scholarly journals Focusing on the Treatment of COVID-19: A Comprehensive Analysis of 226 Trials Registered on Clinicaltrials.gov and ChiCTR

2021 ◽  
Author(s):  
Jincai Guo ◽  
Hui Xie ◽  
Hao Wu
Keyword(s):  
Clinical Trials ◽  
Chinese Medicine ◽  
Phase I ◽  
Phase Ii ◽  
Western Medicine ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Double Blind ◽  
Intervention Measures ◽  
Chinese Medicine Treatment

Abstract Background: The purpose of this study is to analyze the registered clinical trials of COVID-19, and to provide a reference for the clinical treatment of COVID-19. Methods: Chinese ClinicalTrial Registry (ChiCTR) and Clinicaltrials.gov databases were searched for clinical trials of COVID-19, which were registered from inception to February 29, 2020, to screen out the clinical trials on the treatment of COVID-19, and the research units and regions, sample size, study types, study stages, and intervention measures were analyzed. Results: There were 226 clinical trials on COVID-19 in the 2 databases, and all of them were registered by research units in China. The top five registered areas were Hubei, Beijing, Shanghai, Guangdong, and Zhejiang. The study type was as follows: interventional study (207, 91.6%) and observational study (18, 8.0%). Clinical trial staging was as follows: exploratory studies/preliminary trials (91, 40.3%), phase I trials (4, 1.8%), phase II trials (12, 5.3%), phase III trials (12, 5.3%), phase IV trials (47, 20.8%), phase I/II trials (2, 0.9%), phase II/III trials (5, 2.2%), and other trials (57, 25.2%). Intervention measures were as follows: there were 143 (63.3%) trials of western medicine treatment, 50 (22.1%) trials of Chinese medicine treatment, and 21 (9.3%) trials of integrated Chinese medicine treatment and western medicine treatment. Conclusion: Researchers have registered a large number of clinical trials in a short time. The number of existing patients of COVID-19 is not enough to support hundreds of clinical trials. There is a lack of multicenter, randomized, double-blind, placebo-controlled trials.

scholarly journals Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

2006 ◽  
Vol 24 (1) ◽  
pp. 136-140 ◽  
Author(s):  
Andrew J. Vickers ◽  
Joyce Kuo ◽  
Barrie R. Cassileth
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Cancer Patients ◽  
Phase Ii ◽  
Dose Finding ◽  
Phase Iii ◽  
High Dose ◽  
Free Text ◽  
Phase Ii Trials ◽  
Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

scholarly journals Reporting of Incidence and Outcome of Bone Metastases in Clinical Trials Enrolling Patients with Epidermal Growth Factor Receptor Mutated Lung Adenocarcinoma—A Systematic Review

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3144
Author(s):  
Anita Brouns ◽  
Safiye Dursun ◽  
Gerben Bootsma ◽  
Anne-Marie C. Dingemans ◽  
Lizza Hendriks
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Bone Metastases ◽  
Phase Ii ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Double Blind ◽  
Epidermal Growth

Bone metastases, occurring in 30–60% of patients with non-small cell lung cancer (NSCLC), are associated with decreased survival, cancer-induced bone pain, and skeletal-related events (SREs). Those with an activating epidermal growth factor mutation (EGFR+) seem to be more prone to develop bone metastases. To gain more insight into bone metastases-related outcomes in EGFR+ NSCLC, we performed a systematic review on Pubmed (2006–2021). Main inclusion criteria: prospective, phase II/III trials evaluating EGFR-tyrosine kinase inhibitors, ≥10 EGFR+ patients included, data on bone metastases and/or bone-related outcomes available. Out of 663 articles, 21 (3176 EGFR+ patients) met the eligibility criteria; 4 phase III (one double blind), 17 phase II trials (three randomized) were included. In seven trials dedicated bone imaging was performed at baseline. Mean incidence of bone metastases at diagnosis was 42%; 3–33% had progression in the bone upon progression. Except for one trial, it was not specified whether the use of bone target agents was permitted, and in none of the trials, occurrence of SREs was reported. Despite the high incidence of bone metastases in EGFR+ adenocarcinoma, there is a lack of screening for, and reporting on bone metastases in clinical trials, as well as permitted bone-targeted agents and SREs.

scholarly journals Anti-Angiogenic Agents in Management of Sarcoma Patients: Overview of Published Trials

2020 ◽  
Vol 10 ◽  
Author(s):  
Pierre-Yves Cren ◽  
Loïc Lebellec ◽  
Thomas Ryckewaert ◽  
Nicolas Penel
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Double Blind ◽  
Multikinase Inhibitors ◽  
Randomized Phase Ii ◽  
Phase Iii Trials

We reviewed all fully published clinical trials assessing anti-angiogenic agents in sarcoma patients (last issue, January 13, 2020). Anti-angiogenic macromolecules (e.g., bevacizumab or ombrabulin) provide disappointing results. Many multikinase inhibitors have been assessed with non-randomized phase II trials with limited samples and without stratification according to histological subtypes, therefore interpretation of such trials is very challenging. On the contrary, pazopanib, regorafenib, and sorafenib have been assessed using double-blind placebo-controlled randomized phase II or phase III trials. Compared to placebo, sorafenib demonstrates activity in desmoid-type fibromatosis patients. Based on results of phase 3 trial, pazopanib had obtained approval for treatment of pretreated non-adipocytic soft tissue sarcoma. Regorafenib is currently assessed in several clinical settings and provides significant improvement of progression-free survival in pre-treated non-adipocytic soft tissue sarcoma and in advanced pretreated osteosarcoma. Multikinase inhibitors are a breakthrough in sarcoma management. Many trials are ongoing. Nevertheless, predictive factors are still missing.

Evolution of statistical methodology and design of phase II/III clinical trials in non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7108-7108 ◽  
Author(s):  
R. K. Bagai ◽  
A. Dowlati
Keyword(s):  
Clinical Trials ◽  
Survival Time ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Iii ◽  
Type I ◽  
Phase Ii Trials ◽  
Improvement In Survival ◽  
Phase Ii And Iii ◽  
Phase Iii Studies

7108 Background: A significant heterogeneity exists in the design and reporting of phase II and III therapeutic clinical trials in NSCLC. This has led to difficulty in interpretation of these trials leading to over- or underestimation of therapeutic efficacy. We set out to investigate the statistical methodology and design reporting of chemotherapeutic trials in NSCLC published in the Journal of Clinical Oncology (JCO) over 20 years. Methods: We identified all phase II and III NSCLC chemotherapy trials published in the JCO from January 1983 to August 2005. All manuscripts were reviewed to evaluate components of statistical design that were reported, including: sample size calculation, power, type I error, single or multiple drug trials, relative response sought in phase II trials and improvement in survival time or response rate sought in phase III trials. Results: One hundred forty eight trials were identified. 52% of studies were phase III and 48% were phase II. The majority (78%) were conducted in advanced stage NSCLC. Sample size calculations were reported for only 58% of phase III studies and 31% of phase II studies. Power was reported in 66% of phase III studies and 13% of phase II trials. Type I error was reported in 47% of phase III studies and 17% in phase II studies. 60% of phase III trials defined endpoints (percentage improvement in survival time, improvement in survival time in months or increase in response rate). 41% of phase II trails defined the target response rate, ranging from response rates of 15% to 70%. The frequency of adequate reporting of statistical design was shown to increase from 31% in 1990–1995 to 64% in 2000–2005 ( table ). Conclusions: Significant heterogeneity exists in trial design and reporting of phase II and III trials in NSCLC. This impacts the ability to adequately interpret these studies. More widespread application of statistical methods in planning and reporting of lung cancer clinical trials are necessary to increase reliability of data. [Table: see text] No significant financial relationships to disclose.

Association of serious adverse events with type and sponsorship of clinical trials in patients with lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6576-6576
Author(s):  
T. L. Koeneke ◽  
J. O. Armitage ◽  
P. J. Bierman ◽  
R. Bociek ◽  
J. M. Vose ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Phase I ◽  
Phase Ii ◽  
Medical Center ◽  
Stage Iv ◽  
Large Cell ◽  
Phase Iii ◽  
Serious Adverse Events ◽  
Early Phase Clinical Trials

6576 Background: Arguments have been made against early phase clinical trials (CTs) as possibly being unethical because its risk may outweigh its potential benefits. Whether this is true in the light of newer biological treatment for cancer is unknown. We therefore examined the association between the incidence of serious adverse events according to type and sponsorship of CTs in pts with lymphoma. Methods: All IRB approved CTs at the University of Nebraska Medical Center from Jan 2000-June 2005 classified as therapeutic for lymphoma involving a biological agent were included. CTs were classified in two ways: by type of CTs (phase I vs II vs III) and sponsorship (Investigator-initiated vs Industry-initiated. Multivariate logistic regression was used to evaluate the association between types/sponsorship of CTs with the incidence of IRB serious adverse events (SAE; no vs yes) and fatal adverse events (FAE; no vs yes) while adjusting for age, sex, race, lymphoma type and stage, interval from dx to tx, co-morbid conditions, and previous tx. Results: 357 pts with lymphoma enrolled in 29 CTs were included. The median age of pt was 54y (21–88). 41% of the pts had follicular lymphoma, 36% diffuse large cell, 14% mantle cell and 9% were other types. 59% had Stage IV lymphoma. 71% of the pts participated in investigator-initiated CTs, while 29% participated in industry-initiated CTs. 21% of pts were enrolled in phase I, 65% in phase II and 14% in phase III studies. SAEs were seen in 49 pts (14%), while FAEs occurred in 13 pts (4%). Multivariate analysis showed the risk of having SAE was independent of the type or sponsor of CTs. Additionally, the risk of FAEs was not associated with the type of CTs. However, the risk of having FAEs was less in investigator- iniatiated CTs than in industry-iniatiated trials (Odds Ratio: 0.13 (95% CI, 0.03–0.61, p = 0.01). Conclusions: Our study showed that in CTs involving biological treatments, the incidence of SAEs was not associated with the type or sponsor of CTs suggesting that use of biological agents in phase I studies may have similar risks to phase II/III trials. Further studies should be done in other types of malignancies to evaluate further the decrease frequency of FAEs seen in investigator-initiated trials. No significant financial relationships to disclose.

Predictive value of phase II clinical trials in pancreatic cancer: Rethinking the road to progress.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4036-4036 ◽  
Author(s):  
Daniel M. Halperin ◽  
J. Jack Lee ◽  
James C. Yao
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Predictive Value ◽  
Error Rates ◽  
Phase Iii ◽  
Type I ◽  
Type Ii ◽  
Type Ii Error ◽  
Phase Ii Trials ◽  
Fda Approval

4036 Background: Few new therapies for pancreatic adenocarcinoma (PC) have been approved by the Food and Drug Administration (FDA) or recommended by the National Comprehensive Cancer Network (NCCN), reflecting frequent failures in phase III trials. We hypothesize that the high failure rate in large trials is due to a low predictive value for “positive” phase II studies. Methods: Given a median time from initiation of clinical trials to FDA approval of 6.3 years, we conducted a systematic search of the clinicaltrials.gov database for phase II interventional trials of antineoplastic therapy in PC initiated from 1999-2004. We reviewed drug labels and NCCN guidelines for FDA approval and guideline recommendations. Results: We identified 70 phase II trials that met our inclusion criteria. Forty-five evaluated compounds without preexisting FDA approval, 23 evaluated drugs approved in other diseases, and 2 evaluated cellular therapies. With a median follow-up of 12.5 years, none of these drugs gained FDA approval in PC. Four trials, all combining chemotherapy with radiation, eventually resulted in NCCN recommendations. Forty-two of the trials have been published. Of 16 studies providing pre-specified type I error rates, these rates were ≥0.1 in 8 studies, 0.05 in 6 studies and <0.025 in 2 studies. Of 21 studies specifying type II error rates, 7 used >0.1, 10 used 0.1, and 4 used <0.1. Published studies reported a median enrollment of 47 subjects. Fourteen trials reported utilizing a randomized design. Conclusions: The low rate of phase II trials resulting in eventual regulatory approval of therapies for PC reflects the challenge of conquering a tough disease as well as deficiencies in the statistical designs. New strategies are necessary to quantify and improve odds of success in drug development. Statistical parameters of individual or coupled phase II trials should be tailored to achieve the desired predictive value prior to initiating pivotal phase III studies. Positive predictive value of a phase II study assuming a 1%, 2%, or 5% prior probability of success and 10% type II error rate. [Table: see text]

Established and In-trial GPCR Families in Clinical Trials: A Review for Target Selection

2019 ◽  
Vol 20 (5) ◽  
pp. 522-539 ◽  
Author(s):  
Surovi Saikia ◽  
Manobjyoti Bordoloi ◽  
Rajeev Sarmah
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Phase I ◽  
Human Genome ◽  
Phase Ii ◽  
Drug Targets ◽  
Complex Diseases ◽  
Phase Iii ◽  
Computational Techniques ◽  
Receptor Complexes

The largest family of drug targets in clinical trials constitute of GPCRs (G-protein coupled receptors) which accounts for about 34% of FDA (Food and Drug Administration) approved drugs acting on 108 unique GPCRs. Factors such as readily identifiable conserved motif in structures, 127 orphan GPCRs despite various de-orphaning techniques, directed functional antibodies for validation as drug targets, etc. has widened their therapeutic windows. The availability of 44 crystal structures of unique receptors, unexplored non-olfactory GPCRs (encoded by 50% of the human genome) and 205 ligand receptor complexes now present a strong foundation for structure-based drug discovery and design. The growing impact of polypharmacology for complex diseases like schizophrenia, cancer etc. warrants the need for novel targets and considering the undiscriminating and selectivity of GPCRs, they can fulfill this purpose. Again, natural genetic variations within the human genome sometimes delude the therapeutic expectations of some drugs, resulting in medication response differences and ADRs (adverse drug reactions). Around ~30 billion US dollars are dumped annually for poor accounting of ADRs in the US alone. To curb such undesirable reactions, the knowledge of established and currently in clinical trials GPCRs families can offer huge understanding towards the drug designing prospects including “off-target” effects reducing economical resource and time. The druggability of GPCR protein families and critical roles played by them in complex diseases are explained. Class A, class B1, class C and class F are generally established family and GPCRs in phase I (19%), phase II(29%), phase III(52%) studies are also reviewed. From the phase I studies, frizzled receptors accounted for the highest in trial targets, neuropeptides in phase II and melanocortin in phase III studies. Also, the bioapplications for nanoparticles along with future prospects for both nanomedicine and GPCR drug industry are discussed. Further, the use of computational techniques and methods employed for different target validations are also reviewed along with their future potential for the GPCR based drug discovery.

Magnitude of benefit of the addition of bevacizumab (BEVA) to first-line chemotherapy (CT) for advanced/metastatic colorectal cancer (MCRC): Meta-analysis of randomized clinical trials

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15021-e15021
Author(s):  
V. Vaccaro ◽  
F. Cuppone ◽  
F. Loupakis ◽  
M. Milella ◽  
P. Carlini ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Clinical Trials ◽  
Regression Analysis ◽  
Phase Ii ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Meta Regression ◽  
Meta Regression Analysis

e15021 Background: The monoclonal antibody against vascular endothelial growth factor BEVA has recently demonstrated to improve survival for MRC patients (pts). Nevertheless, the magnitude of the provided benefit in the daily practice is still controversial. In order to quantify the benefit of adding BEVA to CT for MCRC, a literature-based meta-analysis was conducted. Methods: Survival Hazard Ratios (HR) were extracted from prospective, randomized clinical trials (RCTs, either phase II/III) reports. HR and event-based relative risks (RR) with 95% confidence intervals (CI) were derived through a random-effect model. Differences in primary (progression-free- and overall-survival, PFS/OS) and secondary outcomes (overall, partial and complete response rates, ORR/PR/CR) were explored. Absolute differences (AD) and the number of patients needed to treat (NNT) were calculated. Heterogeneity test and a meta-regression analysis with clinical predictors for outcomes were conducted as well. A sensitivity analysis according to the trial phase-design was accomplished. Results: Five trials (2,728 pts), 2 phase II (313 pts) and 3 phase III (2,415 pts), were gathered. No significant interaction was found in the sensitivity analysis between phase II and III, although a trend showed a better PFS results for BEVA in phase II trials (p=0.057). At the meta-regression analysis female gender and rectal primary site were significant predictors for PFS (p=0.003, p=0.005). Toxicity analysis is ongoing. Conclusions: Although concerns regarding costs and toxicities still exist, BEVA significantly improves the outcome of untreated MCRC pts. The absolute benefit provided into an unselected population for molecular features should be considered of paramount importance for advanced disease. [Table: see text] No significant financial relationships to disclose.

Identification of a predictive biomarker and two pharmacodynamic biomarkers to ADG106 treatment, a novel anti-CD137 agonist antibody, in phase I clinical trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14505-e14505
Author(s):  
Li Zhang
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase Ii ◽  
Predictive Biomarker ◽  
Phase I Trials ◽  
Tumor Shrinkage ◽  
Target Engagement ◽  
Phase I Clinical Trials ◽  
Phase Ii Trials ◽  
Pharmacodynamic Biomarkers

e14505 Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody that mediates anti-tumor activities via unique mechanisms of action. Here we provide safety and efficacy updates from our phase I trials and report the findings of a predictive biomarker and two pharmacodynamic biomarkers which correlate with patients’ clinical responses to ADG106 treatment and demonstrate target engagement, respectively. Methods: Formalin fixed and paraffin embedded (FFPE), blood and plasma specimens were collected from 92 patients enrolled in our phase I trials. We measured expression across a panel of protein biomarkers in FFPE specimens using three highly sensitive detection technologies: multiple immunohistochemical (IHC) staining of protein expression, the BD Multitest 6-color TBNK reagent for profiling immune cell subpopulations, and the MSD-ECL electrochemiluminescence assay for detection of soluble CD137. Objective tumor responses were determined using RECIST v1.1 for solid tumor patients and Lugano classification for lymphoma patients. Results: As of November 30, 2020, ADG106 has demonstrated a favorable safety profile and efficacy in the phase I clinical trials with a disease control rate of 56%. From a retrospective analysis of 28 pretreatment FFPE specimens, we identified a predictive biomarker that correlated with tumor shrinkage upon ADG106 treatment. We identified four biomarker positive specimens from two patients with lymphoma and two with solid tumors. Three out of four biomarker positive patients achieved greater than 30% tumor shrinkage after 3mg/kg or 5mg/kg ADG106 treatment. One biomarker positive patient with stable disease received a low dose ADG106 treatment at 0.5mg/kg during dose escalation. None of the 24 biomarker negative patients showed significant clinical response. A tissue microarray study confirmed expression of this predictive biomarker in a variety of tumor types suggesting a broad indication for ADG106 therapy. Our biomarker studies also demonstrated target engagement with increased NK cell proliferation and soluble CD137 upon ADG106 treatment. Analysis of safety, efficacy, PK and PD data allowed us to select a recommended dose for the upcoming phase II study. Conclusions: We identified a biomarker predictive of response to antitumor CD137 blockade by ADG106, as well as demonstrated the involvement of NK cells in ADG106 mediated anti-tumor activities. In upcoming phase II trials, we plan to enrich for populations expressing this predictive biomarker to demonstrate a clinical benefit to ADG106 therapy further validating early biomarker-based patient stratification. We will also explore the potential of selecting patients for combination treatment with anti-PD-1 therapies. Clinical trial information: NCT03802955.

Methodologic Lessons Learned From Hot Flash Studies

2001 ◽  
Vol 19 (23) ◽  
pp. 4280-4290 ◽  
Author(s):  
Jeff A. Sloan ◽  
Charles L. Loprinzi ◽  
Paul J. Novotny ◽  
Debra L. Barton ◽  
Beth I. Lavasseur ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Lessons Learned ◽  
Phase Iii ◽  
Validity And Reliability ◽  
Phase Ii Trials ◽  
Flash Intensity ◽  
Hot Flash ◽  
Parametric Data ◽  
Patient Reported

PURPOSE: In the course of conducting a series of prospective clinical trials devoted to defining new treatment opportunities for hot flashes in cancer survivors, considerable experience has been acquired with related methodologic issues. This article has been written in response to many queries regarding this methodology. PATIENTS AND METHODS: A series of seven different clinical trials that involved 968 patients was used for this work. Reliable and valid definitions of hot flash intensity were developed from patient-reported descriptions. Concomitant validity and reliability assessment of patient-completed diaries was undertaken to compare hot flash data with toxicity and quality-of-life (QOL) end points and to examine consistency across patient groups using variability analysis and correlation procedures. Parametric data from this meta-analysis was used to examine relative power considerations for the design of phase II and phase III clinical trials. RESULTS: Daily diaries used in these studies exhibited consistency and reliability and had few missing data. Hot flash frequency and hot flash score (frequency multiplied by average severity) variables produced almost identical end point results. For phase III placebo-controlled studies, 50 patients per treatment arm seem appropriate to provide sufficient power specifications to detect a clinically meaningful change in hot flash activity. For phase II trials, 25 patients per trial seem to provide reasonable estimates of eventual hot flash efficacy to screen potential agents for more definitive testing. CONCLUSION: Given the data gained from these experiences, we can plan and carry out more efficient trials to identify efficacious agents for the reduction of hot flash activity.

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