A multi-center, adaptive, randomized, platform trial to evaluate the effect of repurposed medicines in outpatients with early coronavirus disease 2019 (COVID-19) and high-risk for complications: the TOGETHER master trial protocol

Background: Although vaccines are currently available for coronavirus disease 2019 (COVID-19), there remains a need for an effective and affordable outpatient treatment for early COVID-19. Multiple repurposed drugs have shown promise in treating COVID-19. We describe a master protocol that will assess the efficacy of different repurposed drugs as treatments for early COVID-19 among outpatients at a high risk for severe complications. Methods: The TOGETHER Trial is an international (currently in Brazil and Africa), multi-center platform adaptive randomized, placebo-controlled, clinical trial. Patients are included if they are at least 18 years of age, have a positive antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and have an indication for high risk of disease severity, including co-morbidities, older age, or high body mass index. Eligible patients are randomized with equal chance to an investigational product (IP) or to placebo. The primary endpoint is hospitalization due to clinical worsening of COVID-19 or emergency room required observation for more than 6 hours up to 28 days after randomization. Key secondary endpoints include viral clearance, clinical improvement, hospitalization for any cause, mortality for any cause, and safety and tolerability of each IP. Scheduled interim analyses are conducted and reviewed by the Data and Safety Monitoring Committee (DSMC), who make recommendations on continuing or stopping each IP. The platform adaptive design go-no-go decision rules are extended to dynamically incorporate external evidence on COVID-19 interventions from ongoing independent randomized clinical trials. Discussion: Results from this trial will assist in the identification of therapeutics for COVID-19 that can easily be scaled in low- and middle-income settings. The novel methodological extension of the platform adaptive design to dynamically incorporate external evidence is one of the first of its kind and may provide highly valuable information for all COVID-19 trials going forward. Clinicaltrials.gov registration: NCT04727424 (27/01/2021)

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A multi-center, adaptive, randomized, platform trial to evaluate the effect of repurposed medicines in outpatients with early coronavirus disease 2019 (COVID-19) and high-risk for complications: the TOGETHER master trial protocol

Gates Open Research ◽

10.12688/gatesopenres.13304.2 ◽

2021 ◽

Vol 5 ◽

pp. 117

Author(s):

Gilmar Reis ◽

Eduardo Augusto dos Santos Moreira Silva ◽

Daniela Carla Medeiros Silva ◽

Kristian Thorlund ◽

Lehana Thabane ◽

...

Keyword(s):

High Risk ◽

Adaptive Design ◽

Randomized Clinical Trials ◽

Decision Rules ◽

High Body Mass Index ◽

Controlled Clinical Trial ◽

Emergency Setting ◽

External Evidence ◽

Equal Chance ◽

Repurposed Drugs

Background: There remains a need for an effective and affordable outpatient treatment for early COVID-19. Multiple repurposed drugs have shown promise in treating COVID-19. We describe a master protocol that will assess the efficacy of different repurposed drugs as treatments for early COVID-19 among outpatients at a high risk for severe complications. Methods: The TOGETHER Trial is a multi-center platform adaptive randomized, placebo-controlled, clinical trial. Patients are included if they are at least 18 years of age, have a positive antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and have an indication for high risk of disease severity, including co-morbidities, older age, or high body mass index. Eligible patients are randomized with equal chance to an investigational product (IP) or to placebo.The primary endpoint is hospitalization defined as either retention in a COVID-19 emergency setting for greater than 6 hours or transfer to tertiary hospital due to COVID-19. Secondary outcomes include mortality, adverse events, adherence, and viral clearance. Scheduled interim analyses are conducted and reviewed by the Data and Safety Monitoring Committee (DSMC), who make recommendations on continuing or stopping each IP. The platform adaptive design go-no-go decision rules are extended to dynamically incorporate external evidence on COVID-19 interventions from ongoing independent randomized clinical trials. Discussion: Results from this trial will assist in the identification of therapeutics for the treatment of early diagnosed COVID-19. The novel methodological extension of the platform adaptive design to dynamically incorporate external evidence is one of the first of its kind and may provide highly valuable information for all COVID-19 trials going forward. Clinicaltrials.gov registration: NCT04727424 (27/01/2021)

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What should be monitored? The past, present, and future of physiological monitoring

Clinical Chemistry ◽

10.1093/clinchem/36.8.1536 ◽

1990 ◽

Vol 36 (8) ◽

pp. 1536-1543 ◽

Cited By ~ 4

Author(s):

W C Shoemaker

Keyword(s):

High Risk ◽

Randomized Clinical Trials ◽

Decision Rules ◽

Vital Signs ◽

Normal Function ◽

Monitoring Systems ◽

Predictive Index ◽

Mortality And Morbidity ◽

Therapeutic Goals ◽

Hemodynamic Variables

Abstract The status of conventional monitoring by vital signs and present concepts of invasive monitoring with the balloon-tipped pulmonary artery (Swan-Ganz) catheter are reviewed. Survivors of high-risk general surgery were observed to have cardiac index (CI) values averaging 4.5 L/min.m2, oxygen delivery (DO2) greater than 600 mL/min.m2, and oxygen consumption (VO2) greater than 170 mL/min.m2. By contrast, those who subsequently died during their hospitalization maintained relatively normal CI, DO2, and VO2 values. However, in the immediate postoperative period, values for other hemodynamic variables were not greatly different for survivors and nonsurvivors or different from the normal range. A predictive index based on these observations predicted outcome correctly in 94% of the subjects in a subsequent prospective study. The use of survivor values as appropriate therapeutic goals was tested in prospective randomized clinical trials and was found to reduce mortality and morbidity significantly. Simultaneous invasive and noninvasive hemodynamic and oxygen-transport monitoring systems were evaluated in high-risk postoperative patients to describe unanticipated adverse circulatory events. Before the monitored event, about three-fourths of the patients exhibited normal function. At the nadir, cardiac functions decreased in about two-thirds, perfusion decreased in more than one-half, and paO2 fell in only one-fourth. Two-thirds recovered with increased cardiac function, more than one-half had improved perfusion, and paO2 increased in fewer than one-fifth of monitored events. These data provide an information base for criteria needed to develop therapeutic decision rules for noninvasive monitoring systems. When noninvasive data are continuously displayed early in the course of critical illness and high-risk conditions, therapy may be instituted early, while physiological deficits are still minimal and easily reversible.

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Efficacy of add-on treosulfan and melphalan high-dose therapy in patients with high-risk metastatic Ewing sarcoma: Report from the International Ewing 2008R3 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.11501 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 11501-11501

Author(s):

Uta Dirksen ◽

Vivek Bhadri ◽

Bénédicte Brichard ◽

Trude Butterfass-Bahloul ◽

Sona Cyprova ◽

...

Keyword(s):

Clinical Trial ◽

High Risk ◽

Primary Endpoint ◽

Ewing Sarcoma ◽

Adaptive Design ◽

Phase Iii ◽

Controlled Clinical Trial ◽

High Dose ◽

Type I ◽

Hematopoietic Stem

11501 Background: Ewing 2008R3 (EudraCT2008-003658-13) was conducted in 12 countries. It evaluated the effect of treosulfan and melphalan high dose chemotherapy followed by re-infusion of autologous hematopoietic stem cells (HDTreoMel) on event-free (EFS, primary endpoint) and overall survival (OS) in high-risk Ewing Sarcoma (EwS). Methods: Phase III, open label, prospective, multi-center, randomized controlled clinical trial. Eligible patients (pts) had disseminated EwS with metastases to bone and/or other sites, excluding pts with only pleuropulmonary metastases. Pts received 6 cycles of VIDE induction and 8 cycles of VAC consolidation therapy. Patients were randomized to receive additional HDTreoMel chemotherapy or no further treatment (control), They were further stratified by number of bone metastases (1, 2-5, > 5). One-sided adaptive inverse-normal 4-stage design, changed after the 1st interim analysis via Müller-Schäfer method. Initial sample size 185 pts, type I error rate 2.5%, power 80%. Results: 109 pts were randomized between 2009 and 2018: 55 were randomized to HDTreoMel. With a median follow-up of 3.3 years, the primary endpoint EFS was not significantly different between HDTreoMel and control in the adaptive design (HR 0.85, 95% CI 0.55-1.32, intention-to-treat). 3-year (3y) EFS was 20.9 % (95% CI 11.5-37.9%) in HDTreoMel and 19.2 % (95% CI 10.8-34.4%) in control pts. Results were similar in the per protocol collective. Subgroup analyses showed that independent of treatment, male patients had a worse outcome than female patients: 3y EFS 13.3% (95% CI 5.7-31.1%) vs 25.2% (95% CI 15.5-40.8%); p = 0.07. Patients aged < 14 had a better outcome when treated in the HDTreoMel group: 3y EFS 39.3% (95% CI 20.4-75.8%) vs 9% (95% CI 2.4-34%); p = 0.016; HR 0.40 (0.19-0.87). These effects were similar in the per protocol collective. Severe toxicities of hematology, gut, general condition and infection were more pronounced in the HDTreoMel group (p < 0.05). Conclusions: In patients with very high risk EwS, additional HDTreoMel was of no benefit for the entire cohort of patients. HDTreoMel may be of benefit for children age < 14. This observation is supported by comparable results from a non-randomized trial EE99 R3 (Ladenstein et al. JCO, 2010). Clinical trial information: NCT00987636 .

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LINC-28. EPIDEMIOLOGICAL CHARACTERISTICS AND SURVIVAL OUTCOMES OF CHILDREN WITH MEDULLOBLASTOMA TREATED AT THE NATIONAL CANCER INSTITUTE (INCA) IN RIO DE JANEIRO, BRAZIL

Neuro-Oncology ◽

10.1093/neuonc/noaa222.462 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii383-iii384

Author(s):

Gabriela Oigman ◽

Diana Osorio ◽

Joseph Stanek ◽

Jonathan Finlay ◽

Denizar Vianna ◽

...

Keyword(s):

High Risk ◽

Maternal Education ◽

Survival Outcomes ◽

Middle Income ◽

Female Ratio ◽

High Risk Patients ◽

Presenting Symptoms ◽

Risk Patients ◽

Epidemiological Characteristics ◽

Standard Risk

Abstract BACKGROUND Medulloblastoma (MB), the most malignant brain tumor of childhood has survival outcomes exceeding 80% for standard risk and 60% for high risk patients in high-income countries (HIC). These results have not been replicated in low-to-middle income countries (LMIC), where 80% of children with cancer live. Brazil is an upper-middle income country according to World Bank, with features of LMIC and HIC. METHODS We conducted a retrospective review of 126 children (0–18 years) diagnosed with MB from 1997 to 2016 at INCA. Data on patients, disease characteristics and treatment information were retrieved from the charts and summarized descriptively; overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier Method. RESULTS The male/female ratio was 1.42 and the median age at diagnosis was 7.9 years. Headache (79%) and nausea/vomiting (75%) were the most common presenting symptoms. The median time from onset of symptoms to surgery was 50 days. The OS for standard-risk patients was 69% and 53% for high-risk patients. Patients initiating radiation therapy within 42 days after surgery (70.6% versus 59.6% p=0.016) experienced better OS. Forty-five patients (35%) had metastatic disease at admission. Lower maternal education correlated with lower OS (71.3% versus 49% p=0.025). Patients who lived >40km from INCA fared better (OS= 68.2% versus 51.1% p=0.032). Almost 20% of families lived below the Brazilian minimum wage. CONCLUSIONS These findings suggest that socioeconomic factors, education, early diagnosis and continuous data collection, besides oncological treatment must be adressed to improve the survival of children with MB.

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Monoclonal Antibodies Targeting CGRP: From Clinical Studies to Real-World Evidence—What Do We Know So Far?

Pharmaceuticals ◽

10.3390/ph14070700 ◽

2021 ◽

Vol 14 (7) ◽

pp. 700

Author(s):

Theodoros Mavridis ◽

Christina I. Deligianni ◽

Georgios Karagiorgis ◽

Ariadne Daponte ◽

Marianthi Breza ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Real World ◽

Large Scale ◽

Randomized Clinical Trials ◽

Clinical Investigation ◽

Phase Iii ◽

Real World Evidence ◽

Symptomatic Management ◽

Repurposed Drugs ◽

Cephalic Pain

Now more than ever is the time of monoclonal antibody use in neurology. In headaches, disease-specific and mechanism-based treatments existed only for symptomatic management of migraines (i.e., triptans), while the standard prophylactic anti-migraine treatments consist of non-specific and repurposed drugs that share limited safety profiles and high risk for interactions with other medications, resulting in rundown adherence rates. Recent advances in headache science have increased our understanding of the role of calcitonin gene relate peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) pathways in cephalic pain neurotransmission and peripheral or central sensitization, leading to the development of monoclonal antibodies (mAbs) or small molecules targeting these neuropeptides or their receptors. Large scale randomized clinical trials confirmed that inhibition of the CGRP system attenuates migraine, while the PACAP mediated nociception is still under scientific and clinical investigation. In this review, we provide the latest clinical evidence for the use of anti-CGRP in migraine prevention with emphasis on efficacy and safety outcomes from Phase III and real-world studies.

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Finding Children with High Risk of Non-Vaccination in 92 Low- and Middle-Income Countries: A Decision Tree Approach

Vaccines ◽

10.3390/vaccines9060646 ◽

2021 ◽

Vol 9 (6) ◽

pp. 646

Author(s):

Thiago M. Santos ◽

Bianca O. Cata-Preta ◽

Cesar G. Victora ◽

Aluisio J. D. Barros

Keyword(s):

High Risk ◽

Decision Tree ◽

Immunization Coverage ◽

Risk Groups ◽

Demographic And Health Surveys ◽

Middle Income ◽

Agenda 2030 ◽

Middle Income Countries ◽

Tree Approach ◽

Low And Middle Income

Reducing vaccination inequalities is a key goal of the Immunization Agenda 2030. Our main objective was to identify high-risk groups of children who received no vaccines (zero-dose children). A decision tree approach was used for 92 low- and middle-income countries using data from Demographic and Health Surveys and Multiple Indicator Cluster Surveys, allowing the identification of groups of children aged 12–23 months at high risk of being zero dose (no doses of the four basic vaccines—BCG, polio, DPT and measles). Three high-risk groups were identified in the analysis combining all countries. The group with the highest zero-dose prevalence (42%) included 4% of all children, but almost one in every four zero-dose children in the sample. It included children whose mothers did not receive the tetanus vaccine during and before the pregnancy, who had no antenatal care visits and who did not deliver in a health facility. Separate analyses by country presented similar results. Children who have been missed by vaccination services were also left out by other primary health care interventions, especially those related to antenatal and delivery care. There is an opportunity for better integration among services in order to achieve high and equitable immunization coverage.

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Hypofractionated radiotherapy versus conventional radiotherapy in patients with intermediate- to high-risk localized prostate cancer: a meta-analysis of randomized controlled trials

BMC Cancer ◽

10.1186/s12885-019-6285-x ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Wei Guo ◽

Yun-Chuan Sun ◽

Jian-Qiang Bi ◽

Xin-Ying He ◽

Li Xiao

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Adverse Events ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Localized Prostate Cancer ◽

Hypofractionated Radiotherapy ◽

Cancer Specific Survival ◽

Conventional Radiotherapy ◽

Results Of Treatment

Abstract Background Prostate cancer is one of the most common cancers in the world. The results of treatment after hypofractionated radiotherapy only have been reported from several small randomized clinical trials. Therefore, we conducted a meta-analysis to compare clinical outcomes of hypofractionated radiotherapy versus conventional radiotherapy in the treatment of intermediate- to high-risk localized prostate cancer. Methods Relevant studies were identified through searching related databases till August 2018. Hazard ratio (HR) or risk ratio (RR) with its corresponding 95% confidence interval (CI) was used as pooled statistics for all analyses. Results The meta-analysis results showed that overall survival (HR = 1.12, 95% CI: 0.93–1.35, p = 0.219) and prostate cancer-specific survival (HR = 1.29, 95% CI: 0.42–3.95, p = 0.661) were similar in two groups. The pooled data showed that biochemical failure was RR = 0.90, 95% CI: 0.76–1.07, p = 0.248. The incidence of acute adverse gastrointestinal events (grade ≥ 2) was higher in the hypofractionated radiotherapy (RR = 1.70, 95% CI: 1.12–2.56, p = 0.012); conversely, for late grade ≥ 2 gastrointestinal adverse events, a significant increase in the conventional radiotherapy was found (RR = 0.75, 95% CI: 0.61–0.91, p = 0.003). Acute (RR = 1.01, 95% CI: 0.89–1.15, p = 0.894) and late (RR = 0.98, 95% CI: 0.86–1.10, p = 0.692) genitourinary adverse events (grade ≥ 2) were similar for both treatment groups. Conclusion Results suggest that the efficacy and risk for adverse events are comparable for hypofractionated radiotherapy and conventional radiotherapy in the treatment of intermediate- to high-risk localized prostate cancer.

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Follicular lymphoma: are we ready for a risk-adapted approach?

Hematology ◽

10.1182/asheducation-2017.1.358 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 358-364 ◽

Cited By ~ 10

Author(s):

Brad S. Kahl

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

Randomized Clinical Trials ◽

International Prognostic Index ◽

Prognostic Index ◽

Predictive Biomarkers ◽

Western Hemisphere ◽

Ongoing Research ◽

High Risk Patients ◽

Risk Patients

Abstract Follicular lymphoma is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. The natural history of FL appears to have been favorably impacted by the introduction of rituximab after randomized clinical trials demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Yet, the disease is biologically and clinically heterogeneous with wide variations in outcomes for individual patients. The ability to accurately risk-stratify patients and then tailor therapy to the individual is an area of ongoing research. Historically, tumor grade, tumor burden, and the FL international prognostic index (version 1 and version 2) have been used to distinguish low-risk from high-risk patients. Biologic factors such as mutations in key genes can identify patients at high risk for poor outcomes to first-line therapy (mutational status of 7 genes [EZH2, ARID1A, MEF2B, EP300, FOX01, CREBBP, and CARD11] with Follicular Lymphoma International Prognostic Index). More recently, the quality of the response to initial therapy, as measured by either PET imaging or by remission duration, has been show to identify individuals at high risk. However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation.

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Adjuvant vs. salvage radiation therapy in men with high-risk features after radical prostatectomy: Survey of North American genitourinary expert radiation oncologists

Canadian Urological Association Journal ◽

10.5489/cuaj.5470 ◽

2018 ◽

Vol 13 (5) ◽

Author(s):

Shearwood McClelland 3rd ◽

Kiri A. Sandler ◽

Catherine Degnin ◽

Yiyi Chen ◽

Timur Mitin

Keyword(s):

Radiation Therapy ◽

High Risk ◽

Radical Prostatectomy ◽

North American ◽

Randomized Clinical Trials ◽

Current View ◽

Adjuvant Radiation ◽

Exact Test ◽

Salvage Radiation Therapy ◽

Radiation Oncologists

Introduction: The management of patients with high-risk features after radical prostatectomy (RP) is controversial. Level 1 evidence demonstrates that adjuvant radiation therapy (RT) improves survival compared to no treatment; however, it may overtreat up to 30% of patients, as randomized clinical trials (RCTs) using salvage RT on observation arms failed to reveal a survival advantage of adjuvant RT. We, therefore, sought to determine the current view of adjuvant vs. salvage RT among North American genitourinary (GU) radiation oncology experts. Methods: A survey was distributed to 88 practicing North American GU physicians serving on decision-making committees of cooperative group research organizations. Questions pertained to opinions regarding adjuvant vs. salvage RT for this patient population. Treatment recommendations were correlated with practice patterns using Fisher’s exact test. Results: Forty-two of 88 radiation oncologists completed the survey; 23 (54.8%) recommended adjuvant RT and 19 (45.2%) recommended salvage RT. Recommendation of active surveillance for Gleason 3+4 disease was a significant predictor of salvage RT recommendation (p=0.034), and monthly patient volume approached significance for recommendation of adjuvant over salvage RT; those seeing <15 patients/month trended towards recommending adjuvant over salvage RT (p=0.062). No other demographic factors approached significance. Conclusions: There is dramatic polarization among North American GU experts regarding optimal management of patients with highrisk features after RP. Ongoing RCTs will determine whether adjuvant RT improves survival over salvage RT. Until then, the almost 50/50 division seen from this analysis should encourage practicing clinicians to discuss the ambiguity with their patients.

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Dexamethasone in Patients with Spontaneous Intracerebral Hemorrhage: An Updated Meta-Analysis

Cerebrovascular Diseases ◽

10.1159/000510040 ◽

2020 ◽

Vol 49 (5) ◽

pp. 495-502

Author(s):

Stephanie Wintzer ◽

Josef Georg Heckmann ◽

Hagen B. Huttner ◽

Stefan Schwab

Keyword(s):

Clinical Trials ◽

High Risk ◽

Intracerebral Hemorrhage ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Risk Of Bias ◽

Spontaneous Intracerebral Hemorrhage ◽

Control Groups ◽

Language Data ◽

Negative Effect

Background: Spontaneous intracerebral hemorrhage (ICH) is a frequent cerebrovascular disorder and still associated with high mortality and poor clinical outcomes. The purpose of this review was to update a 15-year-old former meta-analysis on randomized clinical trials (RCTs) addressing the question of whether ICH patients treated with dexamethasone have better outcomes than controls. Methods: The electronic databases PubMed, SCOPUS, and Cochrane as well as web platforms on current clinical trials were searched for the years 1970–2020 without constriction on language. Data were extracted and outcomes were pooled for conventional and cumulative meta-analysis using a commercial software program (www.Meta-Analysis.com). Results: Finally, 7 RCTs were identified and analyzed including 248 participants in the dexamethasone groups and 242 in the control groups. Five studies showed a high risk of bias. The overall relative risk (RR) for death was 1.32 (95% confidence interval [CI] 0.99–1.76; p = 0.06) and did not differ significantly between the 2 groups. After exclusion of studies with high risk of bias, the RR for death was 1.37 (95% CI 0.54–3.42; p = 0.51). The RR for poor outcome did not differ significantly between the 2 groups analyzed for all included studies (RR = 0.69; 95% CI 0.47–1; p = 0.05) and after exclusion of studies with high risk of bias (RR = 0.7; 95% CI 0.45–1.08; p = 0.11). The RR for complications did not differ significantly including all studies (RR = 1.29; 95% CI 0.77–2.17; p = 0.34) and after exclusion of studies with high risk of bias (RR = 1.27; 95% CI 0.18–8.89; p = 0.81). The cumulative statistics delivered no other results; however, it pointed out fewer complications over time in the dexamethasone group. Conclusion: Clear evidence of a beneficial or negative effect of dexamethasone is still lacking. Modern RCTs or observational studies with propensity design are necessary to evaluate the efficacy and safety of treatment with dexamethasone in patients with ICH.

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