scholarly journals A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19

2020 ◽  
Author(s):  
Drifa Belhadi ◽  
Nathan Peiffer-Smadja ◽  
François-Xavier Lescure ◽  
Yazdan Yazdanpanah ◽  
France Mentré ◽  
...  
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Data Extraction ◽  
Antiviral Agents ◽  
Median Number ◽  
Antiviral Drugs ◽  
Open Label ◽  
Double Blind ◽  
Stem Cells Therapy ◽  
Novel Coronavirus

ABSTRACTBackgroundAlthough a number of antiviral agents have been evaluated for coronaviruses there are no approved drugs available. To provide an overview of the landscape of therapeutic research for COVID-19, we conducted a review of registered clinical trials.MethodsA review of currently registered clinical trials was performed on registries, including the Chinese (chictr.org.cn) and US (clinicaltrials.gov) databases to identify relevant studies up to March, 7th 2020. The search was conducted using the search terms “2019-nCoV”, “COVID-19”, “SARS-CoV-2”, “Hcov-19”, “new coronavirus”, “novel coronavirus”. We included interventional clinical trials focusing on patients with COVID-19 and assessing antiviral drugs or agents.FindingsOut of the 353 studies identified, 115 clinical trials were selected for data extraction. Phase IV trials were the most commonly reported study type (n=27, 23%). However, 62 trials (54%) did not describe the phase of the study. Eighty percent (n=92) of the trials were randomized with parallel assignment and the median number of planned inclusions was 63 (IQR, 36-120). Open-label studies were the most frequent (46%) followed by double-blind (13%) and single blind studies (10%). The most frequently assessed therapies were: stem cells therapy (n=23 trials), lopinavir/ritonavir (n=15), chloroquine (n=11), umifenovir (n=9), hydroxychloroquine (n=7), plasma treatment (n=7), favipiravir (n=7), methylprednisolone (n=5), and remdesivir (n=5). Remdesivir was tested in 5 trials with a median of 400 (IQR, 394-453) planned inclusions per trial, while stem cells therapy was tested in 23 trials, but had a median of 40 (IQR, 23-60) planned inclusions per trial. Lopinavir/ritonavir was associated with the highest total number of planned inclusions (2606) followed by remdesivir (2155). Only 52% of the clinical trials reported the treatment dose (n=60) and only 34% (n=39) the duration. The primary outcome was clinical in 76 studies (66%), virological in 27 (23%); radiological in 9 (8%) or immunological in three studies (3%).InterpretationNumerous clinical trials have been registered since the beginning of the COVID-19 outbreak, however, a number of information regarding drugs or trial design were lacking.FundingNone

Modafinil Augmentation for Residual Symptoms of Fatigue in Patients with a Partial Response to Antidepressants

2007 ◽  
Vol 41 (6) ◽  
pp. 1005-1012 ◽  
Author(s):  
Jenny Y Lam ◽  
Maisha Kelly Freeman ◽  
Marshall E Cates
Keyword(s):  
Clinical Trials ◽  
Data Extraction ◽  
Controlled Clinical Trials ◽  
Open Label ◽  
Double Blind ◽  
Residual Symptoms ◽  
Randomized Controlled ◽  
Manual Search ◽  
Number Of Patients ◽  
Residual Fatigue

OBJECTIVE: To evaluate the literature discussing the use of modafinil in the treatment of residual symptoms of fatigue in patients with depression. DATA SOURCES: PubMed (1966–March 2007) and International Pharmaceutical Abstracts(1970–March 2007) were searched using the key words modafinil and depression. A manual search of the reference section of the articles retrieved was conducted to identify articles not indexed in either of these sources. STUDY SELECTION AND DATA EXTRACTION: All articles published in English were evaluated. Studies were included if modafinil was used to treat patients with residual fatigue from depression and the effects were measured with validated fatigue subscales. DATA SYNTHESIS: One retrospective study, 5 open-label trials, and 2 randomized controlled clinical trials met the inclusion criteria for assessment of residual symptoms of fatigue as assessed by commonly used fatigue subscales after modafinil administration. Although improvement with fatigue has occurred with modafinil therapy, literature regarding the topic is limited by the lack of well-controlled clinical trials. Modafinil does appear to improve residual fatigue with depression as evidenced by open-label trials; however, the efficacy of this agent has not been duplicated in randomized controlled trials. The open-label trials that have been conducted often had no comparator and a small number of patients. In addition, outcome measures used in the studies were not consistent between trials. Modafinil appears to be well tolerated, with the main adverse effects being headache and nausea. CONCLUSIONS: Open-label trials indicate that modafinil may be effective in ameliorating fatigue associated with depression; however, this effect has not been reproduced in randomized, double-blind, placebo-controlled clinical trials. Therefore, the use of modafinil for the treatment of residual fatigue is not recommended due to the lack of reproducible data of its efficacy. Long-term, adequately powered clinical trials should be conducted to determine its place in therapy.

Recent Advances towards Drug Design Targeting the Protease of 2019 novel coronavirus (2019-nCoV)

2020 ◽  
Vol 27 ◽  
Author(s):  
Sehrish Bano ◽  
Abdul Hameed ◽  
Mariya Al-Rashida ◽  
Shafia Iftikhar ◽  
Jamshed Iqbal
Keyword(s):  
Drug Design ◽  
Rna Polymerase ◽  
Drug Targets ◽  
Antiviral Agents ◽  
Structural Features ◽  
Antiviral Drugs ◽  
Rna Dependent Rna Polymerase ◽  
Mortality And Morbidity ◽  
Functional Relationships ◽  
Novel Coronavirus

Background: The 2019 novel coronavirus (2019-nCoV), also known as coronavirus 2 (SARS-CoV-2) acute respiratory syndrome has recently emerged and continued to spread rapidly with high level of mortality and morbidity rates. Currently, no efficacious therapy is available to relieve coronavirus infections. As new drug design and development takes much time, there is a possibility to find an effective treatment from existing antiviral agents. Objective: In this case, there is a need to find out the relationship between possible drug targets and mechanism of action of antiviral drugs. This review discusses about the efforts to develop drug from known or new molecules. Methods: Viruses usually have two structural integrities, proteins and nucleic acids, both of which can be possible drug targets. Herein, we systemically discuss the structural-functional relationships of the spike, 3-chymotrypsin-like protease (3CLpro), papain like protease (PLpro) and RNA-dependent RNA polymerase (RdRp), as these are prominent structural features of corona virus. Certain antiviral drugs such as Remdesivir are RNA dependent RNA polymerase inhibitor. It has the ability to terminate RNA replication by inhibiting ATP. Results: It is reported that ATP is involved in synthesis of coronavirus non-structural proteins from 3CLpro and PLpro. Similarly, mechanisms of action of many other antiviral agents has been discussed in this review. It will provide new insights into the mechanism of inhibition, and let us develop new therapeutic antiviral approaches against novel SARS-CoV-2 coronavirus. Conclusion: In conclusion, this review summarizes recent progress in developing protease inhibitors for SARS-CoV-2.

scholarly journals Effects of open-label placebos in clinical trials: a systematic review and meta-analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Melina von Wernsdorff ◽  
Martin Loef ◽  
Brunna Tuschen-Caffier ◽  
Stefan Schmidt
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Medical Condition ◽  
Data Extraction ◽  
Meta Analysis ◽  
Risk Of Bias ◽  
Open Label ◽  
Cancer Related Fatigue ◽  
Promising Treatment ◽  
Irritable Bowel

AbstractOpen-label placebos (OLPs) are placebos without deception in the sense that patients know that they are receiving a placebo. The objective of our study is to systematically review and analyze the effect of OLPs in comparison to no treatment in clinical trials. A systematic literature search was carried out in February 2020. Randomized controlled trials of any medical condition or mental disorder comparing OLPs to no treatment were included. Data extraction and risk of bias rating were independently assessed. 1246 records were screened and thirteen studies were included into the systematic review. Eleven trials were eligible for meta-analysis. These trials assessed effects of OLPs on back pain, cancer-related fatigue, attention deficit hyperactivity disorder, allergic rhinitis, major depression, irritable bowel syndrome and menopausal hot flushes. Risk of bias was moderate among all studies. We found a significant overall effect (standardized mean difference = 0.72, 95% Cl 0.39–1.05, p < 0.0001, I2 = 76%) of OLP. Thus, OLPs appear to be a promising treatment in different conditions but the respective research is in its infancy. More research is needed, especially with respect to different medical and mental disorders and instructions accompanying the OLP administration as well as the role of expectations and mindsets.

scholarly journals A Scoping Insight on Potential Prophylactics, Vaccines and Therapeutic Weaponry for the Ongoing Novel Coronavirus (COVID-19) Pandemic- A Comprehensive Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Priyanka Dash ◽  
Subhashree Mohapatra ◽  
Sayantan Ghosh ◽  
Bismita Nayak
Keyword(s):  
Clinical Trials ◽  
Therapeutic Strategy ◽  
Antiviral Agents ◽  
Fast Response ◽  
Etiologic Agent ◽  
Prolonged Treatment ◽  
Rdrp Activity ◽  
Open Label ◽  
Plasma Therapy ◽  
Mesenchymal Stem Cell Therapy

The emergence of highly virulent CoVs (SARS-CoV-2), the etiologic agent of novel ongoing “COVID-19” pandemics has been marked as an alarming case of pneumonia posing a large global healthcare crisis of unprecedented magnitude. Currently, the COVID-19 outbreak has fueled an international demand in the biomedical field for the mitigation of the fast-spreading illness, all through the urgent deployment of safe, effective, and rational therapeutic strategies along with epidemiological control. Confronted with such contagious respiratory distress, the global population has taken significant steps towards a more robust strategy of containment and quarantine to halt the total number of positive cases but such a strategy can only delay the spread. A substantial number of potential vaccine candidates are undergoing multiple clinical trials to combat COVID-19 disease, includes live-attenuated, inactivated, viral-vectored based, sub-unit vaccines, DNA, mRNA, peptide, adjuvant, plant, and nanoparticle-based vaccines. However, there are no licensed anti-COVID-19 drugs/therapies or vaccines that have proven to work as more effective therapeutic candidates in open-label clinical trial studies. To counteract the infection (SARS-CoV-2), many people are under prolonged treatment of many chemical drugs that inhibit the PLpro activity (Ribavirin), viral proteases (Lopinavir/Ritonavir), RdRp activity (Favipiravir, Remdesivir), viral membrane fusion (Umifenovir, Chloroquine phosphate (CQ), Hydroxychloroquine phosphate (HCQ), IL-6 overexpression (Tocilizumab, Siltuximab, Sarilumab). Mesenchymal Stem Cell therapy and Convalescent Plasma Therapy have emerged as a promising therapeutic strategy against SARS-CoV-2 virion. On the other hand, repurposing previously designed antiviral agents with tolerable safety profile and efficacy could be the only promising approach and fast response to the novel virion. In addition, research institutions and corporations have commenced the redesign of the available therapeutic strategy to manage the global crisis. Herein, we present succinct information on selected anti-COVID-19 therapeutic medications repurposed to combat SARS-CoV-2 infection. Finally, this review will provide exhaustive detail on recent prophylactic strategies and ongoing clinical trials to curb this deadly pandemic, outlining the major therapeutic areas for researchers to step in.

scholarly journals Safety and Effectiveness of Favipiravir for Novel Coronavirus (COVID-19): A Rapid Review of Available Evidence

2021 ◽  
Author(s):  
Mohammadreza Mobinizadeh ◽  
Morteza Arab-Zozani
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Therapeutic Potential ◽  
Data Extraction ◽  
Rapid Review ◽  
Eligibility Criteria ◽  
Clinical Trial Registration ◽  
Registration System ◽  
Novel Coronavirus ◽  
First Time

Context: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appeared for the first time in December 2019 in Wuhan, China. Due to the lack of unified and integrated evidence for Favipiravir, this study was conducted to rapidly review the existing evidence to help evidence-based decision-making on the therapeutic potential of this drug in the treatment of COVID-19 patients. Evidence Acquisition: This study is a rapid Health Technology Assessment (HTA). By searching pertinent databases, the research team collected relevant articles and tried to create a policy guide through a thematic approach. This rapid review was done in four steps: (1) Searching for evidence through databases; (2) screening the evidence considering eligibility criteria; (3) data extraction; and (4) analyzing the data through thematic analysis. Results: After applying the inclusion criteria, four studies were finally found, including three review studies and a clinical trial that was temporarily removed by its publisher from the journal’s website. After searching the sources mentioned in the articles, two ongoing clinical trials were found in China. Also, by searching the clinical trial website, www.clinicaltrials.gov, five clinical trials were found in the search. The result of the search in the clinical trial registration system in Iran showed a study that is in the process of patient recruitment. A limited number of other articles were found, mostly in the form of reflections from physicians or researchers and letters to editors who have predicted the drug’s performance on SARS-CoV-2, which needs further clinical study to be approved. Conclusions: With the available evidence, it is not possible to make a definite conclusion about the safety and efficacy of Favipiravir in the treatment of patients with COVID-19.

scholarly journals M42. INDEPENDENT REVIEW & MONITORING IMPROVES QUALITY OF PANSS DATA IN GLOBAL CLINICAL TRIALS

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S150-S150
Author(s):  
Barbara Echevarria ◽  
Cong Liu ◽  
Selam Negash ◽  
Mark Opler ◽  
Patricio Molero ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Data Quality ◽  
Working Group ◽  
Double Blind Study ◽  
Open Label ◽  
Rater Training ◽  
Double Blind ◽  
Open Label Extension ◽  
Expert Working Group ◽  
Independent Review

Abstract Background The Positive and Negative Syndrome Scale (PANSS) (1) is the most widely used endpoint for measuring change in schizophrenia clinical trials. A set of flags have been developed by ISCTM expert working group to identify potential scoring errors in PANSS assessments (2). Measures have been taken by sponsors (pharmaceutical industry) with the goal of increasing scoring reliability and data quality, such as the use of Independent Review (IRev). We evaluated changes in data quality when site raters stop being recorded and monitored via IRev by comparing two studies with the same cohort of raters, one with independent review and one without. Methods Data from PANSS assessments in two global multisite schizophrenia clinical trials were analyzed. We selected data from raters participating in both studies (which run concurrently for a significant period of time). Raters were rigorously trained on administration and scoring conventions and certified prior to the study through demonstration of adequate interrater reliability. In addition to these steps, raters in study A were required to audio record all PANSS assessments with a selected subset of visits being subject to IRev. PANSS assessments in study B were neither recorded nor monitored via IRev. Data quality after study completion was examined by calculating the frequency of anomalous data patterns identified as “high” (very probable or definite error) by the ISCTM Working Group in both studies. Additionally, we examined the percentage of assessments with lower than expected PANSS interview duration as captured via an eCOA platform. Results There were 9441 eCOA PANSS assessments in study A and 6178 in study B included in this analysis. The proportions of flags that represented highly probable/definite error differed significantly between the studies (9% vs 18% for Study A and B, respectively, p&lt;.01). The most significant differences in ISCTM flags were related to overly consistent scoring patterns (27 or more items scored identically to the prior visit) occurring with higher frequency in study B. Additionally, study B also had a significantly higher frequency of assessments flagged for low interview duration (&lt; 15 minutes) (1% vs 4% for Study A and B, respectively, p&lt;.01). Discussion Initial rater training is necessary but not sufficient to ensure adequate data quality in schizophrenia trials. Implementation of additional in-study oversight through Independent Review or similar methods reduces the probability of data error in PANSS assessments, including the appearance of improbable rating patterns and decreased time spent interviewing study subjects. One potential limitation is that study A is a double-blind study whereas study B is an open label extension of study A.

scholarly journals Topical Corticosteroids a Viable Solution for Oral Graft versus Host Disease? A Systematic Insight on Randomized Clinical Trials

Medicina ◽  
2020 ◽  
Vol 56 (7) ◽  
pp. 349
Author(s):  
Arin Sava ◽  
Andra Piciu ◽  
Sergiu Pasca ◽  
Alexandru Mester ◽  
Ciprian Tomuleasa
Keyword(s):  
Clinical Trials ◽  
Graft Versus Host Disease ◽  
Randomized Clinical Trials ◽  
Open Label ◽  
Double Blind ◽  
Host Disease ◽  
Graft Versus Host ◽  
Overall Response ◽  
Topical Corticosteroids ◽  
Oral Gvhd

Background and Objectives: This research attempts to provide a clear view of the literature on randomized clinical trials (RCTs) concerning the efficacy of topical dexamethasone, clobetasol and budesonide in oral graft versus host disease (GVHD). Materials and Methods: An electronic search of the PubMed, Web of Science and Scopus databases was carried out for eligible RCTs. Studies were included if they had adult patients with oral GVHD treatment with topical corticosteroids, and if the RCT study was published in English. The Cochrane Risk of Bias tool was used to assess the quality of these studies. Overall, three RCTs were included (an Open, Randomized, Multicenter Trial; a Randomized Double-Blind Clinical Trial; and an Open-Label Phase II Randomized Trial). Results: The trials involved 76 patients, of which 44 patients received topical dexamethasone, 14 patients received topical clobetasol and 18 patients received topical budesonide. Topical agents were most frequently used when oral tissues were the sole site of involvement. It appears that the best overall response is present for budesonide with no difference between the four arms, followed by clobetasol, and then by dexamethasone. The limitation of the current study is mainly represented by the fact that overall response was derived in two of the studies from other parameters. Moreover, both budesonide and clobetasol were used in only one study each, while two assessed dexamethasone. Conclusions: Based on the clinical trials, all three agents seem to be effective in treating oral GVHD and had a satisfactory safety profile. There is still a need for assessing high quality RCTs to assess the efficacy of these therapies on a larger cohort.

Sildenafil for Pulmonary Hypertension

2005 ◽  
Vol 39 (5) ◽  
pp. 869-884 ◽  
Author(s):  
Audrey J Lee ◽  
Teresa B Chiao ◽  
Mildred P Tsang
Keyword(s):  
Nitric Oxide ◽  
Clinical Trials ◽  
Pulmonary Hypertension ◽  
Vascular Resistance ◽  
Resistance Index ◽  
Data Sources ◽  
Cochrane Library ◽  
Open Label ◽  
Vascular Effects ◽  
Double Blind

OBJECTIVE: To evaluate the efficacy of sildenafil for treatment of pulmonary hypertension. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1977–March 2005), Cochrane Library, and International Pharmaceutical Abstracts (1977–March 2005) using the terms sildenafil and pulmonary hypertension. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles in English identified from the data sources were evaluated. Studies including >5 patients with primarily adult populations were included in the review. DATA SYNTHESIS: The treatment of pulmonary hypertension is challenging. Sildenafil has recently been studied as monotherapy and in combination with other vasodilators in the management of pulmonary hypertension. Eight hemodynamic studies and 12 clinical trials were reviewed (1 retrospective, 3 double-blind, 8 open-label). Sildenafil reduced pulmonary arterial hypertension and pulmonary vascular resistance/peripheral vascular resistance index and tended to increase cardiac output/cardiac index compared with baseline. Sildenafil was comparable to nitric oxide and at least as effective as iloprost or epoprostenol in terms of its pulmonary vasoreactivity. Combination therapy with iloprost, nitric oxide, or epoprostenol resulted in enhanced and prolonged pulmonary vascular effects. Clinical trials suggest that sildenafil improves exercise tolerance and New York Heart Association functional class, but large, randomized controlled trials are needed to confirm these findings. Overall, sildenafil was well tolerated. CONCLUSIONS: Overall, sildenafil is a promising and well-tolerated agent for management of pulmonary hypertension. Further well-designed trials are warranted to establish its place in the treatment of pulmonary hypertension.

New Drug Approvals: Romiplostim Management of Immune Thrombocytopenic Purpura

2009 ◽  
Vol 43 (5) ◽  
pp. 914-919 ◽  
Author(s):  
Heather J Ipema ◽  
Michelle Y Jung ◽  
Amy E Lodolce
Keyword(s):  
Immune Thrombocytopenic Purpura ◽  
Data Extraction ◽  
Reticuloendothelial System ◽  
Pharmacokinetic Data ◽  
Open Label ◽  
Double Blind ◽  
Thrombocytopenic Purpura ◽  
Time To Peak ◽  
Study Selection ◽  
Open Label Extension

Objective To review the pharmacology, pharmacokinetics, efficacy, and safety of romiplostim, the first drug approved for use in patients with immune thrombocytopenic purpura (ITP). Data Sources Articles were identified through searches of MEDLINE (1966–January 2009) and International Pharmaceutical Abstracts (1970–January 2009) using the key words romiplostim and AMG 531. Searches were limited to articles published in English. The manufacturer was contacted for additional data. Study Selection And Data Extraction Clinical trials and pharmacokinetic data were selected for review. Data Synthesis Romiplostim is a second-generation thrombopoietic receptor agonist that exerts its therapeutic effect by stimulating megakaryopoiesis. Subcutaneous therapy results in a dose-dependent increase in platelets; however, interindividual variability exists. Time to peak concentration is approximately 14 hours, and the elimination half-life is approximately 3.5 days (range 1–34). Romiplostim undergoes endothelial recirculation and is eliminated by the reticuloendothelial system. The results of 2 Phase 3, randomized, double-blind, placebo-con trolled trials have demonstrated the efficacy of romiplostim for increasing platelet counts in patients with ITP refractory to other therapies, including splenectomy. Effects on platelets were transient and decreased within 2 weeks of discontinuing the drug. Interim results of an open-label extension study revealed that romiplostim has sustained efficacy and tolerability for up to 156 weeks at a dosage range of 1–17 μg/kg/wk (mean 5.9 ± 3.9). The most common adverse effects include headache, fatigue, epistaxis, and contusion. Romiplostim is also under investigation for treatment of thrombocytopenia associated with myelodysplastic syndrome. The drug must be ordered directly from the manufacturer through a limited access program, and weekly subcutaneous injections are given in the clinic setting. Conclusions Romiplostim is effective for the management of ITP in adults refractory to other therapies, including splenectomy.

Flibanserin

2016 ◽  
Vol 30 (2) ◽  
pp. 256-260 ◽  
Author(s):  
Ximena Vallejos ◽  
Christine Wu
Keyword(s):  
Clinical Trials ◽  
Sexual Desire ◽  
English Language ◽  
Human Subjects ◽  
Data Extraction ◽  
Premenopausal Women ◽  
Relevant Information ◽  
Time Frame ◽  
Double Blind ◽  
Study Selection

Objective: To review pivotal clinical trials, pharmacology, contraindications, precautions, and key patient education points of flibanserin for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. Data Sources: A literature search of PubMed using the key words flibanserin and HSDD was conducted in September 2015. There was no time frame to exclude relevant clinical trials. All trials referenced were published between March 2012 and June 2014. Other relevant information was obtained from the Food and Drug Administration (FDA) Web site, press releases, prescribing information from the manufacturer, and ClinicalTrials.gov . Study Selection/Data Extraction: All articles in the English language and involving human subjects were reviewed. Data Synthesis: There are three 24-week, multicenter, randomized, double-blind, placebo-controlled trials that evaluated the efficacy of flibanserin in North American premenopausal women with HSDD. There was 1 trial that studied the effects of flibanserin in postmenopausal women. In all of the trials, the investigators found statistical significant improvements in Female Sexual Function Index (FSFI) desire domain score and satisfying sexual events (SSEs). The most frequently reported adverse events in all flibanserin arms of treatment were somnolence, dizziness, and nausea. Conclusion: Flibanserin, a novel, nonhormonal agent that modulates excitatory and inhibitory neurotransmitters was studied in premenopausal women and has shown efficacy in improving sexual desire and SSEs.

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