COMBACTE-NET

IMI's COMBACTE projects are the foundation of ECRAID, a network to support the full range of clinical research into new antimicrobial agents. ###

As it currently stands, clinical studies of new antimicrobial drugs have to be set up from scratch, leading to wasted time and resources. Now a new entity called ECRAID has been set up to be able to quickly and efficiently launch and carry out clinical trials of potential new antibiotics. The new entity will provide the full breadth of clinical studies on infectious diseases, from observational and interventional studies to prevention, treatment, diagnostics, screening, epidemiological, quality of life, and health economics research. It will also support phase one to phase four clinical trials.

ECRAID is an outgrowth of IMI's COMBACTE projects and the EU-funded PREPARE programme. COMBACTE is part of the IMI-funded programme ND4BB (New Drugs for Bad Bugs) progreamme and focuses on improving the clinical development of antibiotics. COMBACTE has been building a high-quality clinical and laboratory research network for new options to treat or prevent bacterial infections in the EU and affiliated countries.

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Launched in 2014, the COMBACTE project’s CLIN-Net and LAB-Net network provides strong infrastructure to run clinical trials of new antimicrobial agents across multiple sites, and is the only one of its kind in the world, putting Europe in a leadership position in clinical research into infectious diseases.###

The network was quickly put to use, allowing pharma partners in the project to test novel antibacterials faster, more effectively and more economically. As additional support, EPI-Net was established to meet the need for a comprehensive source of published data related to the epidemiological aspects of AMR.

Although CLIN-Net and LAB-Net were originally conceived to respond to the threat of AMR, they were involved in the PREPARE project, which focuses rapid scientific response to infectious disease threats. When COVID-19 emerged, the network was immediately used for finding suitable clinical sites in hospitals and primary care for COVID-19-related studies.

Looking to the future, the networks built under COMBACTE will gradually become a new entity called the European Clinical Research Alliance for Infectious Diseases (ECRAID). It will be a separate legal entity led by the key players of the COMBACTE networks, among others.

ECRAID will set up several perpetual observational studies (POS). The disease areas for which POSs are currently being established are infections picked up via ventilation in intensive care, as well as complicated urinary tract infections and yeast infections in new-borns, among others.

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The US Food and Drug Administration (FDA) has granted ‘fast track designation’ to Da Volterra’s DAV132 for the prevention of Clostridioides difficile infection (CDI). The FDA fast track designation is intended to speed up the review of drug candidates for treating or preventing serious conditions. ###

DAV132 is a first-in-class microbiome protector designed to inactivate antibiotics that are circulating in the colon and disrupting the gut microbiome. It is destined for use in patients for whom microbiome disruption can be life-threatening, such as those with cancer. The product was developed by French SME Da Volterra, which is a partner in IMI’s COMBACTE-NET project.

As part of COMBACTE-NET, Da Volterra is about to launch an international phase 3 clinical trial called MICROCARE to evaluate DAV132 in patients with haematologic malignancies. MICROCARE will assess the efficacy of DAV132 in protecting intestinal microbiome diversity, preventing intestinal colonisation with potentially pathogenic bacteria, preventing bloodstream infections, and improving overall survival.

It will build on the results of ANTICIPATE, a multi-centre, prospective, observational study conducted within COMBACTE-NET to identify microbial factors predictive of CDI, the results of which were published recently in Nature Communications.

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COMBACTE-NET partner Da Volterra has been given a green light to move forward with a phase 3 trial of an innovative product to protect the microbiome of cancer patients from antibiotic-induced disruption.###

The microbiome of cancer patients is constantly assaulted by numerous prescribed drugs, in particular life-saving antibiotics. The consequences of this include a higher risk of picking up infections, lower efficacy of anti-cancer treatments, and even potentially lower survival due to interference with the immune system. There is now hope for change.

In a world first, French biotech Da Volterra, a partner in the COMBACTE-NET project, has been granted authorisation to proceed to phase 3 trial to get evidence on the efficacy and safety of its product, DAV132, in patients with hematologic malignancies (cancers of the blood, bone marrow and lymph nodes). The product, they claim, will protect the microbiome of these patients in spite of massive antibiotic use.

The MICROCARE study will enrol 900 patients mainly in Europe and the USA. The objective is to show that DAV132 contributes to decreasing the occurrence of life-threatening complications of hematologic malignancies in people who are undergoing chemotherapy.

The study is a major milestone. It is a testament to the capacity of the quality clinical and laboratory research network set up by COMBACTE-NET and its ability to successfully conduct the first-ever phase 3 study of the project, thus facilitating market access of novel products to combat life-threatening conditions and antimicrobial resistance (AMR).

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A study of potential coronavirus treatments, announced in March by the French national institute of health and medical research (INSERM), is receiving support from an IMI-funded network of clinical trial sites and laboratories. The INSERM coordinators contacted the team behind the IMI-funded COMBACTE-NET project to help recruit patients with COVID-19 and coordinate the clinical sites involved in the multicentre, multi-country study.### DisCoVery is a large, international, open randomised trial studying a number of drugs that could prove effective against SARS-CoV-2, the virus that causes COVID-19.

‘These are drugs that in the lab in vitro and in animal models have an effect on the virus, but we don't know whether that effect can also be reproduced in the patient,’ says Marc Bonten from University Medical Centre Utrecht and academic leader for COMBACTE-NET. ‘What (INSERM) needed was to be able to identify the sites that could move rapidly because this is a race against the clock. We were able to identify in our network the sites that we think can manage this problem of having this set up in in a few weeks’ time.’

COMBACTE-NET will also contribute to the new H2020 project RECOVER; COMBACTE-NET’s established clinical and laboratory networks will be used to study disease spectrum and severity, risk factors, spread and outcomes of COVID-19 in patients in hospital care.

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• The article in full
• Press release: Launch of a European clinical trial against COVID-19
• COMBACTE-NET website

This month IMI announced a new funding Call in reaction to the spread of COVID-19. The process is being fast-tracked, just like the call for Ebola projects in 2014. However, as IMI Executive Director Pierre Meulien points out in a new opinion piece published on the IMI website, there’s nothing unexpected about the emergence of these epidemics.###

‘Every year, viruses jump from animals to the human population, including certain strains of influenza,’ he writes. ‘The closer we live to animals, the more of these ‘jumps’ we’re going to see.’

The scientific community needs to get ready to respond regardless of where the next virus comes from. In that respect, two ongoing IMI projects now look particularly prescient: the ZAPI project was set up to deliver a platform and technologies to facilitate a rapid response to future disease outbreaks. In 2019, the project demonstrated that certain antibodies can stop the MERS coronavirus from infecting new cells, and they’re now assessing whether the antibodies could also be effective against SARS-CoV-2, the virus that causes COVID-19. COMBACTE-NET, part of the antimicrobial resistance programme, has set up a network of clinical and laboratory sites across Europe that has been mobilised to support global efforts to standardise the information gathered from patients with suspected or confirmed COVID-19.

COVID-19 has put everyone on the alert because there’s so much we don’t know about it. Dr Meulien concludes: ‘In the coming months, the scientific community will no doubt be able to answer more questions about the epidemiology and modes of transmission of the virus, and the story will gradually recede from the headlines. Meanwhile, the projects that will result from the IMI coronavirus call will outlast the news cycle, putting everything in place for the next outbreaks, wherever or however they may emerge.’

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• Read Pierre Meulien’s opinion piece in full

Researchers recently showed that an injection of monoclonal antibodies can be used to decrease the virulence of Staphylococcus aureus bacteria in patients who are hooked up to breathing machines in hospital. The phase II trial was carried out by the IMI project COMBACTE-NET, as part of the SAATELLITE study, using a monoclonal antibody developed by AstraZeneca called Suvratoxumab.###

Patients in intensive care units (ICUs) who are breathing with the help of ventilating machines are at high risk of contracting pneumonia. The S. aureus bacteria make their way into healthy lungs by attaching to the medical tubing that connects to the outside world. S. aureus is extremely virulent and increasingly resistant to antibiotics. The objective of the trial was to see if patients whose lungs are already colonised by S. aureus could avoid pneumonia by being dosed with a one-off shot that would block the bacteria’s virulence, i.e. the potential for infection.  

The results were promising. The researchers enrolled about 200 ventilated ICU patients in a double blind placebo controlled trial. The percentage of people in the placebo arm that contracted pneumonia was 26%, while those who had received the monoclonal antibodies injection was 18%. This is a relative reduction of 31%. Dr Bruno François from the University Hospital of Limoges, who was involved in the SAATELLITE study, is cautiously optimistic about the results.

‘This was the first trial with this type of drug to be used as a preventative,’ says Dr François. ‘This could represent a true opportunity to decrease the number of pneumonia infections in the ICU without needing any antibiotics. Of course it’s only a phase two so you would need a confirmatory trial, but it’s completely innovative.’

Read more

• IMI’s news story
• The COMBACTE-NET project factsheet
• COMBACTE-NET website
• More AMR stories from IMI projects

Researchers from STAT-Net, a group of experts from IMI’s COMBACTE-NET project, have issued a white paper with recommendations for improving the design and analysis of clinical trials of drugs to treat resistant infections. ###In the paper, published in the journal Clinical Infectious Diseases, the team states that the recommendations represent ‘a solid, evidence-based approach to develop new, and established, antibacterials and address this public health challenge’. The clinical development of a new antibacterial is far from easy; for example, using standard clinical trial designs, it is difficult to find enough patients with a resistant infection to adequately assess the safety and efficacy of a new treatment. With this in mind, the COMBACTE-NET team assessed a number of ways of improving the situation, and scored each one on its alignment with regulatory frameworks; its technical feasibility; ease of data interpretation; ease of practical implementation; and the strength of the evidence base for the recommendation. The authors note that not all recommendations will be applicable to all trials, and some score better than others on the different criteria. Nevertheless, they note that ‘they are all relevant to the debate supporting change’. The team concludes: ‘Hopefully, these recommendations and their continued evaluation and evolution will accelerate antibacterial approval and ensure appropriate use of established antibiotics to help those in need as soon and as best as possible.’

Scientists and clinicians have completed the enrolment of 767 people, 213 of whom have been randomised, into the SAATELLITE study of a novel antimicrobial drug, the COMBACTE-NET project has announced. The goal of SAATELLITE is to study the safety, characteristics and efficacy of suvratoxumab (MEDI4893) in patients at high risk of developing ventilator-associated pneumonia in an intensive care unit. Suvratoxumab is an antibody that targets a toxin produced by Staphylococcus aureus, a bacteria which often causes hospital-associated infections and has been linked to resistance issues. In a statement, the project thanked the clinical sites involved in the study, noting: ‘SAATELLITE is the largest pre-emptive approach study to date, and would have been impossible without the hard work at the investigator sites.’

• Find out more about the COMBACTE projects in this video

The Antibacterial Resistance Leadership Group (ARLG) has become the first US consortium to take part in clinical studies run by IMI’s COMBACTE programme on antimicrobial resistance. In a statement, the project described the news as a ‘major milestone’ that ‘clearly demonstrates the benefits of public-private collaboration and international collaboration between COMBACTE and ARLG’. ###The ARLG is joining two studies on treatments design to prevent pneumonia in people in intensive care who require a ventilator to help them breathe. The SAATELLITE study focuses on pneumonia caused by Staphylococcus aureus, while EVADE focuses on infections caused by Pseudomonas aeruginosa. Currently, 15 US sites are slated to participate in the trials; the first, in Detroit, was activated in January. ‘It is becoming increasingly common for hospitalised patients—especially those with weakened immune systems—to develop severe, hard-to-treat bacterial infections,’ said Anthony S. Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID) which is supporting the ARLG’s participation in the studies. ‘These clinical trials […] are part of a global collaborative effort to explore innovative ways to mitigate the threat of antimicrobial resistance.’ Meanwhile COMBACTE-NET coordinator Hasan Jafri of MedImmune said: ‘We believe collaboration with world-renowned experts, such as those within COMBACTE and the ARLG, is one of the best models to advance development in this area, and bring novel and effective anti-infectives to patients.’

The case of a young girl with a life-threatening infection has shed new light on how the body prevents common bacteria from causing serious disease. The research, funded in part by IMI through the COMBACTE-NET project, is published in the prestigious journal Cell. ###Staphylococcus aureus is a common bacterium that can be found on the skin and in the nostrils of most healthy people. However, it can also cause infections and in some cases, these infections can result in serious illness. This case revolves around a young girl who, at the age of three months, was admitted to intensive care with pneumonia and sepsis caused by S. aureus. Fortunately, doctors were able to treat her and she made a full recovery. Nevertheless, her case was puzzling because she did not have any risk factors (e.g. a weakened immune system) for serious S. aureus infection, and no-one else in her family appeared to be affected. A DNA analysis revealed that she had a mutation in a gene that codes for a protein called TIRAP, which plays a key role in the ‘innate’ immune system that develops before we are born and helps the body to identify invaders. However, seven members of her family turned out to share this mutation, yet had no history of falling ill with S. aureus infection. Further research revealed that the family members were protected from infection by their acquired immune defences, which develop after birth and build up over time as and when we are exposed to new bugs. In contrast, the patient’s immune system had not learnt to recognise staphylococcal bacteria, leaving her vulnerable to infection. ‘Her illness likely resulted from failures in both lines of immunity,’ explained the lead author of the paper, Jean-Laurent Casanova of the Howard Hughes Medical Institute. ‘In her family, the second layer of defence compensated for genetic defects in the first. More broadly, it offers insight into how two people with the same infection, and even the same DNA, can have very different illnesses.’

 - Read the press release from the Rockefeller University

Antimicrobial resistance (AMR) project COMBACTE-NET has gained two new partners in the form of French small and medium-sized enterprise (SME) Da Volterra and US-based The Medicines Company. The companies were selected to join the project following an open Call for proposals for antimicrobial agents or approaches that could benefit from COMBACTE-NET’s pan-European clinical and laboratory networks and the expertise of the current partners.### As a result, COMBACTE-NET will now run a study on the incidence of Clostridium difficile infections in hospital patients. This will pave the way for a phase 2/3 clinical trial of Da Volterra’s DAV132 product, which is designed to protect bacteria that live in the gut, but do not cause disease, from the effects of antibiotics. The Medicines Company’s intravenous formulation of minocycline is the subject of another forthcoming trial in COMBACTE-NET. Injected minocycline is one of just a few treatments available for certain multi-drug resistant infections. Finally, the open Call also allowed the project to extend its ongoing SAATELLITE study to Phase 3. SAATELLITE focuses on MEDI4893, which is designed to tackle Staphylococcus aureus infection, which is commonly associated with hospital-acquired infections.

IMI’s COMBACTE project has started work on the ASPIRE-ICU study at a site in the Netherlands. ASPIRE is an epidemiological study of healthcare-associated infections caused by Staphylococcus aureus  and Pseudomonas aeruginosa to determine the incidence of infection in different patient populations and the association between factors such as co-morbidities, colonisation status, relevant biomarkers and infection risk.### Getting the study off the ground required intense collaboration between the COMBACTE partners to obtain ethical approval and to ensure the research team had the necessary training in protocols, procedures and particularly importantly, in specimen sample management. The study has two stages. In stage 1, information from existing intensive care unit (ICU) and surgical surveillance databases will be collected and analysed. In stage 2, ICU and surgical epidemiologic data will be collected from ongoing surveillance which includes collecting bacterial isolates and serum samples for in-depth microbiological and immunological studies. There are plans to launch the study in Spain next and the ASPIRE-ICU study team is working closely together with the regional coordinator there to obtain the required approvals in order to start in late summer 2015. Overall, the ASPIRE-ICU will be initiated in about 30 sites across between 10 to 12 countries. COMBACTE is working to improve clinical trials for antibiotics and is one of the seven projects included in IMI’s New Drugs for Bad Bugs (ND4BB) platform. 

COMBACTE has launched an open call for clinical trial programmes or studies to join the project. The open call aims to identify potential replacement antimicrobial agents or approaches developed by EFPIA companies that could fulfil the overall objectives### of the project i.e. to conduct prospective clinical trials with novel trial designs to deliver safety, pharmacology, and proof of efficacy data for novel agents directed towards treatment, prevention or sequelae of infections due to priority pathogens. COMBACTE is one of the first IMI projects to be launched under the ND4BB programme with the aim of developing a broad European network of fully capable and Good Clinical Practice (GCP) compliant clinical investigation sites associated to microbiological labs to execute clinical trials enabling the registration of novel agents to be used in the treatment of patients with bacterial infections. Following the early termination of development of GSK1322322, the first novel agent to be developed within COMBACTE, there is now opportunity for other clinical trial programmes or studies to join the COMBACTE project. A webinar on the open call is planned - details will be published on the COMBACTE website.

• Deadline for submissions: 29 April 2015 at 19:00 Central European Summer Time (CEST).
• Read the open call protocol and guidelines for submitting proposals
• Download the proposal submission template and evaluation criteria

The first patient has been enrolled into a clinical trial of a novel antibiotic run by IMI’s COMBACTE project. The patient, who is based in Belgium, is the first participant in a Phase II trial of a medicine called MEDI4893,### which is designed to prevent Staphyolococcus aureus pneumonia in intensive care patients who need a machine to help them breathe. S. aureus is a common cause of hospital-associated infections and drug-resistant strains of the bacteria have been identified. MEDI4893, which was developed by pharmaceutical company MedImmune, works by targeting a toxin produced by S. aureus. The enrolment of the first patient in the trial is the result of months of hard work on the part of the project partners, who come from academia and industry and worked closely together to set up the study. ‘An increase in emergence of antimicrobial resistance and a steady decline in the number of novel antimicrobials being developed across industry have significantly limited treatment options for diseases like pneumonia caused by Staphylococcus aureus,’ said MedImmune’s Hasan Jafri, EFPIA Lead for the study.’ Novel biologics under investigation such as MEDI4893 may offer a unique opportunity to help prevent these serious infections without inducing antimicrobial resistance. We believe collaboration with world-renowned experts such as those within COMBACTE is one of the best models to advance development in this area, and supports our commitment to bring novel and effective anti-infectives to patients.’

Read the project’s press release. 

COMBACTE has released a short video on antibiotic resistance (AMR) and how the project is working to fight AMR.

The video explains why COMBACTE is in a unique position to tackle AMR and how it is pioneering new ways of designing and implementing efficient clinical trials for new antibiotics.### COMBACTE is creating a new environment for the clinical development of new antibiotics to fight AMR. By 2020 COMBACTE aims to show that high quality, cost-effective clinical trials characterised by a shorter recruitment period can be a reality.

COMBACTE is the first public-private partnership with pharmaceutical companies in drug development for infectious diseases. With this initiative, Europe takes the lead in tackling the global threat of AMR.

Bacterial infections are becoming more and more resistant to antibiotics. However, only two new classes of antibiotics have been brought to the market in the last three decades. According to the World Health Organization (WHO), AMR is becoming a public health emergency of yet unknown proportions. In the European Union, AMR is responsible for some 25 000 deaths every year.

• Watch the video

IMI’s antimicrobial resistance project COMBACTE will be present at the 24th European Congress of Clinical Microbiology and Infectious Diseases taking place in Barcelona, Spain from 10 to 13 May 2014.### You will have the opportunity to meet and ask questions to the project leaders at the COMBACTE exhibition stand (booth 76). Furthermore, the COMBACTE representatives will present the project and its latest progress during a lunchtime meeting on 11 May from 12.30 to 14.15 at hotel Vincchi Maritimo in Barcelona, 7 minute walk from the ECCMID venue. During the meeting a video that was made to make the project better known and accessible to a wider audience will be launched.

The 24th European Congress of Clinical Microbiology and Infectious Diseases will feature exhibition stands, series of keynote lectures, symposium, educational workshops and meet-the-expert sessions on parallel tracks, covering the entire field of infectious diseases and clinical microbiology.

• For more information on COMBACTE’s participation at the Congress click here or contact the COMBACTE project officer Loes Collé by email or phone +31 (0) 8875 55641.
• Register to attend COMBACTE’s lunchtime meeting here
• Learn more about the Congress, the exhibitors and the event programme.

IMI’s first antimicrobial resistance projects, COMBACTE and TRANSLOCATION, have signed a Memorandum of Understanding (MoU) to facilitate their collaboration. The projects are part of the New Drugs for Bad Bugs (ND4BB) programme.### As such, there was always an understanding that the projects would work together – this MoU simply formalises and sets out the framework for collaboration. Specifically, the MoU covers issues such as data sharing (and confidentiality), communication and coordination, as well as the creation of a shared Ethics Committee. One of the tasks of the TRANSLOCATION project is the creation of an Info Centre that would gather data from all ND4BB projects. With this in mind, the MoU also contains a section devoted to data standards and analysis. Looking to the future, the new ND4BB projects that will be set up in the coming months will also be invited to join the MoU.

Meet COMBACTE at ECCMID!
IMI’s COMBACTE family of antimicrobial resistance projects will have a stand at the exhibition of the 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Vienna, Austria on 22-25 April. ###The project team will be at booth 29 at the exhibition. Partners in the COMBACTE-MAGNET project will also present results from their RESCUING study at the conference. RESCUING gathered observational data on the treatment of some 1 000 patients with complicated urinary tract infections in 8 countries where the prevalence of multidrug-resistant Gram-negative bacteria is seen to be high. That includes Bulgaria, Greece, Hungary, Israel, Italy, Romania, Turkey and Spain. In a blog post on the COMBACTE website, COMBACTE-NET’s Bruno François explains why COMBACTE is going to ECCMID: ‘Since ECCMID is one of the biggest, most important microbiology and infectious diseases congresses, I would say it is really ‘the place to be’ for our project. Without a doubt it also creates more visibility. Next to that, the event itself fits with the purpose of COMBACTE.’
(March 2017)

ND4BB – the story so far, in Nature Reviews Microbiology
IMI’s antimicrobial resistance (AMR) programme New Drugs for Bad Bugs (ND4BB) is the focus of a recent comment piece in Nature Reviews Microbiology by John Rex of AstraZeneca, who is involved in ND4BB. The article explains how ###IMI and other projects around the world are tackling the biggest challenges in antibiotic research and development. For example, TRANSLOCATION is investigating how to transport antibiotics into bacteria, while COMBACTE focuses on the design and implementation of more efficient clinical trials. ENABLE, IMI’s newest AMR project, is creating a drug discovery platform to fast-track the development of promising molecules. The article also highlights IMI project RAPP-ID, which is working on point-of-care tests, as well as a number of US-based initiatives. Looking to the future, the article notes that IMI has a project in development which will investigate new business models and economic strategies to incentivise the development of new antibiotics.
The article concludes: ‘Although the [AMR] crisis is far from resolved, the leadership of the European Commission are to be commended for their far-sighted approach to creating ND4BB and its projects, all of which provide hope that the global community will have access to an adequate pipeline of novel antimicrobial agents with which to address the challenge of AMR.’
(April 2014)