a significant proportion of the world population may be treated with such COVID-19 therapies, evaluation of the arrhythmogenic risk of any candidate drug is needed. METHODS AND RESULTS: Using the O'Hara-Rudy computer model of human ventricular wedge, we evaluate the arrhythmogenic potential of clinical factors that can further alter repolarization in COVID-19 patients in addition to hydroxychloroquine (HCQ) and azithromycin (AZM) such as tachycardia, hypokalaemia, and subclinical to mild long QT syndrome. Hydroxychloroquine and AZM drugs have little impact on QT duration and do not induce any substrate prone to arrhythmia in COVID-19 patients with normal cardiac repolarization reserve. Nevertheless, in every tested condition in which this reserve is reduced, the model predicts larger electrocardiogram impairments, as with dofetilide. In subclinical conditions, the model suggests that mexiletine limits the deleterious effects of AZM and HCQ. CONCLUSION: By studying the HCQ and AZM co-administration case, we show that the easy-to-use O'Hara-Rudy model can be applied to assess the QT-prolongation potential of off-label drugs, beyond HCQ and AZM, in different conditions representative of COVID-19 patients and to evaluate the potential impact of additional drug used to limit the arrhythmogenic risk.

Safety and efficacy of hydroxychloroquine for treatment of non-severe COVID-19 among adults in Uganda: a randomized open label phase II clinical trial.

BACKGROUND: Several repurposed drugs such as hydroxychloroquine (HCQ) have been investigated for treatment of COVID-19, but none was confirmed to be efficacious. While in vitro studies have demonstrated antiviral properties of HCQ, data from clinical trials were conflicting regarding its benefit for COVID-19 treatment. Drugs that limit viral replication may be beneficial in the earlier course of the disease thus slowing progression to severe and critical illness. DESIGN: We conducted a randomized open label Phase II clinical trial from October-December 2020. METHODS: Patients diagnosed with COVID-19 using RT-PCR were included in the study if they were 18 years and above and had a diagnosis of COVID-19 made in the last 3 days. Patients were randomized in blocks, to receive either HCQ 400 mg twice a day for the first day followed by 200 mg twice daily for the next 4 days plus standard of care (SOC) treatment or SOC treatment alone. SARS COV-2 viral load (CT values) from RT-PCR testing of samples collected using nasal/orapharyngeal swabs was performed at baseline, day 2, 4, 6, 8 and 10. The primary outcome was median time from randomization to SARS COV-2 viral clearance by day 6. RESULTS: Of the 105 participants enrolled, 55 were assigned to the intervention group (HCQ plus SOC) and 50 to the control group (SOC only). Baseline characteristics were similar across treatment arms. Viral clearance did not differ by treatment arm, 20 and 19 participants respectively had SARS COV-2 viral load clearance by day 6 with no significant difference, median (IQR) number of days to viral load clearance between the two groups was 4(3-4) vs 4(2-4): p = 0.457. There were no significant differences in secondary outcomes (symptom resolution and adverse events) between the intervention group and the control group. There were no significant differences in specific adverse events such as elevated alkaline phosphatase, prolonged QTc interval on ECG, among patients in the intervention group as compared to the control group. CONCLUSION: Our results show that HCQ 400 mg twice a day for the first day followed by 200 mg twice daily for the next 4 days was safe but not associated with reduction in viral clearance or symptom resolution among adults with COVID-19 in Uganda. TRIAL REGISTRATION:  NCT04860284.

Efficacy and safety of hydroxychloroquine/chloroquine against SARS-CoV-2 infection: A systematic review and meta-analysis.

INTRODUCTION: Hydroxychloroquine (HCQ)/Chloroquine (CQ) has been evaluated for treatment and prophylaxis against SARS-CoV-2 infection in various studies with conflicting results. We performed a systematic review to synthesize the currently available evidence over the efficacy and safety of HCQ/CQ therapy alone against SARS-CoV-2 infection. METHODS: We searched Embase, PubMed, Web of Science, and Cochrane central for randomized controlled trials (RCTs) and prospective cohort studies published until October 15, 2020 and assessing the efficacy of HCQ alone against SARS-CoV-2 infection. We included studies evaluating HCQ/CQ alone as intervention and placebo/standard care as a control group. Retrospective studies and studies using other drugs (namely azithromycin, corticosteroids, immunomodulators, etc.) we excluded. Thirteen RCTs and three prospective cohort studies were included in this review. We pooled data using a random-effect model. RESULTS: Pooled data from 12 studies (9917 participants) showed that HCQs increase mortality as compared to placebo/standard of care (RR 1.10; 95% CI:1.00-1.20). Hydroxychloroquine did not reduce the need for hospitalization in out-patients (RR 0.57; 95% CI 0.31-1.02). HCQ group has a significantly higher rate of any adverse event (RR 2.68; 95% CI 1.55-4.64), as compared to the control group. Also, using HCQ for prophylaxis against SARS-CoV-2 infection did not reduce the risk of acquiring SARS-CoV-2 infection (RR 1.04; 95% CI 0.58-1.88). CONCLUSIONS: HCQ therapy for COVID-19 is associated with an increase in mortality and other adverse events. The negative effects are more pronounced in hospitalized patients. Therefore, with the available evidence, HCQ should not be used in prophylaxis or treatment of patients with COVID-19.

Early Outpatient Treatment of Symptomatic, High-Risk COVID-19 Patients That Should Be Ramped Up Immediately as Key to the Pandemic Crisis.

More than 1.6 million Americans have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more than 10 times that number carry antibodies to it. High-risk patients with progressing symptomatic disease currently have only hospitalization treatment, with its high mortality, available to them. An outpatient treatment that prevents hospitalization is desperately needed. Two candidate medications have been widely discussed: remdesivir and hydroxychloroquine (HCQ) + azithromycin (AZ). Remdesivir has shown mild effectiveness in hospitalized inpatients, but no trials in outpatients have been registered. HCQ + AZ has been widely misrepresented in both clinical reports and public media, and results of outpatient trials are not expected until September. Early outpatient illness is very different from later florid disease requiring hospitalization, and the treatments differ. Evidence about use of HCQ alone, or of HCQ + AZ in inpatients, is irrelevant with regard to the efficacy of HCQ + AZ in early high-risk outpatient disease. Five studies, including 2 controlled clinical trials, have demonstrated significant major outpatient treatment efficacy. HCQ + AZ has been used as the standard of care in more than 300,000 older adults with multiple comorbid conditions; the estimated proportion of such patients diagnosed with cardiac arrhythmia attributable to the medications is 47 per 100,000 users, among whom estimated mortality is less than 20% (9/100,000 users), as compared with the 10,000 Americans now dying each week. These medications need to be made widely available and promoted immediately for physicians to prescribe.

Glucocorticoids and antimalarials in systemic lupus erythematosus: an update and future directions.

PURPOSE OF REVIEW: The purpose of this review is highlighting the most recent evidence on the clinical efficacy and toxicity of glucocorticoids and antimalarials in systemic lupus erythematosus (SLE) and provide recommendations on their current use. RECENT FINDINGS: Glucocorticoid toxicity is well known. Recent data confirm the increased risk of infection and damage accrual. An observational study form Hong Kong has seen increased mortality among users of high-dose prednisone regimes. Several studies support the efficacy of medium-low doses and methyl-prednisolone pulses in lupus patients, both with and without nephritis.New data confirm the effects of antimalarials in preventing SLE activity, damage and infections, and in decreasing mortality. New screening recommendations for hydroxychloroquine maculopathy have been recently published. Combining mepacrine and hydroxychloroquine in patients with refractory cutaneous and/or articular lupus activity has proved highly effective. SUMMARY: Universal therapy with hydroxychloroquine should be aimed to patients with SLE without contraindications. Doses greater than 4 mg/kg/day should be avoided and regular eye screening warranted to minimize the risk of macular toxicity. Every effort should be made to reduce the dose of oral glucocorticoids. In moderate-severe flares, pulse methyl-prednisolone are more effective and much less toxic than increasing the oral doses of prednisone.

Clinical effectiveness of finasteride versus hydroxychloroquine in the treatment of frontal fibrosing alopecia: A randomized controlled trial.

BACKGROUND: Frontal fibrosing alopecia (FFA) is a cicatricial alopecia with rapid epidemic growth. However, there is no agreement on the best therapeutic approach. AIMS: To compare the therapeutic effects of finasteride as a first-line systemic treatment of FFA versus hydroxychloroquine as a relatively safe and effective immunosuppressive drug. METHODS: Thirty-four female FFA patients were randomly assigned to receive either 400 mg/day of hydroxychloroquine or 2.5 mg/day of finasteride for 6 months. Topical treatments in both groups include pimecrolimus, mometasone, and minoxidil. Treatment efficacy was evaluated using the Frontal Fibrosing Alopecia Severity Score (FFASS), photography, and trichoscopy after 3 and 6 months. RESULTS: Both the finasteride and hydroxychloroquine groups showed significant improvements in FFASS and trichoscopic scores (p < 0.01). However, there was no significant difference between the two groups during the study. Photographic assessment showed that more than 60% of patients in both groups had improved without statistically significant differences between the two groups. CONCLUSIONS: Both finasteride and hydroxychloroquine are equally effective, safe, and well-tolerable for treating FFA patients.

Hydroxychloroquine-induced phospholipidosis in a case of SLE: the wolf in zebra clothing.

A 30 year old lady patient of SLE on steroid and hydroxychloroquine therapy presented with lupus nephritis and later developed cardiac symptoms. Her renal biopsy revealed features of Class III lupus nephritis. Also seen was typical lamellated myelinoid material in the glomerulus. The alpha-galactosidase A activity was normal. The clinical morphological and biochemical findings were consistent with Lupus nephritis showing changes of hydroxychloroquine induced phopholipidosis. Electron microscopy along with careful clinical examination and follow up status was instrumental in the diagnosis of the latter.

Hydroxychloroquine for pre-exposure prophylaxis of COVID-19 in health care workers: a randomized, multicenter, placebo-controlled trial Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine (HERO-HCQ).

OBJECTIVES: To determine whether hydroxychloroquine (HCQ) is safe and effective at preventing COVID-19 infections among health care workers (HCWs). METHODS: In a 1: 1 randomized, placebo-controlled, double-blind, parallel-group, superiority trial at 34 US clinical centers, 1360 HCWs at risk for COVID-19 infection were enrolled between April and November 2020. Participants were randomized to HCQ or matched placebo. The HCQ dosing included a loading dose of HCQ 600 mg twice on day 1, followed by 400 mg daily for 29 days. The primary outcome was a composite of confirmed or suspected COVID-19 clinical infection by day 30, defined as new-onset fever, cough, or dyspnea and either a positive SARS-CoV-2 polymerase chain reaction test (confirmed) or a lack of confirmatory testing due to local restrictions (suspected). RESULTS: Study enrollment closed before full accrual due to recruitment challenges. The primary end point occurred in 41 (6.0%) participants receiving HCQ and 53 (7.8%) participants receiving placebo. No difference in the proportion of participants experiencing clinical infection (estimated difference of -1.8%, 95% confidence interval -4.6-0.9%, P = 0.20) was identified nor any significant safety issues. CONCLUSION: Oral HCQ taken as prescribed appeared safe among HCWs. No significant clinical benefits were observed. The study was not powered to detect a small but potentially important reduction in infection. TRIAL REGISTRATION: NCT04334148.