Drug Safety Assessment Research Articles

Current Approaches to COVID-19 Drug Discovery and Safety Assessment.

Various methods currently being explored to treat COVID-19 were discussed during a symposium at the Fall 2022 ACS conference. These methods included the inhibiting of immune responses and viral replication pathways as well as repurposing known drugs.

Adaptability of AI for safety evaluation in regulatory science: A case study of drug-induced liver injury.

Artificial intelligence (AI) has played a crucial role in advancing biomedical sciences but has yet to have the impact it merits in regulatory science. As the field advances, in silico and in vitro approaches have been evaluated as alternatives to animal studies, in a drive to identify and mitigate safety concerns earlier in the drug development process. Although many AI tools are available, their acceptance in regulatory decision-making for drug efficacy and safety evaluation is still a challenge. It is a common perception that an AI model improves with more data, but does reality reflect this perception in drug safety assessments? Importantly, a model aiming at regulatory application needs to take a broad range of model characteristics into consideration. Among them is adaptability, defined as the adaptive behavior of a model as it is retrained on unseen data. This is an important model characteristic which should be considered in regulatory applications. In this study, we set up a comprehensive study to assess adaptability in AI by mimicking the real-world scenario of the annual addition of new drugs to the market, using a model we previously developed known as DeepDILI for predicting drug-induced liver injury (DILI) with a novel Deep Learning method. We found that the target test set plays a major role in assessing the adaptive behavior of our model. Our findings also indicated that adding more drugs to the training set does not significantly affect the predictive performance of our adaptive model. We concluded that the proposed adaptability assessment framework has utility in the evaluation of the performance of a model over time.

Structured Benefit-Risk Assessments: An Illustrative Case Study of Paracetamol.

This paper aims to provide an overview of the steps in developing a structured benefit-risk assessment, along with a simple, salient, and timely example of its implications. Using the time-tested, non-prescription drug paracetamol (a.k.a. acetaminophen) as an example, we demonstrate the fundamental role a well-structured benefit-risk assessment may play in clarifying the safety profile of even well-established medicinal products. The benefit-risk balance assessment performed by drug manufacturers and others involved in keeping drugs on the market is integral to a non-stop drug safety assessment continuum throughout a product’s lifecycle. This provides further reassurance that, as the world grapples with new diseases, pharmacovigilance systems with robust tools such as structured benefit-risk assessments can evolve and adapt by developing essential preventive and mitigative strategies. All these examples and practices contain the through-line of consideration for the protection of public health, a foundational cornerstone of pharmacovigilance practice. While a wealth of information may be explored on each aspect of the presented topics, the authors aim to give even those readers with only minimal background in pharmacovigilance an appreciation for the value of structured benefit-risk assessments.

Endpoints for safety in health technology assessments–The experiences of the Danish Medicines Council

ObjectivesThere are no international guidelines on how the requirements for added clinical value (endpoints) should be prepared in terms of drug safety by entities performing health technology assessments (HTAs). The study aimed to review the Danish Medicines Council's drug safety endpoints MethodsSafety endpoints prepared by the Danish Medicines Council's expert committees were reviewed from their assessment reports for 50 treatments, of which 25 were for the treatment of cancer and 25 were for the treatment of other types of diseases. Similarities and differences were identified ResultsThe 139 endpoints for safety were grouped into 14 categories. The use of endpoints varied and all endpoints were based on an expert assessment. Serious adverse reactions/events were used as an endpoint in most of the cases: 43.2% (N=60)/15.8% (N=22), following treatment discontinuation based on four different causes 16.4% (N=32). A numerical grading scale for adverse events were predominately used for endpoints for cancer treatment (19.8%, N=20 vs. 2.1%, N=2) ConclusionsThe variation in the use of endpoints reflects the complexity of safety assessments and the need for more standardization to promote stringency and transparency. The authors propose five recommendations for actions, which may promote more generalizability and transparency. International HTA entities and researchers are also encouraged to investigate the possibilities of establishing a universal grading system for adverse events and to develop international guidelines for safety assessment in HTAs. Public interest abstractNew medicines often have to be evaluated against the treatment already available in order to compare effectiveness, safety and price. If one treatment is superior, it will often be referred to as having added clinical value. This evaluation is known as a health technology assessment (HTA). All medicines can cause side effects and the assessment of safety in HTAS is therefore essential. No international guidelines for drug safety assessment in HTAs however exist. The requirements for safety prepared by the Danish Medicines Council's expert committees were therefore reviewed from their assessment reports for 50 treatments in order to present their approach to drug safety assessment. A total of 139 safety requirements, also referred to as endpoints, were identified. The use of endpoints varied which reflects the complexity of safety assessments and the need for more standardization to promote stringency. The authors propose five recommendations for actions, which may promote more generalizability and transparency in Denmark and internationally.

Event Monitoring and Evaluation by Community Pharmacists in Japan: A Pilot Study on Fenofibrate and Pemafibrate.

The Japan Pharmaceutical Association has conducted drug event monitoring to detect drug events related to pemafibrate. As there are a few studies on the safety of pemafibrate in clinical settings, a pilot study evaluating the association between drug use and detected events was performed in Japan. In this study, the association between detected events and the use of pemafibrate, utilizing pharmacy records maintained by community pharmacists, was investigated. We identified the newuser cohort using a test and active comparison drug and collected the baseline information. An active comparison group comprising new users was used to assess the events. A retrospective cohort study using questionnaires regarding baseline and event data was conducted by community pharmacists belonging to the Japan Pharmaceutical Association. The incidence of event and estimated hazard ratio were calculated using the Cox proportional hazards model that was adjusted for confounding factors, such as age and sex. A total of 1294 patients using pemafibrate and 508 patients using fenofibrate were identified as new drug users. The most reported events involving suspected adverse reactions and add-on drugs were increased blood pressure and lipid-lowering effects with pemafibrate use, and nasopharyngitis, pruritus, dizziness, and lipid-lowering effects with fenofibrate use. No significant differences were found in commonly occurring events, except that an add-on anti-hypertensive drug has been used by pemafibrate users compared to fenofibrate users. This study conducted by pharmacists can facilitate the safety assessment of newly marketed drugs, as few drug use investigations with a comparator are carried out by the Japanese authority for pharmaceutical companies. However, further research is required.

Development of a drug risk analysis and assessment system and its application in signal excavation and analysis of 263 cases of fluoroquinolone-induced adverse reactions.

Background: Adverse drug reaction (ADR) signal mining is essential for assessing drug safety. However, the currently available methods for this are rather cumbersome. Objective: We aimed to develop a drug risk analysis and assessment system using Java language and conduct pharmacovigilance data mining for fluoroquinolones at our hospital. Methods: We used ADR data reported by Shandong Provincial Third Hospital between July 2007 and August 2021. The signal detection methods included proportional reporting ratio (PRR), reporting odds ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), Medicines and Healthcare products Regulatory Agency (MHRA). The BCPNN method was used as the reference standard for comparing the remaining three signal detection methods based on sensitivity, specificity, positive predictive value, negative predictive value, and Jorden index. Results: The hospital database contained a total of 2,621 ADR reports, among which 263 were attributed to fluoroquinolones. There were 391 fluoroquinolone-ADR pairs. Using the PRR, ROR, MHRA, and BCPNN method, we detected 13 signals, 13 signals, 10 signals, and 11 weak signals, respectively. After signal detection, levofloxacin and moxifloxacin were shown to induce high risk signals for mental and sleep disorders, with the signal intensity of moxifloxacin being the most significant. Compared with BCPNN, the PRR and ROR methods showed better sensitivity, whereas the MHRA method showed better specificity. Conclusion: We developed a drug risk analysis and assessment system that can help hospitals and other medical institutions to detect and analyse ADR signals in the self-reporting system database, and thus improve drug safety. Further, it indicates that the central nervous system damage caused by fluoroquinolones should be monitored closely, and thus provides a reference for the clinical application of these drugs.

Developing Role for Artificial Intelligence in Drug Discovery in Drug Design, Development, and Safety Assessment.

Artificial intelligence (AI) is a rapidly growing discipline in the field of chemical toxicology. Herein, we provide a broad overview of research presented at the Fall 2022 American Chemical Society meeting, highlighting how AI is being applied across various facets of drug design, development, and safety assessment.

Integrated Genotoxicity Testing of three anti-infective drugs using the TGx-DDI transcriptomic biomarker and high-throughput CometChip® assay in TK6 cells.

Genotoxicity testing relies on the detection of gene mutations and chromosome damage and has been used in the genetic safety assessment of drugs and chemicals for decades. However, the results of standard genotoxicity tests are often difficult to interpret due to lack of mode of action information. The TGx-DDI transcriptomic biomarker provides mechanistic information on the DNA damage-inducing (DDI) capability of chemicals to aid in the interpretation of positive in vitro genotoxicity data. The CometChip® assay was developed to assess DNA strand breaks in a higher-throughput format. We paired the TGx-DDI biomarker with the CometChip® assay in TK6 cells to evaluate three model agents: nitrofurantoin (NIT), metronidazole (MTZ), and novobiocin (NOV). TGx-DDI was analyzed by two independent labs and technologies (nCounter® and TempO-Seq®). Although these anti-infective drugs are, or have been, used in human and/or veterinary medicine, the standard genotoxicity testing battery showed significant genetic safety findings. Specifically, NIT is a mutagen and causes chromosome damage, and MTZ and NOV cause chromosome damage in conventional in vitro tests. Herein, the TGx-DDI biomarker classified NIT and MTZ as non-DDI at all concentrations tested, suggesting that NIT’s mutagenic activity is bacterial specific and that the observed chromosome damage by MTZ might be a consequence of in vitro test conditions. In contrast, NOV was classified as DDI at the second highest concentration tested, which is in line with the fact that NOV is a bacterial DNA-gyrase inhibitor that also affects topoisomerase II at high concentrations. The lack of DNA damage for NIT and MTZ was confirmed by the CometChip® results, which were negative for all three drugs except at overtly cytotoxic concentrations. This case study demonstrates the utility of combining the TGx-DDI biomarker and CometChip® to resolve conflicting genotoxicity data and provides further validation to support the reproducibility of the biomarker.

Medication history-wide association studies for pharmacovigilance of pregnant patients

BackgroundSystematic exclusion of pregnant people from interventional clinical trials has created a public health emergency for millions of patients through a dearth of robust safety data for common drugs.MethodsWe harnessed an enterprise collection of 2.8 M electronic health records (EHRs) from routine care, leveraging data linkages between mothers and their babies to detect drug safety signals in this population at full scale. Our mixed-methods signal detection approach stimulates new hypotheses for post-marketing surveillance agnostically of both drugs and diseases—by identifying 1,054 drugs historically prescribed to pregnant patients; developing a quantitative, medication history-wide association study; and integrating a qualitative evidence synthesis platform using expert clinician review for integration of biomedical specificity—to test the effects of maternal exposure to diverse drugs on the incidence of neurodevelopmental defects in their children.ResultsWe replicated known teratogenic risks and existing knowledge on drug structure-related teratogenicity; we also highlight 5 common drug classes for which we believe this work warrants updated assessment of their safety.ConclusionHere, we present roots of an agile framework to guide enhanced medication regulations, as well as the ontological and analytical limitations that currently restrict the integration of real-world data into drug safety management during pregnancy. This research is not a replacement for inclusion of pregnant people in prospective clinical studies, but it presents a tractable team science approach to evaluating the utility of EHRs for new regulatory review programs—towards improving the delicate equipoise of accuracy and ethics in assessing drug safety in pregnancy.

Application of ARE-reporter systems in drug discovery and safety assessment

The human body is continuously exposed to xenobiotics and internal or external oxidants. The health risk assessment of exogenous chemicals remains a complex and challenging issue. Alternative toxicological test methods have become an essential strategy for health risk assessment. As a core regulator of constitutive and inducible expression of antioxidant response element (ARE)-dependent genes, nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in maintaining cellular redox homeostasis. Consistent with the properties of Nrf2-mediated antioxidant response, Nrf2-ARE activity is a direct indicator of oxidative stress and thus has been used to identify and characterize oxidative stressors and redox modulators. To screen and distinguish chemicals or environmental insults that affect the cellular antioxidant activity and/or induce oxidative stress, various in vitro cell models expressing distinct ARE reporters with high-throughput and high-content properties have been developed. These ARE-reporter systems are currently widely applied in drug discovery and safety assessment. In the present review, we provide an overview of the basic structures and applications of various ARE-reporter systems employed for discovering Nrf2-ARE modulators and characterizing oxidative stressors.

Freeze Substitution and Low Temperature Processing of Cryo Protected Tissues into Lowicryl HM23 Resin for Correlated Light and Immunogold Electron Microscopy in Drug Discovery and Safety Assessment Research

Freeze Substitution and Low Temperature Processing of Cryo Protected Tissues into Lowicryl HM23 Resin for Correlated Light and Immunogold Electron Microscopy in Drug Discovery and Safety Assessment Research - Volume 28 Issue S1

Clinical Significance of Transient Asymptomatic Elevations in Aminotransferase (TAEAT) in Oncology.

Monitoring for liver injury remains an important aspect of drug safety assessment, including for oncotherapeutics. When present, drug-induced liver injury may limit the use or result in the discontinuation of these agents. Drug-induced liver injury can exhibit with a wide spectrum of clinical and biochemical manifestations, ranging from transient asymptomatic elevations in aminotransferases (TAEAT) to acute liver failure. Numerous oncotherapeutics have been associated with TAEAT, with published reports indicating a phenomenon in which patients may be asymptomatic without overt liver injury despite the presence of grade ≥3 aminotransferase elevations. In this review, we discuss the occurrence of TAEAT in the context of oncology clinical trials and clinical practice, as well as the clinical relevance of this phenomenon as an adverse event in response to oncotherapeutics and the related cellular and molecular mechanisms that may underlie its occurrence. We also identify several gaps in knowledge relevant to the diagnosis and the management of TAEAT in patients receiving oncotherapeutics, and identify areas warranting further study to enable the future development of consensus guidelines to support clinical decision-making.

Selection of Comparator Group in Observational Drug Safety Studies: Alternatives to the Active Comparator New User Design.

A valid study design is essential when assessing the safety of drugs based on observational data. The comparator group is a key element of the design and can greatly influence the results. The active comparator new user design is a go-to design in observational drug safety research where a target trial of initiation of a study drug versus usual care is emulated. A comparison with another treatment that targets similar patients as the study drug and has no effect on the outcome has great potential to reduce bias. However, the active comparator new user design can be difficult to implement because no suitable comparator drug is available or because it requires extensive exclusion of study drug initiators. In this analysis, we evaluated alternative study designs that can be used in drug safety assessments when the active comparator new user design is not optimal. Using target trial emulation as a common framework, we defined and evaluated the following designs: traditional no use, no-use episodes, active comparator new user, prevalent new user, generalized prevalent new user, and hierarchical prevalent new user. We showed that all designs can be implemented by using sequential cohorts and simply altering the patient selection criteria, i.e., identifying increasingly restrictive cohorts. In this way, all designs are nested in each other and the differences between them can be demonstrated clearly. We concluded that many study-specific factors need to be considered when choosing a design, including indication, available comparator drugs, treatment patterns, potential effect modification, and sample size.

Post-Marketing Requirements for Cancer Drugs Approved by the European Medicines Agency, 2004-2014.

To address unresolved questions about drug safety and efficacy at the time of approval, the European Medicines Agency (EMA) may require that manufacturers conduct additional studies during the postmarketing period. As a growing proportion of new cancer drugs are approved on the basis of limited evidence of clinical benefit, timely completion of postmarketing requirements is important. We used publicly available regulatory documents to evaluate key characteristics of pivotal studies supporting EMA‐approved cancer drugs from 2004–2014 and assessed completion rates of postmarketing data collection requirements after a minimum of 5 years. From 2004–2014, 79% (45/57) of EMA‐approved cancer drugs had to fulfill postmarketing requirements. Pivotal trials supporting the approval of cancer drugs with postmarketing requirements were less likely to have randomized designs (41/61, 67% vs. 11/11, 100%), include an active comparator (20/61, 33% vs. 10/11, 91%), or measure overall survival as the primary study end point (18/61, 30% vs. 6/11, 55%) compared with pivotal trials for drugs without postmarketing requirements. Among 200 postmarketing requirements, almost half were designed to assess drug safety. After a minimum of 5 years, 60% (121/200) of requirements were completed, 10% (19/200) were ongoing, and 30% (60/200) were delayed. About half (40/75, 53%) of postmarketing requirements for new clinical studies were completed on time. Delays in the completion of postmarketing requirements often did not impact the likelihood of drugs receiving permanent marketing authorization (87%, 39/45) after 5 years. Our findings highlight the need for EMA to better enforce its authority to require timely completion of postmarketing requirements and studies.

A New Immortalized Human Alveolar Epithelial Cell Model to Study Lung Injury and Toxicity on a Breathing Lung-On-Chip System.

The evaluation of inhalation toxicity, drug safety and efficacy assessment, as well as the investigation of complex disease pathomechanisms, are increasingly relying on in vitro lung models. This is due to the progressive shift towards human-based systems for more predictive and translational research. While several cellular models are currently available for the upper airways, modelling the distal alveolar region poses several constraints that make the standardization of reliable alveolar in vitro models relatively difficult. In this work, we present a new and reproducible alveolar in vitro model, that combines a human derived immortalized alveolar epithelial cell line (AXiAEC) and organ-on-chip technology mimicking the lung alveolar biophysical environment (AXlung-on-chip). The latter mimics key features of the in vivo alveolar milieu: breathing-like 3D cyclic stretch (10% linear strain, 0.2 Hz frequency) and an ultrathin, porous and elastic membrane. AXiAECs cultured on-chip were characterized for their alveolar epithelial cell markers by gene and protein expression. Cell barrier properties were examined by TER (Transbarrier Electrical Resistance) measurement and tight junction formation. To establish a physiological model for the distal lung, AXiAECs were cultured for long-term at air-liquid interface (ALI) on-chip. To this end, different stages of alveolar damage including inflammation (via exposure to bacterial lipopolysaccharide) and the response to a profibrotic mediator (via exposure to Transforming growth factor β1) were analyzed. In addition, the expression of relevant host cell factors involved in SARS-CoV-2 infection was investigated to evaluate its potential application for COVID-19 studies. This study shows that AXiAECs cultured on the AXlung-on-chip exhibit an enhanced in vivo-like alveolar character which is reflected into: 1) Alveolar type 1 (AT1) and 2 (AT2) cell specific phenotypes, 2) tight barrier formation (with TER above 1,000 Ω cm2) and 3) reproducible long-term preservation of alveolar characteristics in nearly physiological conditions (co-culture, breathing, ALI). To the best of our knowledge, this is the first time that a primary derived alveolar epithelial cell line on-chip representing both AT1 and AT2 characteristics is reported. This distal lung model thereby represents a valuable in vitro tool to study inhalation toxicity, test safety and efficacy of drug compounds and characterization of xenobiotics.

Firm evidence for the detoxification of senecionine-induced hepatotoxicity via N-glucuronidation in UGT1A4–humanized transgenic mice

Uridine diphosphate glucuronosyltransferase (UGT)1A4 is responsible for N-glucuronidation of tertiary amines but is a pseudogene in commonly used rodent models in toxicity and safety assessment. As a continuation of our investigation into the toxicity and safety assessment of pyrrolizidine alkaloid (PA)-containing herbs, we generated a UGT1A4–humanized (hUGT1A4) transgenic mouse model to systematically study the toxicity, metabolism network, and toxicokinetic characteristics of senecionine (a representative toxic PA) and compared with that in the wide-type controls in parallel. As results, senecionine-induced toxicity was significantly decreased as approved by mortality, pathology, and biochemistry assays in hUGT1A4 mice and cultured primary hepatocytes. More importantly N-glucuronidation adduct was exclusively identified in all the hUGT1A4 mice, liver microsomes, and cultured primary hepatocytes, yet absent in the wide-type controls. The variation in toxicokinetic characters was also observed between hUGT1A4 mice and the wide-type controls with a notably inhibition of the toxification metabolites, i.e., pyrrole-protein adducts, in hUGT1A4 mice. Conclusively, UGT1A4 plays an important role in detoxification of senecionine and the hUGT1A4 mouse model is promising for the pre-clinical evaluation of the efficacy and toxicity of tertiary amine agents in drug development and safety assessment.

Does Geographical Origin of Long-Tailed Macaques (Macaca fascicularis) Matter in Drug Safety Assessment?: A Literature Review and Proposed Conclusion.

Long-tailed macaques are the predominant nonhuman primate species for the nonclinical safety testing of biopharmaceuticals. This species comprises 9 subspecies with Macaca fascicularis fascicularis naturally occurring in Southeast Asia. Since the 17th century, M. f. fascicularis also occurs on Mauritius. Cynomolgus macaques do not naturally occur in China, but are bred in many farms across the country. The current shortage in animal supply raises the question whether geographical animal origin matters and if animals from different geographical regions can be combined on a drug development program or even a single experiment. This article reviews geographical animal origin in relation to selected endpoints that are relevant in nonclinical drug safety testing. Animals from different countries within Asia mainland do not appear to show any meaningful difference. Very little data are available for animals from Asia island. Mauritian animals show consistent differences from Asian animals in several clinical and anatomical pathology parameters. For developmental parameters, animals from Mauritius and Asia are comparable with the exception that Mauritian animals mature faster. In the authors' view, differences between the geographical clusters can be accounted for as long as baseline and reference data are available.

Development of human pluripotent stem cell-derived hepatic organoids as an alternative model for drug safety assessment

Human in vitro hepatic models that faithfully recapitulate liver function are essential for successful basic and translational research. A limitation of current in vitro models, which are extensively used for drug discovery and toxicity testing, is the loss of drug metabolic function due to the low expression and activity of cytochrome P450 (CYP450) enzymes. Here, we aimed to generate human pluripotent stem cell-derived hepatic organoids (hHOs) with a high drug metabolic ability. We established a two-step protocol to produce hHOs from human pluripotent stem cells for long-term expansion and drug testing. Fully differentiated hHOs had multicellular composition and exhibited cellular polarity and hepatobiliary structures. They also displayed remarkable CYP450 activity and recapitulated the metabolic clearance, CYP450-mediated drug toxicity, and metabolism. Furthermore, hHOs successfully modeled Wilson's disease in terms of Cu metabolism, drug responses, and diagnostic marker expression and secretion. In conclusion, hHOs exhibit high capacity for drug testing and disease modeling. Hence, this hepatic model system provides an advanced tool for studying hepatic drug metabolism and diseases.

Statistical learning in preclinical drug proarrhythmic assessment

ABSTRACT Torsades de pointes (TdP) is an irregular heart rhythm characterized by faster beat rates and potentially could lead to sudden cardiac death. Much effort has been invested in understanding the drug-induced TdP in preclinical studies. However, a comprehensive statistical learning framework that can accurately predict the drug-induced TdP risk from preclinical data is still lacking. We proposed ordinal logistic regression and ordinal random forest models to predict low-, intermediate-, and high-risk drugs based on datasets generated from two experimental protocols. Leave-one-drug-out cross-validation, stratified bootstrap, and permutation predictor importance were applied to estimate and interpret the model performance under uncertainty. The potential outlier drugs identified by our models are consistent with their descriptions in the literature. Our method is accurate, interpretable, and thus useable as supplemental evidence in the drug safety assessment.

The effectiveness and safety of Chaiqin Qingning Capsule in upper respiratory tract infections with fever: A prospective, double-blinded, randomized, multicenter controlled trial

Background and aimPresently, over-the-counter drugs that can treat upper respiratory tract infections (URTI) are rarely effective and safe. Chaiqin Qingning Capsule (CQQNC), a Chinese patent medicine, which has been verified by long-term clinical practice is recommended by Chinese experts for the treatment of URTI with fever. This study conducted a prospective, double-blinded, randomized, multicenter controlled trial to evaluate the effectiveness and safety of CQQNC in the treatment of URTI. MethodsThe study was conducted at 4 clinical centers in China. Eligible subjects were recruited and randomized 1:1 to the CQQNC group and Qingkailing Capsule (QKLC) group. Both groups were administered orally three times a day for three consecutive days. Primary outcomes were the antipyretic onset time and the temperature recovery time. Secondary outcomes included the symptom disappearance rate, symptom score, and drug safety assessment. ResultsA total of 269 subjects were analyzed (134 subjects in the CQQNC group, 135 subjects in the QKLC group). The antipyretic onset time and the temperature recovery time were significantly shortened in the CQQNC group (median: 5 h vs. 10 h, p < 0.0001, median: 19 h vs. 27 h, p < 0.0001). CQQNC was more effective than the QKLC in improving the symptoms of pharyngodynia and rhinobyon (85.07% vs. 71.11%, p = 0.008; 76.99% vs. 64.41%, p = 0.043), and in improving the overall symptom scores (−15.10 ± 3.23 vs. −13.35 ± 3.58, p < 0.0001). During the trial, no serious adverse events were reported in the two groups. ConclusionCQQNC is effective and safe in the treatment of URTI with fever, and worthy of clinical application. (http://www.chictr.org.cn, ChiCTR-IPR-16009049).