scholarly journals Evaluation of new or repurposed treatments for COVID-19: protocol for the phase Ib/IIa DEFINE trial platform

BMJ Open ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. e054442
Author(s):  
Erin Gaughan ◽  
Tom Quinn ◽  
Annya Bruce ◽  
Jean Antonelli ◽  
Vikki Young ◽  
...  
Keyword(s):  
Safety Data ◽  
Standard Of Care ◽  
Assisted Ventilation ◽  
Early Warning Score ◽  
Ordinal Scale ◽  
Experimental Therapy ◽  
Experimental Medicine ◽  
Open Label ◽  
Link Type ◽  
Hospitalised Patients

IntroductionCOVID-19 is a new viral-induced pneumonia caused by infection with a novel coronavirus, SARS-CoV-2. At present, there are few proven effective treatments. This early-phase experimental medicine protocol describes an overarching and adaptive trial designed to provide safety data in patients with COVID-19, pharmacokinetic (PK)/pharmacodynamic (PD) information and exploratory biological surrogates of efficacy, which may support further development and deployment of candidate therapies in larger scale trials of patients positive for COVID-19.Methods and analysisDefine is an ongoing exploratory multicentre-platform, open-label, randomised study. Patients positive for COVID-19 will be recruited from the following cohorts: (a) community cases; (b) hospitalised patients with evidence of COVID-19 pneumonitis; and (c) hospitalised patients requiring assisted ventilation. The cohort recruited from will be dependent on the experimental therapy, its route of administration and mechanism of action. Randomisation will be computer generated in a 1:1:n ratio. Twenty patients will be recruited per arm for the initial two arms. This is permitted to change as per the experimental therapy. The primary statistical analyses are concerned with the safety of candidate agents as add-on therapy to standard of care in patients with COVID-19. Secondary analysis will assess the following variables during treatment period: (1) the response of key exploratory biomarkers; (2) change in WHO ordinal scale and National Early Warning Score 2 (NEWS2) score; (3) oxygen requirements; (4) viral load; (5) duration of hospital stay; (6) PK/PD; and (7) changes in key coagulation pathways.Ethics and disseminationThe Define trial platform and its initial two treatment and standard of care arms have received a favourable ethical opinion from Scotland A Research Ethics Committee (REC) (20/SS/0066), notice of acceptance from The Medicines and Healthcare Products Regulatory Agency (MHRA) (EudraCT 2020-002230-32) and approval from the relevant National Health Service (NHS) Research and Development (R&D) departments (NHS Lothian and NHS Greater Glasgow and Clyde). Appropriate processes are in place in order to be able to consent adults with and without capacity while following the necessary COVID-19 safe procedures. Patients without capacity could be recruited via a legal representative. Witnessed electronic consent of participants or their legal representatives following consent discussions was established. The results of each study arm will be submitted for publication in a peer-reviewed journal as soon as the treatment arm has finished recruitment, data input is complete and any outstanding patient safety follow-ups have been completed. Depending on the results of these or future arms, data will be shared with larger clinical trial networks, including the Randomised Evaluation of COVID-19 Therapy trial (RECOVERY), and to other partners for rapid roll-out in larger patient cohorts.Trial registration numberISRCTN14212905, NCT04473053.

scholarly journals DEFINE: A Phase IIa Randomised Controlled Trial to Evaluate Repurposed Treatments for COVID-19

2021 ◽  
Author(s):  
Erin Gaughan ◽  
Tom Michael Quinn ◽  
Annya Bruce ◽  
Jean Antonelli ◽  
Vikki Young ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Study Drug ◽  
Standard Of Care ◽  
Assisted Ventilation ◽  
Ordinal Scale ◽  
Experimental Therapy ◽  
Experimental Medicine ◽  
Open Label ◽  
Randomised Study ◽  
Hospitalised Patients

Abstract: Introduction; COVID-19 (Coronavirus Disease 2019) is a new viral-induced pneumonia caused by infection with a novel coronavirus, SARS CoV2 (Severe Acute Respiratory Syndrome Coronavirus 2). At present there are few proven effective treatments. This early phase experimental medicine protocol describes an overarching and adaptive trial designed to provide safety, pharmacokinetic (PK)/ pharmacodynamic (PD) information and exploratory biological surrogates of efficacy, which may support further development and deployment of candidate therapies in larger scale trials of COVID-19 positive patients. Methods and analysis; DEFINE is an ongoing exploratory multicentre platform, open label, randomised study. COVID-19 positive patients will be recruited from the following cohorts; a) community cases b) hospitalised patients with new changes on a chest x-ray (CXR) or a computed tomography (CT) scan or requiring supplemental oxygen and c) hospitalised patients requiring assisted ventilation. Participants may be recruited from all three of these cohorts, depending on the experimental therapy, its route of administration and mechanism of action. The primary statistical analyses are concerned with the safety of candidate agents as add-on therapy to standard of care in patients with COVID-19. Safety will be assessed using: - Haematological and biochemical safety laboratory investigations. - Physical examination - Vital signs (blood pressure/heart rate/temperature and respiratory rate) - Daily electrocardiogram (ECG) readings - Adverse events The analysis population will consist of (i) all patients randomised to a treatment arm who receive any dose of the study drug and (ii) all patients randomised to the control arm who would also have been eligible to receive a study drug. Secondary analysis will assess the following variables during treatment period 1) the response of key exploratory biomarkers 2) change in WHO ordinal scale and NEWS2 score 3) oxygen requirements 4) viral load 5) duration of hospital stay 6) PK/PD and 7) changes in key coagulation pathways. Ethics and dissemination; The DEFINE trial platform and its initial two treatment and standard of care arms have received full ethical approval from Scotland A REC (20/SS/0066), the MHRA (EudraCT 2020-002230-32) and NHS Lothian and NHS Greater Glasgow and Clyde. The results of each study arm will be published as soon as the treatment arm has finished recruitment, data input is complete and any outstanding patient safety follow-ups have been completed. Depending on the results of these or future arms, data will be shared with larger clinical trial networks, including RECOVERY, and to other partners for rapid roll out in larger patient cohorts.

scholarly journals Prospective, Randomized, Parallel-Group, Open-Label Study to Evaluate the Efficacy and Safety of IMU-838, in Combination with Oseltamivir, in Adults with Coronavirus Disease 19 The IONIC Trial

2021 ◽  
Author(s):  
Kavi Sharma ◽  
Dr Lisa Berry ◽  
Dr Evangelos Vryonis ◽  
Dr Asad Ali ◽  
Dr Beatriz Lara ◽  
...  
Keyword(s):  
Clinical Improvement ◽  
Trial Design ◽  
Standard Of Care ◽  
Ordinal Scale ◽  
Therapeutic Effects ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Link Type ◽  
Discharge From Hospital

Background: Globally there is a scarcity of effective treatments for SARS-CoV-2 infections (causing COVID 19). Repurposing existing medications may offer the best hope for treating COVID 19 patients to curb the pandemic. IMU-838 is a dihydroorotate dehydrogenase (DHODH) inhibitor, which is an effective mechanism for antiviral effects against respiratory viruses. When used synergistically with Oseltamivir, therapeutic effects have been observed against influenza and SARS-CoV-2 in rodents.(13) The IONIC trial is a randomized control trial that will investigate whether time to clinical improvement in COVID 19 patients is improved following a 14 day course of IMU-838 + Oseltamivir versus Oseltamivir alone. Methods: IONIC trial is an open label study in which participants will be randomised 1:1 in two parallel arms; the intervention arm (IMU-838 + Oseltamivir) and control arm (Oseltamivir only). The primary outcome is time-to-clinical improvement; defined as the time from randomisation to: a 2-point improvement on WHO ordinal scale; discharge from hospital, or death (whichever occurs first). The study is sponsored by UHCW NHS Trust and funded by LifeArc. Discussion: The IONIC Protocol describes an overarching trial design to provide reliable evidence on the efficacy of IMU-838 (vidofludimus calcium) when delivered in combination with an antiviral therapy (Oseltamivir) [IONIC Intervention] for confirmed or suspected COVID-19 infection in adult patients receiving usual standard of care. Trial Registration: The trial was registered with EudraCT (2020-001805-21) on 09.04.2020 and ISRCTN on 23.09.2020 (ISRCTN53038326) and Clinicaltrials.gov on 17.08.2020 (NCT04516915) Strengths and Limitations: This study is the first to recruit participants in the trial exploring the effectiveness of IMU-838 in COVID-19. In addition, we believe it is the only trial exploring the effectiveness of IMU-838 in combination with Oseltamivir (Tamiflu) in patients with moderate to severe COVID-19. However, to make the trial design flexible due to the on-going pandemic the trial is un-blinded.

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 AGILE: a seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment: an update to the structured summary of a study protocol for a randomised platform trial letter

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Gareth O. Griffiths ◽  
Richard FitzGerald ◽  
Thomas Jaki ◽  
Andrea Corkhill ◽  
Helen Reynolds ◽  
...  
Keyword(s):  
Phase I ◽  
Early Stage ◽  
Late Phase ◽  
Optimum Dose ◽  
Open Label ◽  
Link Type ◽  
Hospitalised Patients ◽  
Volunteer Study ◽  
The Uk ◽  
Phase Trial

Abstract Background There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. Methods/design AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. Discussion Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. Trial registration EudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183 19 February 2021 ISRCTN reference: 27106947

scholarly journals COVIDENZA - A prospective, multicenter, randomized PHASE II clinical trial of enzalutamide treatment to decrease the morbidity in patients with Corona virus disease 2019 (COVID-19): a structured summary of a study protocol for a randomised controlled trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Karin Welén ◽  
Anna K Överby ◽  
Clas Ahlm ◽  
Eva Freyhult ◽  
David Robinsson ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Virus Disease ◽  
Controlled Trial ◽  
Scale Up ◽  
Standard Of Care ◽  
University Hospital ◽  
Ordinal Scale ◽  
Open Label ◽  
Full Protocol ◽  
Exploration Phase

Abstract Objectives The main goal of the COVIDENZA trial is to evaluate if inhibition of testosterone signalling by enzalutamide can improve the outcome of patients hospitalised for COVID-19. The hypothesis is based on the observation that the majority of patients in need of intensive care are male, and the connection between androgen receptor signalling and expression of TMPRSS2, an enzyme important for SARS-CoV-2 host cell internalization. Trial design Hospitalised COVID-19 patients will be randomised (2:1) to enzalutamide plus standard of care vs. standard of care designed to identify superiority. Participants Included participants, men or women above 50 years of age, must be hospitalised for PCR confirmed COVID-19 symptoms and not in need of immediate mechanical ventilation. Major exclusion criteria are breast-feeding or pregnant women, hormonal treatment for prostate or breast cancer, treatment with immunosuppressive drugs, current symptomatic unstable cardiovascular disease (see Additional file 1 for further details). The trial is registered at Umeå University Hospital, Region Västerbotten, Sweden and 8 hospitals are approved for inclusion in Sweden. Intervention and comparator Patients randomised to the treatment arm will be treated orally with 160 mg (4x40 mg) enzalutamide (Xtandi®) daily, for five consecutive days. The study is not placebo controlled. The comparator is standard of care treatment for patients hospitalised with COVID-19. Main outcomes The primary endpoints of the study are (time to) need of mechanical ventilation or discharge from hospital as assessed by a clinical 7-point ordinal scale (up to 30 days after inclusion). Randomisation Randomisation was stratified by center and sex. Each strata was randomized separately with block size six with a 2:1 allocation ratio (enzalutamide + “standard of care”: “standard of care”). The randomisation list, with consecutive subject numbers, was generated by an independent statistician using the PROC PLAN procedure of SAS version 9.4 software (SAS Institute, Inc, Cary, North Carolina) Blinding (masking) This is an open-label trial. Numbers to be randomised (sample size) The trial is designed to have three phases. The first, an exploration phase of 45 participants (30 treatment and 15 control) will focus on safety and includes a more extensive laboratory assessment as well as more frequent safety evaluation. The second prolongation phase, includes the first 100 participants followed by an interim analysis to define the power of the study. The third phase is the continuation of the study up to maximum 600 participants included in total. Trial Status The current protocol version is COVIDENZA v2.0 as of September 10, 2020. Recruitment started July 29, 2020 and is presently in safety pause after the first exploration phase. Recruitment is anticipated to be complete by 31 December 2021. Trial registration Eudract number 2020-002027-10 ClinicalTrials.gov Identifier: NCT04475601, registered June 8, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

scholarly journals Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults

BMJ Open ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. e041437
Author(s):  
Florence Ader
Keyword(s):  
Controlled Trial ◽  
Clinical Status ◽  
Antiviral Agents ◽  
Randomised Trial ◽  
Phase Iii ◽  
Ordinal Scale ◽  
Control Group ◽  
National Agency ◽  
Open Label ◽  
Hospitalised Patients

IntroductionTo find effective and safe treatments for COVID-19, the WHO recommended to systemically evaluate experimental therapeutics in collaborative randomised clinical trials. As COVID-19 was spreading in Europe, the French national institute for Health and Medical Research (Inserm) established a transdisciplinary team to develop a multi-arm randomised controlled trial named DisCoVeRy. The objective of the trial is to evaluate the clinical efficacy and safety of different investigational re-purposed therapeutics relative to Standard of Care (SoC) in patients hospitalised with COVID-19.Methods and analysisDisCoVeRy is a phase III, open-label, adaptive, controlled, multicentre clinical trial in which hospitalised patients with COVID-19 in need of oxygen therapy are randomised between five arms: (1) a control group managed with SoC and four therapeutic arms with re-purposed antiviral agents: (2) remdesivir + SoC, (3) lopinavir/ritonavir + SoC, (4) lopinavir/ritonavir associated with interferon (IFN)-β−1a + SoC and (5) hydroxychloroquine + SoC. The primary endpoint is the clinical status at Day 15 on the 7-point ordinal scale of the WHO Master Protocol (V.3.0, 3 March 2020). This trial involves patients hospitalised in conventional departments or intensive care units both from academic or non-academic hospitals throughout Europe. A sample size of 3100 patients (620 patients per arm) is targeted. This trial has begun on 22 March 2020. Since 5 April 2020, DisCoVeRy has been an add-on trial of the Solidarity consortium of trials conducted by the WHO in Europe and worldwide. On 8 June 2020, 754 patients have been included.Ethics and disseminationInserm is the sponsor of DisCoVeRy. Ethical approval has been obtained from the institutional review board on 13 March 2020 (20.03.06.51744) and from the French National Agency for Medicines and Health Products (ANSM) on 9 March 2020. Results will be submitted for publication in peer-reviewed journals.Trial registration numberNCT04315948 Eudra-CT 2020-000936-23.

scholarly journals Safety and Efficacy of Tofacitinib, an Oral Janus Kinase Inhibitor, for the Treatment of Rheumatoid Arthritis in Open-label, Longterm Extension Studies

2014 ◽  
Vol 41 (5) ◽  
pp. 837-852 ◽  
Author(s):  
Jürgen Wollenhaupt ◽  
Joel Silverfield ◽  
Eun Bong Lee ◽  
Jeffrey R. Curtis ◽  
Susan P. Wood ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Incidence Rate ◽  
Kinase Inhibitor ◽  
Safety Data ◽  
Janus Kinase ◽  
Upper Respiratory Tract ◽  
Open Label ◽  
Safety And Efficacy ◽  
Mean Values ◽  
Link Type

Objective.To describe the longterm safety and efficacy profile of tofacitinib in patients with moderate to severe active rheumatoid arthritis (RA).Methods.Data were pooled from 2 open-label studies (NCT00413699, NCT00661661) involving patients who had participated in qualifying phase I, II, or III index studies of tofacitinib. Safety data included over 60 months of observation; efficacy data are reported up to Month 48. Treatment was initiated with tofacitinib 5 or 10 mg twice daily. Primary endpoints were adverse events (AE) and laboratory safety data. Secondary endpoints included American College of Rheumatology (ACR) response rates, and Disease Activity Score (28 joints) (DAS28)-4[erythrocyte sedimentation rate (ESR)] and Health Assessment Questionnaire-Disability Index (HAQ-DI) assessments.Results.Overall, 4102 patients were treated for 5963 patient-years; mean (maximum) treatment duration was 531 (1844) days; 20.8% of patients discontinued treatment over 60 months. The most common AE were nasopharyngitis (12.7%) and upper respiratory tract infection (10.5%). Serious AE were reported in 15.4% of patients with an exposure-estimated incidence rate of 11.1 events/100 patient-years. Serious infections were reported in 4.5% of patients with an exposure-estimated incidence rate of 3.1 events/100 patient-years (95% CI: 2.66–3.55). Mean values for laboratory variables were stable over time and consistent with phase II and III studies. Persistent efficacy was demonstrated through Month 48, as measured by ACR response rate (ACR20/50/70) DAS28-4-ESR, and HAQ-DI. Safety and efficacy were similar for patients receiving tofacitinib as monotherapy or with background nonbiologic disease-modifying antirheumatic drugs.Conclusion.Tofacitinib demonstrated consistent safety and persistent efficacy over 48 months in patients with RA.

A phase Ib/II, open-label, platform study evaluating the efficacy and safety of AB928-based treatment combinations in participants with metastatic castrate-resistant prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS272-TPS272
Author(s):  
David R. Wise ◽  
Olivia Gardner ◽  
Houston N. Gilbert ◽  
Aimee Rieger ◽  
Melissa Constance Paoloni ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Molecule ◽  
Single Agent ◽  
Specific Antigen ◽  
Standard Of Care ◽  
The United States ◽  
Experimental Therapy ◽  
Efficacy And Safety ◽  
Open Label ◽  
Castrate Resistant

TPS272 Background: The tumor microenvironment contains high levels of immunosuppressive adenosine, which binds to and activates the A2a and A2b receptors (R) on immune cells, resulting in an ineffective anti-tumor immune response. Extracellular adenosine is primarily produced by the enzyme CD73. In prostate cancer (PC), the activity of prostatic acid phosphatase produces additional adenosine. AB928 is the first clinical-stage small molecule dual antagonist of both A2aR and A2bR, which is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Targeting the adenosine pathway in combination with standard of care regimens may have a more profound effect on activating and inducing sustained anti-tumor immunity. Methods: This Phase 1b/2, open-label, multi-cohort platform study will evaluate the efficacy and safety of AB928 combination therapy in participants with metastatic castrate resistant PC (mCRPC). Each cohort will independently assess AB928 plus AB122 (anti-PD-1 antibody) in combination with standard of care (SOC; enzalutamide, docetaxel) or AB928 plus AB680 (CD73 inhibitor) with or without AB122. Cohort eligibility is informed by prior treatment history. In Ph1b, up to 15 participants will receive investigational products at the single-agent recommended dose with SOC per label guidance. Provided safety and activity stopping criteria are not met, further accrual will proceed in Ph2 and, depending on treatment cohort, may involve randomization to enzalutamide or docetaxel; crossover to experimental therapy will be allowed following progression on control treatment. Investigator-assessed antitumor response (radiologic, prostate specific antigen) will follow PCWG3 criteria. Conclusions: This Ph1b/2 study is the first to target the adenosine axis using a dual A2aR/A2bR antagonist (AB928) together with a small molecule CD73 inhibitor (AB680), anti-PD-1 antibody (AB122), and SOC for mCRPC. Study enrollment is proceeding in the United States; results will be shared in upcoming scientific conferences.

scholarly journals 1042. Safety of Investigational Microbiota-Based Live Biotherapeutic RBX2660 in Individuals with Recurrent Clostridioides difficile Infection: Data from Five Prospective Clinical Studies

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S611-S611
Author(s):  
Tricia Braun ◽  
Beth Guthmueller ◽  
Adam J Harvey
Keyword(s):  
Clinical Studies ◽  
Ad Hoc ◽  
Safety Data ◽  
Standard Of Care ◽  
Oral Antibiotic ◽  
Open Label ◽  
Two Phase ◽  
Oral Antibiotic Therapy ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

Abstract Background Microbiota-based treatments have shown promise to reduce recurrence, morbidity, and mortality for recurrent Clostridioides difficile infections (rCDI), but consistent and reliable safety data are needed to support regulatory approvals and broaden patient access. Here we provide cumulative safety data from 5 prospective clinical studies evaluating RBX2660—a standardized, microbiota-based investigational live biotherapeutic—for reducing rCDI. Methods This analysis included three Phase 2 (PUNCH CD, PUNCH CD2, PUNCH CD Open Label) and two Phase 3 trials (PUNCH CD3, PUNCH CD3-OLS ad hoc analysis). Participants were ≥18 years old with documented rCDI who completed standard-of-care oral antibiotic therapy prior to treatment with RBX2660. PUNCH CD3-OLS allowed participants with comorbidities of irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). Depending on the trial, assigned study treatment was 1 or 2 doses of RBX2660 (or placebo), administered rectally. Participants whose CDI recurred within 8 weeks were eligible for additional RBX2660 treatment. Treatment-emergent adverse events (TEAEs) were recorded for at least 6 months following last study treatment; CD2 and CD Open Label recorded TEAEs for 24 months. Results Among 620 participants who received at least one RBX2660 dose (assigned treatment or after recurrence), 324 (52.3%) received 1, 270 (43.5%) received 2, 14 (2.3%) received 3, and 12 (1.9%) received 4. 83 participants received blinded placebo only. A total of 1980 TEAEs were reported from 432 (69.7%) RBX2660-treated participants, compared to 174 TEAEs in 50 (60.2%) placebo-only treated participants. Most TEAEs were mild or moderate in severity, with diarrhea common in all treatment groups. No potentially life-threatening TEAEs were considered related to RBX2660. Study discontinuation due to TEAEs was minimal (< 1%) with none related to RBX2660. There were no reported infections for which the causative pathogen was traced to RBX2660. Conclusion Across five clinical studies with consistent investigational product, RBX2660 was well-tolerated in rCDI participants. In aggregate, this data provides compelling and consistent safety data for RBX2660. Disclosures Tricia Braun, PharmD, Rebiotix, a Ferring Company (Employee) Beth Guthmueller, AS, Rebiotix Inc, A Ferring Company (Employee) Adam J. Harvey, PhD, Rebiotix, A Ferring Company (Employee)

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.

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