Targeting metaplasticity mechanisms to promote sustained antidepressant actions.

The discovery that subanesthetic doses of (R, S)-ketamine (ketamine) and (S)-ketamine (esketamine) rapidly induce antidepressant effects and promote sustained actions following drug clearance in depressed patients who are treatment-resistant to other therapies has resulted in a paradigm shift in the conceptualization of how rapidly and effectively depression can be treated. Consequently, the mechanism(s) that next generation antidepressants may engage to improve pathophysiology and resultant symptomology are being reconceptualized. Impaired excitatory glutamatergic synapses in mood-regulating circuits are likely a substantial contributor to the pathophysiology of depression. Metaplasticity is the process of regulating future capacity for plasticity by priming neurons with a stimulation that alters later neuronal plasticity responses. Accordingly, the development of treatment modalities that specifically modulate the duration, direction, or magnitude of glutamatergic synaptic plasticity events such as long-term potentiation (LTP), defined here as metaplastogens, may be an effective approach to reverse the pathophysiology underlying depression and improve depression symptoms. We review evidence that the initiating mechanisms of pharmacologically diverse rapid-acting antidepressants (i.e., ketamine mimetics) converge on consistent downstream molecular mediators that facilitate the expression/maintenance of increased synaptic strength and resultant persisting antidepressant effects. Specifically, while the initiating mechanisms of these therapies may differ (e.g., cell type-specificity, N-methyl-D-aspartate receptor (NMDAR) subtype-selective inhibition vs activation, metabotropic glutamate receptor 2/3 antagonism, AMPA receptor potentiation, 5-HT receptor-activating psychedelics, etc.), the sustained therapeutic mechanisms of putative rapid-acting antidepressants will be mediated, in part, by metaplastic effects that converge on consistent molecular mediators to enhance excitatory neurotransmission and altered capacity for synaptic plasticity. We conclude that the convergence of these therapeutic mechanisms provides the opportunity for metaplasticity processes to be harnessed as a druggable plasticity mechanism by next-generation therapeutics. Further, targeting metaplastic mechanisms presents therapeutic advantages including decreased dosing frequency and associated diminished adverse responses by eliminating the requirement for the drug to be continuously present.

Characteristics of clinical trials of new oncology drugs approved in China.

BACKGROUND: Since reforms were introduced to incentivize drug innovation in 2015, the Chinese pharmaceutical market has experienced unprecedented prosperity, with more new drugs than ever before, especially anticancer treatments. In 2021, Chinese regulatory agencies issued the new guideline for clinical research and development of antitumor drugs, triggering a series of responses on the drug market. Limited research has outlined the nature of the original new drugs in China to understand the dynamic response of the market. METHODS: The objective of this article was to map the clinical development of approved new oncology drugs in China from 2015 to 2021 and differed from previous studies by focusing on original new drugs, using the United States as a benchmark, and elaborating the endogenous features of clinical trials. RESULTS: Clinical trials conducted in China have risen to a level similar to that of the United States in many aspects of trial design, but there is still distance between the implementation and operational details of clinical trials. In the meantime, China has made significant breakthroughs in drug approval. Greater than 60% of novel anticancer drugs in China received accelerated approved for their first listing. Approximately 90% of the pivotal clinical trials supporting initial drug approval used surrogate measures as end points, and one half were nonrandomized or did not have a control group. However, duplicate development without evidence of a clinical advantage compared with current therapies was widely observed. CONCLUSIONS: By presenting a multidimensional landscape of clinical trials and approvals in the real world, this review allows interested researchers, developers, and even regulators to understand what has been done and what should be done next in anticancer drug development in China.

Polyploid speciation in Zea (Poaceae): cytogenetic insights.

MAIN CONCLUSION: The analysis of meiotic pairing affinities and genomic formulae in species and hybrids of Zea allowed us to speculate an evolutionary model to recreate the ancient polyploidization of maize and allied species. The meiotic pairing affinities and the genomic formulae analysis in Zea species and hybrids obtained in new and previous crosses, together with the molecular data known in the genus, allowed us to speculate an evolutionary model to attempt to recreate the ancient polyploidization process of Zea species. We propose that x = 5 semispecies are the ancestors of all modern species of the genus. The complex evolutionary process that originated the different taxa could be included hybridization between sympatric diploid ancestral semispecies (2n = 10) and recurrent duplication of the hybrid chromosome number, resulting in distinct auto- and allopolyploids. After the merger and doubling of independent genomes would have undergone cytological and genetical diploidization, implying revolutionary changes in genome organization and genic balance processes. Based on the meiotic behaviour of the 2n = 30 hybrids, that showed homoeology between the A subgenomes of all parental species, we propose that this subgenome A would be pivotal in all the species and would have conserved the rDNA sequences and the pairing regulator locus (PrZ). In the hypothetical model postulated here, the ancestral semispecies with the pivotal subgenome A would have had a wide geographic distribution, co-occurring and hybridizing with the semispecies harbouring B subgenomes, thus enabling sympatric speciation.

Comparing clinical trial population representativeness to real-world users of 17 biologics approved for immune-mediated inflammatory diseases: An external validity analysis of 66,639 biologic users from the Italian VALORE project.

To date, no population-based studies have specifically explored the external validity of pivotal randomized clinical trials (RCTs) of biologics simultaneously for a broad spectrum of immuno-mediated inflammatory diseases (IMIDs). The aims of this study were, firstly, to compare the patients' characteristics and median treatment duration of biologics approved for IMIDs between RCTs' and real-world setting (RW); secondly, to assess the extent of biologic users treated for IMIDs in the real-world setting that would not have been eligible for inclusion into pivotal RCT for each indication of use. Using the Italian VALORE distributed database (66,639 incident biologic users), adult patients with IMIDs treated with biologics in the Italian real-world setting were substantially older (mean age ± SD: 50 ± 15 years) compared to those enrolled in pivotal RCTs (45 ± 15 years). In the real-world setting, certolizumab pegol was more commonly used by adult women with psoriasis/ankylosing spondylitis (F/M ratio: 1.8-1.9) compared to RCTs (F/M ratio: 0.5-0.6). The median treatment duration (weeks) of incident biologic users in RW was significantly higher than the duration of pivotal RCTs in almost all indications for use and most biologics (4-100 vs. 6-167). Furthermore, almost half (46.4%) of biologic users from RW settings would have been ineligible for inclusion in the respective indication-specific pivotal RCTs. The main reasons were: advanced age, recent history of cancer and presence of other concomitant IMIDs. These findings suggest that post-marketing surveillance of biologics should be prioritized for those patients.

Challenges in conducting efficacy trials for new COVID-19 vaccines in developed countries.

The protection from COVID-19 vaccination wanes a few months post-administration of the primary vaccination series or booster doses. New COVID-19 vaccine candidates aiming to help control COVID-19 should show long-term efficacy, allowing a possible annual administration. Until correlates of protection are strongly associated with long-term protection, it has been suggested that any new COVID-19 vaccine candidate must demonstrate at least 75% efficacy (although a 40%-60% efficacy would be sufficient) at 12 months in preventing illness in all age groups within a large randomized controlled efficacy trial. This article discusses four of the many scientific, ethical, and operational challenges that these trials will face in developed countries, focusing on a pivotal trial in adults. These challenges are (1) the comparator and trial population; (2) how to enroll sufficient numbers of adult participants of all age groups considering that countries will recommend COVID-19 booster doses to different populations; (3) whether having access to a comparator booster for the trial is actually feasible; and (4) the changing epidemiology of severe acute respiratory syndrome coronavirus 2 across countries involved in the trial. It is desirable that regulatory agencies publish guidance on the requirements that a trial like the one discussed should comply with to be acceptable from a regulatory standpoint. Ideally, this should happen even before there is a vaccine candidate that could fulfill the requirements mentioned above, as it would allow an open discussion among all stakeholders on its appropriateness and feasibility.

New strategies for confirmatory testing of secondary hypotheses on combined data from multiple trials.

BACKGROUND: Pivotal evidence of efficacy of a new drug is typically generated by (at least) two clinical trials which independently provide statistically significant and mutually corroborating evidence of efficacy based on a primary endpoint. In this situation, showing drug effects on clinically important secondary objectives can be demanding in terms of sample size requirements. Statistically efficient methods to power for such endpoints while controlling the Type I error are needed. METHODS: We review existing strategies for establishing claims on important but sample size-intense secondary endpoints. We present new strategies based on combined data from two independent, identically designed and concurrent trials, controlling the Type I error at the submission level. We explain the methodology and provide three case studies. RESULTS: Different strategies have been used for establishing secondary claims. One new strategy, involving a protocol planned analysis of combined data across trials, and controlling the Type I error at the submission level, is particularly efficient. It has already been successfully used in support of label claims. Regulatory views on this strategy differ. CONCLUSIONS: Inference on combined data across trials is a useful approach for generating pivotal evidence of efficacy for important but sample size-intense secondary endpoints. It requires careful preparation and regulatory discussion.

The generalized order statistics arising from three populations with the lower truncated proportional hazard rate models and its application to the sensitivity to the early disease stage.

In this paper, we present some results to make inference about the parameters of lower truncated proportional hazard rate models with the same baseline distributions based on three independent generalized order statistics samples. Then, especially by considering the results of the diagnostic tests for the non-diseased, early-diseased stage and fully diseased populations, we make inference about sensitivity to the early disease stage parameter. The maximum likelihood estimator, a generalized pivotal estimator and some Bayes estimators are obtained for different structures of prior distributions. The percentile bootstrap confidence interval, a generalized pivotal confidence interval and some Bayesian credible intervals are also presented. A Monte Carlo simulation study is used to evaluate the performances of the obtained point estimators and confidence/credible intervals and two competitors. We use two real datasets to illustrate the proposed methods.

The Incredible Adventure of Omalizumab.

The basis of our current understanding of allergies begins with the discovery of IgE in the mid-1960s. The whole theory of the physiology and pathophysiology of allergic diseases, including rhinitis and asthma, dates from that period. Among the key regions of IgE identified were the FAB (fragment antigen binding) portion that has the ability to capture allergens, and the Cε3 domain, through which IgE binds to its membrane receptor. It was then postulated that blocking IgE at the level of the Cε3 domain would prevent it from binding to its receptor and thus set in motion the allergic cascade. This was the beginning of the development of omalizumab, a monoclonal antibody with an anti-IgE effect. In this article, we review the pathophysiology of allergic disease and trace the clinical development of omalizumab. We also review the benefits of omalizumab treatment that are apparently unrelated to allergies, such as its effect on immunity and bronchial remodeling.

Generalized Confidence Intervals for Ratios of Standard Deviations Based on Log-Normal Distribution when Times Follow Weibull Distributions.

Modern anesthetic drugs ensure the efficacy of general anesthesia. Goals include reducing variability in surgical, tracheal extubation, post-anesthesia care unit, or intraoperative response recovery times. Generalized confidence intervals based on the log-normal distribution compare variability between groups, specifically ratios of standard deviations. The alternative statistical approaches, performing robust variance comparison tests, give P-values, not point estimates nor confidence intervals for the ratios of the standard deviations. We performed Monte-Carlo simulations to learn what happens to confidence intervals for ratios of standard deviations of anesthesia-associated times when analyses are based on the log-normal, but the true distributions are Weibull. We used simulation conditions comparable to meta-analyses of most randomized trials in anesthesia, n ≈ 25 and coefficients of variation ≈ 0.30 . The estimates of the ratios of standard deviations were positively biased, but slightly, the ratios being 0.11% to 0.33% greater than nominal. In contrast, the 95% confidence intervals were very wide (i.e., > 95% of P ≥ 0.05). Although substantive inferentially, the differences in the confidence limits were small from a clinical or managerial perspective, with a maximum absolute difference in ratios of 0.016. Thus, P < 0.05 is reliable, but investigators should plan for Type II errors at greater than nominal rates.

QCM sensor provides insight into the role of pivotal ions in cellular regulatory volume decrease.

All vertebrate cells generally self-regulate for sustaining homeostasis and cell functions. As a major regulatory mechanism, regulatory volume decrease (RVD) occurs in hypotonicity-induced cell swelling, and then shrinking by the efflux of intracellular osmolytes and water, in which the ions K+, Cl-, and Ca2+ play a key role in the RVD process. We observed that these pivotal ions could result in novel RVD behaviors under repeatedly hypotonic stimulation. However, there is a lack of valid means for assessing the effect of pivotal ions on RVD. In this work, we proposed an effective measurement process based on a quartz crystal microbalance (QCM) combined with cell function of RVD for revealing acute variations in cell volume regulation induced by the pivotal ions. A QCM sensor was implemented by adhering MCF-7 cells to a poly-l-lysine-modified gold chip and cyclic stimulation with hypotonic NaCl medium, in which a frequency shift (Δf) showed the superior feasibility of the technique in exhibiting RVD behaviors. With the increase in the number of cycles, the RVD values decreased progressively under three stimulation cycles with hypotonic NaCl alone. Compared with the first cycle, the RVD level in the second and third cycles declined by 60.7±1.7% and 82.1±1.6% (n=3), respectively; conversely, it recovered in NaCl-KCl solution, but was significantly enhanced by 52.2±0.8% in NaCl-CaCl2 solution. Moreover, the inhibition of chloride channels to block Cl- efflux also decreased the RVD level by 56.2±3.0%. The results indicate that these ions (K+, Cl-, Ca2+) are all able to affect the function of RVD, among which intracellular Cl- depletion reduced RVD during measurement, but which recovered with K+ supplement, and Ca2+ enhanced RVD due to activation of ion channels. Therefore, this work provides a comprehensive assessment of cellular behavior and offers an innovative method for gaining insight into cellular functions and mechanisms. A novel strategy was conducted by integrating a quartz crystal microbalance (QCM) with the function of cell volume regulation for analyzing the role of the pivotal ions ( K+, Cl-, Ca2+) in NaCl media on the behaviors of regulatory cell volume decrease (RVD).

Efficacy and safety of BT595 (10% human intravenous immunoglobulin) in adult patients with chronic immune thrombocytopenia.

PURPOSE: This trial investigated the efficacy and safety of the new 10% human intravenous immunoglobulin (IVIg) BT595 (Yimmugo®). METHODS: Adult patients with chronic immune thrombocytopenia (ITP) received a total dose of 2 g/kg body weight (bw) IVIg either over 2 or 5 days. RESULTS: Response as defined by the European Medicines Agency (EMA) was achieved in 18 of 34 patients (52.9%) in the full analysis set (FAS), with a complete response in 11 patients (32.4%). The median time to response was 1.0 days (range 1-4); the median duration was 28.0 days. In a subgroup with a baseline platelet count <20*109 /L evaluated according to FDA criteria, a platelet response ≥50*109 /L was achieved in 18 of 19 patients at day 8. No fatal case occured. One serious treatment-emergent adverse event (TEAE) (anaemia, not related) was reported (2.9%). The most frequent infusional adverse drug reaction (ADR) was headache, which was reported for 14.7% of all patients. All other infusional ADRs (pyrexia, [intravascular] haemolysis, skin reaction, tinnitus, and Coombs test positive) occurred in only one patient (2.9%). Premedication was administered only once. The 5-day schedule showed less side effects with similar efficacy. CONCLUSION: The benefit-risk profile of BT595 is favourable. TRIAL REGISTRATION NUMBER: Eudra CT Number 2015-003653-17, ClinicalTrials.gov NCT02859909.

Should the two-trial paradigm still be the gold standard in drug assessment?

Two significant pivotal trials are usually required for a new drug approval by a regulatory agency. This standard requirement is known as the two-trial paradigm. However, several authors have questioned why we need exactly two pivotal trials, what statistical error the regulators are trying to protect against, and potential alternative approaches. Therefore, it is important to investigate these questions to better understand the regulatory decision-making in the assessment of drugs' effectiveness. It is common that two identically designed trials are run solely to adhere to the two-trial rule. Previous work showed that combining the data from the two trials into a single trial (one-trial paradigm) would increase the power while ensuring the same level of type I error protection as the two-trial paradigm. However, this is true only under a specific scenario and there is little investigation on the type I error protection over the whole null region. In this article, we compare the two paradigms by considering scenarios in which the two trials are conducted in identical or different populations as well as with equal or unequal size. With identical populations, the results show that a single trial provides better type I error protection and higher power. Conversely, with different populations, although the one-trial rule is more powerful in some cases, it does not always protect against the type I error. Hence, there is the need for appropriate flexibility around the two-trial paradigm and the appropriate approach should be chosen based on the questions we are interested in.

Exceedance Probabilities of Log-normal Distributions for One Group, Two Groups, and Meta-analysis of Multiple Two-group Studies, With Application to Analyses of Prolonged Times to Tracheal Extubation.

Many randomized trials measure means and standard deviations of anesthesia recovery time (e.g., times to tracheal extubation). We show how to use generalized pivotal methods to compare the probabilities of exceeding a tolerance limit (e.g., > 15 min, prolonged times to tracheal extubation). The topic is important because the economic benefits of faster anesthesia emergence depend on reducing variability, not means, especially prevention of very long recovery times. Generalized pivotal methods are applied using computer simulation (e.g., using two Excel formulas for one group and three formulas for two group comparisons). The endpoint for each study with two groups is the ratio between groups of the probabilities of times exceeding a threshold or the ratio of the standard deviations. Confidence intervals and variances for the incremental risk ratio of the exceedance probabilities and for ratios of standard deviations are calculated using studies' sample sizes, sample means in the time scale of recovery times, and sample standard deviations in the time scale. Ratios are combined among studies using the DerSimonian-Laird estimate of the heterogeneity variance estimate, with Knapp-Hartung adjustment for the relatively small (N = 15) numbers of studies in the meta-analysis. We show larger absolute variability among studies' results when analyzed based on exceedance probabilities rather than standard deviations. Therefore, if an investigator's primary goal is to quantify reductions in the variability of recovery times (e.g., times until patients are ready for post-anesthesia care unit discharge), we recommend analyzing the standard deviations. When exceedance probabilities themselves are relevant, they can be analyzed from the original studies' summary measures.

A cross-sectional study of the FDA approved indications and supporting pivotal trials of small-molecular kinase inhibitors in cancer therapies with the biomarker of cancer driver gene.

Cancer precision medicine with biomarker of cancer driver gene (CDG) has been achieved by many small-molecular kinase inhibitors (SMKIs) approved by the US Food and Drug Administration (FDA). Publicly available FDA documents were collected for all SMKI cancer drugs approved between January 2001 and December 2021. Characteristics of indication and pivotal trial were compared. We identified 62 SMKI cancer drugs with 150 indications approved by the FDA between 2001 and 2021. Of these, 55 indications (36.7%) were CDG biomarker-directed. There was a significant increase of 20.5% per year in the number of approved CDG biomarker-directed indications. CDG biomarker-directed indications were associated with significantly higher odds in receiving accelerated approval (odds ratio [OR] = 2.728; 95% CI, 1.246-5.973; P = .012), designating orphan drug (OR = 3.952; 95% CI, 1.758-8.883; P < .001), initial submission of the application (OR = 2.246; 95% CI, 1.063-4.746; P = .034) and in solid cancer (OR = 7.613; 95% CI, 2.958-19.590; P < .001), and were associated with significantly lower odds in using randomized controlled trials (RCTs) (OR = 0.103; 95% CI, 0.032-0.338; P < .001) with less number of entered patients (OR = 0.998; 95% CI, 0.997-1.000; P = .048). The number of CDG biomarker-directed indications in approved SMKIs increased significantly in past two decades, with higher proportion of approvals using special expedited development and approval pathways at the FDA. Further RCTs should be conducted to prove long-term effectiveness and safety.

Reforms of regulatory pathways for approval of new antineoplastic drugs in Japan from 2004 to 2019 and accompanying changes in pivotal clinical trial designs.

Background The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) was established in 2004. Since then, various pieces of legislation, notices, and guidelines have been issued, and the regulatory approval pathways for domestic drugs have been diversified. However, the effects of these measures have not been fully examined. We examined the impact of these measures on the approval of antineoplastic drugs and the design of pivotal clinical trials for efficacy assessment by the PMDA. Methods We collected data on the antineoplastic drugs approved by the PMDA in fiscal years 2004-2019. We extracted the approval review pathways and the pivotal clinical trial designs from the PMDA review reports, and analyzed them to identify patterns. Results In total, 387 indications in oncology were approved by the PMDA in fiscal years 2004-2019, or 365 indications excluding multiple regulatory pathways. The number of approved indications generally increased year on year (p < 0.001). The largest number of approved indications was under the Orphan Drug Designation (31%, 114/365) and this continues to increase (p < 0.001). In the 288 indications for which clinical trial data were submitted for review, the pivotal clinical trial designs changed significantly (p < 0.001) after the guideline on clinical evaluation for antineoplastic drugs was revised in 2006. Conclusion The number of indications in oncology approved by the PMDA has been increasing over the past 16 years, alongside changes in regulatory pathways. The 2006 guideline on clinical evaluation had a particular impact on pivotal clinical trial designs.

Disparities in reporting and representation by sex, race, and ethnicity in endovascular aortic device trials.

OBJECTIVE: Vulnerable populations, including women and racial and ethnic minorities, have been historically underrepresented in clinical trials. We, therefore, studied the demographics of patients enrolled in pivotal endovascular aortic device trials in the United States. METHODS: We queried the Food and Drug Administration (FDA) medical devices database for all FDA-approved endografts for the treatment of aortic aneurysms, transections, and dissections from September 1999 to November 2021. These included abdominal endovascular aortic repair (EVAR), thoracic EVAR (TEVAR), fenestrated EVAR (FEVAR) devices, and dissection stents. Multiple cases of approval for expanded indications were included separately. The primary outcomes included the proportion of trials reporting participant sex, race, and ethnicity and the proportion of enrolled participants across sex, racial, and ethnic groups. RESULTS: The FDA provided 29 approvals from 29 trials of 24 devices: 15 EVAR devices (52%), 12 TEVAR devices (41%), 1 FEVAR device (3.4%), and 1 dissection stent (3.4%). These trials had included 4046 patients. Of the 29 trials, all had reported on the sex of the participants, and the median female enrollment was 21% (interquartile range [IQR], 11%-34%). The EVAR trials had the lowest female enrollment (11%; IQR, 8.7%-13%) compared with 41% (IQR, 27%-45%) in the TEVAR trials, 21% in the FEVAR trial, and 34% in the dissection stent trial (P < .01 for the difference). Only 52% of the trials had reported the three most common racial groups (White, Black, Asian), and only 48% had reported Hispanic ethnicity. The TEVAR trials were the most likely to report all three racial groups and Hispanic ethnicity (92% and 75%, respectively), while the EVAR trials had the lowest reporting rates (13% and 20%, respectively). Where reported, the median enrollment of racial and ethnic groups across the trials was as follows: Black patients, 9.8% (FEVAR, 0%; EVAR, 1.9%; TEVAR, 12%; dissection stent, 25%; P = .01); Asian patients, 2.4% (EVAR, 0.6%; FEVAR, 2.4%; TEVAR, 2.5%; dissection stent, 11%; P = .24); and Hispanic patients, 3.8% (EVAR, 1.3%; FEVAR, 2.4%; TEVAR, 3.9%; dissection stent, 4.1%; P = .75). CONCLUSIONS: Racial and ethnic minority groups were underrepresented and underreported in pivotal aortic device trials that led to FDA approval. Female patients were also underrepresented in these aortic trials, especially for EVAR. These data suggest the need for standardization of reporting practices and minimum thresholds for minority and female participation in pivotal trials to promote equitable representation.

Response rate of anticancer drugs approved by the Food and Drug Administration based on a single-arm trial.

BACKGROUND: In recent years, an increasing number of anticancer drugs have been approved based on the results of a single-arm trial (SAT). The magnitude of the objective response rate (ORR) in SATs is important for regulatory decisions, but there has been no clear guidance specifying the degree of ORR for approval. METHODS: All anticancer drugs approved by the US Food and Drug Administration (FDA) between January 2016 and December 2019 were identified through the FDA website. From these, we selected drugs approved for solid tumors based on SATs. For each indication, one regimen was selected from the standard-of-care as the best comparison therapy (BCT), which was defined as the latest regimen for the same tumor and treatment line. We compared the ORR of the investigated product with that of the BCT. RESULTS: Of the 31 solid tumor indications identified, we selected BCT for 28. In 23 of the 28 indications (82.1%), the ORR of the investigated product exceeded that of the BCT, and in 16 of these (69.6%), the lower limit of the 95% confidence interval (CI) of the ORR of the investigated product exceeded the point estimate of the BCT ORR. For seven products, the lower limit of the 95% CI was below the point estimate of the BCT ORR, with differences ranging from 1.0% to 3.4%. CONCLUSION: The lower limit of a 95% CI of the ORR of a new drug in an SAT exceeding the point estimate of the BCT ORR could be an important factor in obtaining regulatory approval.

Combination therapies for COVID-19: An overview of the clinical trials landscape.

The COVID-19 pandemic has driven an unprecedented level of global activity in drug discovery and clinical development for effective therapeutics targeting the coronavirus disease. There are currently 744 therapeutics being tested in 2879 clinical trials globally. Almost 90% of these clinical trials are focused on monotherapies. Combination therapies are the mainstay of antiviral therapeutics to increase the potency of the individual compounds and to combat the rapid evolution of resistance, although combination therapies have inherently complex clinical and regulatory development challenges. Increased understanding of the SARS-CoV-2 lifecycle and COVID-19 pathology provides a scientific rationale for evaluating the effectiveness of different combinations. In this paper, we provide an overview of the current clinical trial landscape for combination therapeutics targeting COVID-19 through weekly scanning of national and international clinical trial registries. Our analysis delves specifically into dual combination therapies in what can be defined as "pivotal clinical trials" (active, randomised, controlled and at least phase II), with a focus on new and repurposed therapeutic candidates that have shown positive signals and/or been granted authorisation for emergency use based on positive efficacy and safety data.

No Mortality Signal With Stellarex Low-Dose Paclitaxel DCB: ILLUMENATE Pivotal 4-Year Outcomes.

BACKGROUND: Paclitaxel-coated balloons have shown safety and efficacy in the short- to intermediate-term; however, long-term data remain limited. OBJECTIVES: To report late safety and efficacy outcomes for a low-dose paclitaxel drug-coated balloon (DCB) compared with percutaneous transluminal angioplasty (PTA) in femoropopliteal lesions from a large randomized controlled trial (RCT). METHODS: ILLUMENATE Pivotal is a multicenter, single-blind RCT conducted across 43 US and EU centers to examine the safety and efficacy of the Stellarex DCB for the treatment of femoropopliteal disease. Assessments were recorded for all active patients at 36 and 48 months. Vital status of patients formally exited from the study was also collected. RESULTS: Primary patency through 36 months for patients treated with DCB was significantly higher compared with PTA (p=0.016). The primary safety endpoint through 36 months was 77.4% and 72.4%, respectively (p=0.377). Kaplan-Meier analysis indicated that a higher proportion of DCB subjects were event-free compared with PTA at all study visits. The rate of major adverse event (MAE) through 48 months was 32.9% in the DCB group and 37.9% in the PTA group (p=0.428). No differences in the rate of mortality were evident through 48 months of follow-up with 15.6% in the DCB group and 15.2% in the PTA group (p=0.929). CONCLUSIONS: Stellarex DCB was associated with significantly higher patency compared with PTA through 3 years with no mortality difference detected through 4 years. The data from the ILLUMENATE Pivotal RCT support the long-term safety and efficacy of the low-dose Stellarex DCB.

Evaluation of double-high insert mid-term outcomes in cruciate-retaining medial-pivotal total knee arthroplasty - a propensity score-matched analysis with averaged 8-year follow-up.

BACKGROUND: This study aimed to compare the mid-term clinical and radiographic outcomes between medial-pivotal (MP) insert and double-high (DH) insert used under the cruciate-retaining condition in ADVANCE® total knee arthroplasty (TKA). METHODS: The follow-up was conducted for 158 consecutive patients who underwent unilateral ADVANCE® TKA from January 2011 to April 2014. Eighty-four MP inserts and 74 DH inserts were used under cruciate-retaining conditions. A 1:1 propensity score matching (PSM) analysis was performed between MP inserts and DH inserts to compare the clinical and radiographic outcomes. RESULTS: After a 1:1 PSM, 120 patients (60 pairs) were matched between the MP and DH inserts groups. The baseline demographic parameters and clinical scores were comparable between the two groups. The postoperative clinical outcomes at an averaged 8-year follow-up of both groups were significantly improved. The range of motion (ROM) of the DH group was better than that of the MP group, and equivalent Knee Society Function Score (KSFS) between the two groups was found. However, the Knee Society Score (KSS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, and Forgotten Joint Score (FJS) of the MP group were found to be significantly superior to those of the DH group. Comparable complication and revision rates were observed between the two groups. The radiographic results were also equally good between MP and DH groups. CONCLUSIONS: Although the mid-term clinical and radiographic outcomes of the DH inserts are fairly good, the clinical scores of the DH group were worse than those of the MP group.