scholarly journals Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial

2021 ◽  
Author(s):  
Benjamin A Fisher ◽  
Tonny Veenith ◽  
Daniel Slade ◽  
Charlotte Gaskell ◽  
Matthew Rowland ◽  
...  
Keyword(s):  
Standard Of Care ◽  
Phase 2 ◽  
Proof Of Concept ◽  
Open Label ◽  
Hospitalised Patients

scholarly journals Namilumab or infliximab compared to standard of care in hospitalised patients with COVID-19 (CATALYST): a phase 2 randomised adaptive trial

2021 ◽  
Author(s):  
Benjamin A Fisher ◽  
Tonny Veenith ◽  
Daniel Slade ◽  
Charlotte Gaskell ◽  
Matthew Rowland ◽  
...  
Keyword(s):  
Usual Care ◽  
Clinical Outcomes ◽  
Standard Of Care ◽  
Phase 2 ◽  
Proof Of Concept ◽  
Open Label ◽  
Hospitalised Patients ◽  
Factor Inhibitor ◽  
Poor Outcomes ◽  
Over Time

Background Dysregulated inflammation is associated with poor outcomes in Coronavirus disease 2019 (COVID-19). We assessed the efficacy of namilumab, a granulocyte-macrophage colony-stimulating factor inhibitor and infliximab, a tumour necrosis factor inhibitor in hospitalised patients with COVID-19 in order to prioritise agents for phase 3 trials. Methods In this randomised, multi-arm, parallel group, open label, adaptive phase 2 proof-of-concept trial (CATALYST) we recruited hospitalised patients ≥16 years with COVID-19 pneumonia and C-reactive protein (CRP) ≥40mg/L in nine UK hospitals. Participants were randomly allocated with equal probability to usual care, or usual care plus a single 150mg intravenous dose of namilumab (150mg) or infliximab (5mg/kg). Randomisation was stratified for ward versus ICU. The primary endpoint was improvement in inflammation in intervention arms compared to control as measured by CRP over time, analysed using Bayesian multi-level models. ISRCTN registry number 40580903. Findings Between 15th June 2020 and 18th February 2021 we randomised 146 participants: 54 to usual care, 57 to namilumab and 35 to infliximab. The probabilities that namilumab and infliximab were superior to usual care in reducing CRP over time were 97% and 15% respectively. Consistent effects were seen in ward and ICU patients and aligned with clinical outcomes, such that the probability of discharge (WHO levels 1-3) at day 28 was 47% and 64% for ICU and ward patients on usual care, versus 66% and 77% for patients treated with namilumab. 134 adverse events occurred in 30/55 (54.5%) namilumab patients compared to 145 in 29/54 (53.7%) usual care patients. 102 events occurred in 20/29 (69.0%) infliximab patients versus 112 events in 17/34 (50.0%) usual care patients. Interpretation Namilumab, but not infliximab, demonstrated proof-of-concept evidence for reduction in inflammation in hospitalised patients with COVID-19 pneumonia which was consistent with secondary clinical outcomes. Namilumab should be prioritised for further investigation in COVID-19. Funding Medical Research Council.

scholarly journals US201 Study: A Phase 2, Randomized Proof-of-Concept Trial of Favipiravir for the Treatment of COVID-19

2021 ◽  
Vol 8 (12) ◽  
Author(s):  
Robert W Finberg ◽  
Madiha Ashraf ◽  
Boris Julg ◽  
Folusakin Ayoade ◽  
Jai G Marathe ◽  
...  
Keyword(s):  
Severe Disease ◽  
Neutralizing Antibody ◽  
Standard Of Care ◽  
Viral Clearance ◽  
Phase 2 ◽  
Proof Of Concept ◽  
Open Label ◽  
Loss To Follow Up ◽  
Moderate Disease ◽  
Post Hoc

Abstract Background Favipiravir is used to treat influenza, and studies demonstrate that it has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods We performed a randomized, open-label, multicenter, phase 2 proof-of-concept trial of favipiravir in hospitalized adult patients with polymerase chain reaction (PCR)–positive coronavirus disease 2019 (COVID-19). Patients were randomized to standard of care (SOC) or favipiravir treatment (1800mg per os twice a day [b.i.d.] on day 1, followed by 1000mg b.i.d. for 13 days). The primary end point was time to viral clearance on day 29. Results Fifty patients were enrolled and stratified by disease severity (critical disease, severe disease, or mild to moderate disease). Nineteen patients were censored from the event of viral clearance based on being SARS-CoV-2 PCR-negative at the study outset, being PCR-positive at day 29, or because of loss to follow-up. Data from the 31 remaining patients who achieved viral clearance show enhanced viral clearance in the favipiravir group compared with the SOC group by day 29, with 72% of the favipiravir group and 52% of the SOC group being evaluable for viral clearance through day 29. The median time to viral clearance was 16.0 days (90% CI, 12.0 to 29.0) in the favipiravir group and 30.0 days (90% CI, 12.0 to 31.0) in the SOC group. A post hoc analysis revealed an effect in the subgroup of patients who were neutralizing antibody–negative at randomization. Treatment-emergent adverse events were equally distributed between the groups. Conclusions We demonstrate that favipiravir can be safely administered to hospitalized adults with COVID-19 and believe that further studies are warranted. ClinicalTrials.gov registration NCT04358549.

scholarly journals Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2—azithromycin trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Iwein Gyselinck ◽  
◽  
Laurens Liesenborghs ◽  
Ewout Landeloos ◽  
Ann Belmans ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Standard Of Care ◽  
Ordinal Scale ◽  
Cytokine Signaling ◽  
Nasopharyngeal Swab ◽  
The Novel ◽  
Proof Of Concept ◽  
Open Label ◽  
Novel Coronavirus

Abstract Background The rapid emergence and the high disease burden of the novel coronavirus SARS-CoV-2 have created a medical need for readily available drugs that can decrease viral replication or blunt the hyperinflammatory state leading to severe COVID-19 disease. Azithromycin is a macrolide antibiotic, known for its immunomodulatory properties. It has shown antiviral effect specifically against SARS-CoV-2 in vitro and acts on cytokine signaling pathways that have been implicated in COVID-19. Methods DAWn-AZITHRO is a randomized, open-label, phase 2 proof-of-concept, multicenter clinical trial, evaluating the safety and efficacy of azithromycin for treating hospitalized patients with COVID-19. It is part of a series of trials testing promising interventions for COVID-19, running in parallel and grouped under the name DAWn-studies. Patients hospitalized on dedicated COVID wards are eligible for study inclusion when they are symptomatic (i.e., clinical or radiological signs) and have been diagnosed with COVID-19 within the last 72 h through PCR (nasopharyngeal swab or bronchoalveolar lavage) or chest CT scan showing typical features of COVID-19 and without alternate diagnosis. Patients are block-randomized (9 patients) with a 2:1 allocation to receive azithromycin plus standard of care versus standard of care alone. Standard of care is mostly supportive, but may comprise hydroxychloroquine, up to the treating physician’s discretion and depending on local policy and national health regulations. The treatment group receives azithromycin qd 500 mg during the first 5 consecutive days after inclusion. The trial will include 284 patients and recruits from 15 centers across Belgium. The primary outcome is time from admission (day 0) to life discharge or to sustained clinical improvement, defined as an improvement of two points on the WHO 7-category ordinal scale sustained for at least 3 days. Discussion The trial investigates the urgent and still unmet global need for drugs that may impact the disease course of COVID-19. It will either provide support or else justify the discouragement of the current widespread, uncontrolled use of azithromycin in patients with COVID-19. The analogous design of other parallel trials of the DAWN consortium will amplify the chance of identifying successful treatment strategies and allow comparison of treatment effects within an identical clinical context. Trial registration EU Clinical trials register EudraCT Nb 2020-001614-38. Registered on 22 April 2020

scholarly journals A randomized, multicentre, open-label phase II proof-of-concept trial investigating the clinical efficacy and safety of the addition of convalescent plasma to the standard of care in patients hospitalized with COVID-19: the Donated Antibodies Working against nCoV (DAWn-Plasma) trial

Trials ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Timothy Devos ◽  
Tatjana Geukens ◽  
Alexander Schauwvlieghe ◽  
Kevin K. Ariën ◽  
Cyril Barbezange ◽  
...  
Keyword(s):  
Treatment Group ◽  
Phase Ii ◽  
Clinical Efficacy ◽  
Active Treatment ◽  
Standard Of Care ◽  
Active Treatment Group ◽  
Proof Of Concept ◽  
Efficacy And Safety ◽  
Open Label ◽  
Open Label Phase

Abstract Background The COVID-19 pandemic has imposed an enormous burden on health care systems around the world. In the past, the administration of convalescent plasma of patients having recovered from SARS and severe influenza to patients actively having the disease showed promising effects on mortality and appeared safe. Whether or not this also holds true for the novel SARS-CoV-2 virus is currently unknown. Methods DAWn-Plasma is a multicentre nation-wide, randomized, open-label, phase II proof-of-concept clinical trial, evaluating the clinical efficacy and safety of the addition of convalescent plasma to the standard of care in patients hospitalized with COVID-19 in Belgium. Patients hospitalized with a confirmed diagnosis of COVID-19 are eligible when they are symptomatic (i.e. clinical or radiological signs) and have been diagnosed with COVID-19 in the 72 h before study inclusion through a PCR (nasal/nasopharyngeal swab or bronchoalveolar lavage) or a chest-CT scan showing features compatible with COVID-19 in the absence of an alternative diagnosis. Patients are randomized in a 2:1 ratio to either standard of care and convalescent plasma (active treatment group) or standard of care only. The active treatment group receives 2 units of 200 to 250 mL of convalescent plasma within 12 h after randomization, with a second administration of 2 units 24 to 36 h after ending the first administration. The trial aims to include 483 patients and will recruit from 25 centres across Belgium. The primary endpoint is the proportion of patients that require mechanical ventilation or have died at day 15. The main secondary endpoints are clinical status on day 15 and day 30 after randomization, as defined by the WHO Progression 10-point ordinal scale, and safety of the administration of convalescent plasma. Discussion This trial will either provide support or discourage the use of convalescent plasma as an early intervention for the treatment of hospitalized patients with COVID-19 infection. Trial registration ClinicalTrials.govNCT04429854. Registered on 12 June 2020 - Retrospectively registered.

scholarly journals A Phase 1/1b Open-Label, Multicenter, Two-Part Study of SETD2 Inhibitor EZM0414 in Patients with Relapsed/Refractory Multiple Myeloma or Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1679-1679
Author(s):  
Paul G. Richardson ◽  
Ruben Niesvizky ◽  
Jay Yang ◽  
Neelu Yadav ◽  
Helen Hsu ◽  
...  
Keyword(s):  
Stock Options ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Standard Of Care ◽  
Phase 2 ◽  
Open Label ◽  
Large B Cell Lymphoma ◽  
Phase 1B

Abstract Background: Multiple myeloma (MM) is a heterogeneous disease of monoclonal plasma cells. More than 40% of patients with MM harbor translocations of the immunoglobulin heavy chain (IGH) gene on chromosome 14, leading to overexpression of putative oncogenes which can ultimately lead to plasma cell-derived, post-malignancy MM. One such translocation, t(4;14), is seen in 15% of patients and juxtaposes IGH control elements with two genes on chromosome 4, FGFR3 and MMSET. Patients harboring the (4;14) translocation have a poor response to standard of care therapies and an overall poor prognosis. MMSET expression has been confirmed as a driver in t(4;14) MM pathogenesis, but MMSET inhibitors have not yet been successfully developed in the clinic. Since MMSET generates the substrate for Su(var)3-9, enhancer of zeste, trithorax domain-containing 2 (SETD2) activity, SETD2 inhibition offers promise for targeting the underlying oncogenic mechanism in t(4;14) MM. Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in the United States, with a 5-year relative survival rate of 53% in patients diagnosed with stage IV DLBCL. Given the poor survival outcomes and low remission rates for patients with relapsed or refractory (R/R) DLBCL, there is a need for better treatment options. Although SETD2 mutations are described in DLBCL, the mechanism of action of SETD2 inhibitors remains unclear. EZM0414 is a potent and selective, orally bioavailable small-molecule inhibitor of SETD2. Preclinical data have demonstrated antitumor activity of EZM0414 in both t(4;14) and non-t(4;14) MM and DLBCL models. This study (enrollment scheduled to begin Q3 2021) will evaluate the safety and efficacy of EZM0414 when administered as monotherapy in patients with R/R MM with or without t(4;14), or with R/R DLBCL. Study Design and Methods: This first-in-human, 2-part, multicenter, open-label study will enroll patients aged ≥18 years with R/R MM who have received prior treatment with immune modulators, proteasome inhibitors, and anti-CD38 therapy, or who are intolerant to established therapies known to provide clinical benefit in MM, or with R/R DLBCL who have received at least 2 prior lines of therapy, including treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH); rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper CVAD); or other standard of care therapies. Patients eligible for autologous stem cell transplantation will be excluded from this study. The first part of the study will be a phase 1 dose escalation study using a Bayesian optimal interval design to evaluate the safety and tolerability of EZM0414 in patients with R/R MM with or without t(4;14), or with R/R DLBCL. Six dose levels of 100, 200, 300, 400, 600, and 900 mg administered once daily will be tested. Patients will be enrolled and treated in a cohort size of 3, and up to 36 patients will be enrolled to evaluate at least 10 patients at the maximum tolerated dose (MTD). The MTD will be selected at the dose level with a target dose-limiting toxicity rate ≤25%. The second part of the study (phase 1b) will be a dose expansion at the MTD in patients with R/R MM with or without t(4;14), or with R/R DLBCL using the Bayesian optimal phase 2 design. Dose expansion will include 3 cohorts of up to 20 patients each. Cohort 1 will enroll patients with t(4;14)-positive R/R MM, cohort 2 will enroll patients with t(4;14)-negative R/R MM, and cohort 3 will enroll patients with R/R DLBCL. The primary endpoints will be determining safety, dose-limiting toxicities, the MTD, and a recommended phase 2 dose. Secondary endpoints include the objective response rate, progression-free survival, and duration of response. Exploratory endpoints include a pharmacokinetic/pharmacodynamic profile analysis and the determination of mechanism of action biomarkers, such as histones and histone methylation. The study design will include a futility assessment in the phase 1b part of the study, which will be initiated when clinical data from the first 10, 15, and 20 enrolled patients in the expansion cohort are available. Disclosures Richardson: Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Secura Bio: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; AbbVie: Consultancy; Sanofi: Consultancy; Protocol Intelligence: Consultancy; Oncopeptides: Consultancy, Research Funding. Niesvizky: BMS: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Yang: Epizyme, Inc.: Current Employment, Other: May own stock/options. Yadav: Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Hsu: Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Flowers: Iovance: Research Funding; Adaptimmune: Research Funding; Guardant: Research Funding; Denovo: Consultancy; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Kite: Research Funding; Spectrum: Consultancy; Biopharma: Consultancy; SeaGen: Consultancy; Pharmacyclics/Janssen: Consultancy; Epizyme, Inc.: Consultancy; Acerta: Research Funding; 4D: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Nektar: Research Funding; Sanofi: Research Funding; Morphosys: Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; National Cancer Institute: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Cellectis: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; BeiGene: Consultancy; Xencor: Research Funding; TG Therapeutics: Research Funding; EMD: Research Funding; Burroughs Wellcome Fund: Research Funding; Ziopharm: Research Funding; Pharmacyclics: Research Funding.

scholarly journals Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

2020 ◽  
Author(s):  
Peter W Horby ◽  
Alistair Roddick ◽  
Enti Spata ◽  
Natalie Staplin ◽  
Jonathan R Emberson ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Usual Care ◽  
Rate Ratio ◽  
Invasive Mechanical Ventilation ◽  
Composite Endpoint ◽  
Standard Of Care ◽  
Open Label ◽  
Hospitalised Patients ◽  
Randomised Controlled ◽  
To Receive

Background: Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We evaluated the efficacy and safety of azithromycin in hospitalised patients with COVID-19. Methods: In this randomised, controlled, open-label, adaptive platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once daily by mouth or intravenously for 10 days or until discharge (or one of the other treatment arms). Patients were twice as likely to be randomised to usual care as to any of the active treatment groups. The primary outcome was 28-day mortality. Findings: Between 7 April and 27 November 2020, 2582 patients were randomly allocated to receive azithromycin and 5182 patients to receive usual care alone. Overall, 496 (19%) patients allocated to azithromycin and 997 (19%) patients allocated to usual care died within 28 days (rate ratio 1.00; 95% confidence interval [CI] 0.90-1.12; p=0.99). Consistent results were seen in all pre-specified subgroups of patients. There was no difference in duration of hospitalisation (median 12 days vs. 13 days) or the proportion of patients discharged from hospital alive within 28 days (60% vs. 59%; rate ratio 1.03; 95% CI 0.97-1.10; p=0.29). Among those not on invasive mechanical ventilation at baseline, there was no difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs. 22%; risk ratio 0.97; 95% CI 0.89-1.07; p=0.54). Interpretation: In patients hospitalised with COVID-19, azithromycin did not provide any clinical benefit. Azithromycin use in patients hospitalised with COVID-19 should be restricted to patients where there is a clear antimicrobial indication.

scholarly journals Convalescent plasma for COVID-19 in hospitalised patients: an open-label, randomised clinical trial

2021 ◽  
pp. 2101471
Author(s):  
Leo Sekine ◽  
Beatriz Arns ◽  
Bruna R. Fabro ◽  
Murillo M. Cipolatt ◽  
Rafael R. G. Machado ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Improvement ◽  
Critically Ill ◽  
Primary Outcome ◽  
Ventilatory Support ◽  
Standard Of Care ◽  
Randomised Clinical Trial ◽  
Open Label ◽  
Hospitalised Patients ◽  
Significant Difference

BackgroundThe effects of convalescent plasma (CP) therapy hospitalised patients with coronavirus disease 2019 (COVID-19) remain uncertain. This study investigates the effect CP on clinical improvement in these patients.MethodsThis is an investigator-initiated, randomised, parallel arm, open-label, superiority clinical trial. Patients were randomly (1:1) assigned to two infusions of CP plus standard of care (SOC) or SOC alone. The primary outcome was the proportion of patients with clinical improvement 28 days after enrolment.ResultsA total of 160 (80 in each arm) patients (66.3% were critically ill and 33.7%, severe) completed the trial. The median age was 60.5 years (interquartile range [IQR], 48–68), 58.1% were men and the median time from symptom onset to randomisation was 10 days (IQR, 8–12). Neutralising antibodies titres >1:80 were present in 133 (83.1%) patients at baseline. The proportion of patients with clinical improvement on day 28 was 61.3% in the CP+SOC and 65.0% in the SOC group (difference, −3.7%; 95% Confidence Interval [CI], −18.8%-11.3%). The results were similar in the subgroups of severe and critically ill. There was no significant difference between CP+SOC and SOC groups in prespecified secondary outcomes, including 28-day mortality, days alive and free of respiratory support and duration of invasive ventilatory support. Inflammatory and other laboratorial markers values on days 3, 7 and 14 were similar between groups.ConclusionsCP+SOC did not result in a higher proportion of clinical improvement on at day 28 in hospitalised patients with COVID-19 compared to SOC alone.

scholarly journals The FAFA Trial: A Phase 2 Randomized Clinical Trial on the Effect of a Fan Blowing Air on the Face to Relieve Dyspnea in Filipino Patients with Terminal Cancer

2020 ◽  
Vol 6 (01) ◽  
pp. 03-09 ◽  
Author(s):  
Frederic Ivan Ting ◽  
Sachiko Estreller ◽  
Heinrik Martin Jude Strebel
Keyword(s):  
Intervention Group ◽  
Standard Of Care ◽  
Mean Difference ◽  
Control Group ◽  
Published Data ◽  
Terminal Cancer ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Trial ◽  
The Mean

Abstract Introduction Fan therapy has been suggested by some studies as one of the nonpharmacological supportive interventions to alleviate breathlessness for dyspneic patients with terminal cancer. Unfortunately, data among Asians are limited and there are currently no published data showing that this intervention works among Filipinos—thus this study. Study Design This study was an open-label, randomized, placebo-controlled, crossover Phase 2 trial. The experimental group had a fan blowing air directly to the patient’s face for 5 minutes, and the control group had a fan blowing air to the patient’s legs. Treatment crossover was done after a washout period of 1 hour. The primary outcome, which is dyspnea, was measured subjectively using the Modified Borg Scale (MBS). Differences in the patient’s respiratory rate (RR) and oxygen saturation were also measured. Results A total of 48 patients were enrolled in this trial. The mean age of the patients enrolled was 51 years, and the most common primary tumor was lung cancer (21%). In the control group, results showed that the mean difference before and after intervention in the MBS was 0.15, and the mean difference in RR was 0.25. On the other hand, the intervention group showed a statistically significant decrease in the patient’s dyspnea as evidenced by a mean MBS decrease of 2.79 (p < 0.0001), and a mean RR decrease of 1.88 (p < 0.0001). Conclusion The results of this study reveal that fan on face (FAFA) therapy in terminally ill Filipino cancer patients in addition to the prescribed standard of care can significantly alleviate their level of dyspnea. Thus, FAFA therapy should be considered as an adjunct to standard of care for these patients.

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