̽��ֱ�� of Cambridge - Cambridge Clinical Trials Unit

Training a new breed of clinical triallist

skbf2 — Thu, 03 Feb 2022 11:48:27 +0000

Cambridge's Experimental Medicine Initiative, working with AstraZeneca and GSK, is training specialists who can work out at an earlier stage of clinical trials if a treatment is likely to succeed.

Combining PCR and antibody tests at point of care dramatically increases COVID-19 detection in hospitalised patients

cjb250 — Wed, 02 Sep 2020 08:02:01 +0000

Point-of-care testing – in other words, testing patients as soon as they arrive at the hospital – is essential for enabling healthcare workers to rapidly diagnose patients and direct those who test positive for infection to dedicated wards. A recent study showed that SAMBA II, a new point-of-care PCR test for SARS-CoV-2 developed by Cambridge researchers, was able to dramatically reduce time spent on COVID-19 ‘holding’ wards – allowing patients to be treated or discharged far quicker than with current lab testing set-ups.

PCR tests involve extracting a miniscule amount of RNA from the virus and copying it millions of times, creating an amount large enough to confirm presence of the virus. ̽��ֱ��virus is captured through a swab inside the nostrils and at the back of the throat. However, it can take as long as 14 days for an individual to show symptoms of COVID-19, by which time the virus may have moved away from the nose and throat and into the lungs and other tissues and organs, making it harder to detect via a swab test. As a result, studies have shown that PCR tests can miss as many as a half of infected patients five days after infection.

Antibody tests provide an alternative way of identifying infected individuals, but antibodies – molecules produced by our immune system in response to infection – generally do not appear until at least six days after infection.

Professor Ravi Gupta from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the ̽��ֱ�� of Cambridge said: “We still do not have a gold standard test for diagnosing COVID-19. This poses a challenge to healthcare workers who need to make quick and safe decisions about how and where to treat patients.

“ ̽��ֱ��two main types of test – PCR and antibody tests – both have limitations because of the nature of coronavirus infection and how our body responds. But we’ve shown that if you combine them and carry out both at point of care, their reliability can be hugely increased.”

Professor Gupta led a team that used the approach of combining rapid point-of-care PCR and antibody tests to diagnose 45 patients at Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust. ̽��ֱ��results of this peer-reviewed study are published in Cell Reports Medicine.

̽��ֱ��patients, each of whom had suspected moderate to severe COVID-19 disease, provided nose/throat swabs for the tests detecting nucleic acid (virus genetic material) and blood serum for antibody testing an average (median) of seven days after the onset of illness.

̽��ֱ��authors designed a gold standard reference test made of two parts, either of which could be positive to confirm COVID-19. ̽��ֱ��first part was an in vitro test where artificial SARS-CoV-2 viruses were made and mixed with serum from patients to see whether the serum contained neutralising antibodies. ̽��ֱ��second part of the gold standard was the standard Public Health England laboratory test looking for genetic viral material in nose/throat swabs. Using this gold standard, 24 of the patients had COVID-19.

Professor Gupta’s team used SAMBA II machines, developed by Cambridge spinout company Diagnostics for the Real World, for the nucleic acid tests, and a combination of two finger prick antibody tests, both of which test for antibodies against the spike protein on the surface of the SARS-CoV-2 virus.

Overall, the nucleic acid tests could identify eight out of ten patients with COVID-19, but when combined with the rapid antibody tests, 100% of the COVID-19 patients were correctly identified. Among the 21 patients who did not have COVID-19, there were four false positive results with one antibody test and only one false positive with the second antibody test, demonstrating that one performed better than the other.

“Combining point-of-care PCR and antibody testing could be a game-changer for rapidly identifying those patients with moderate to severe COVID-19 infection,” said Professor Gupta. “This could prove extremely useful, particularly in the event of a second wave arising during flu season, when it will not be immediately clear whether the patients had COVID-19 or seasonal flu.”

Professor Gupta envisages that hospitals deploying this approach would carry out a finger prick blood test and nose/throat swab at the same time on admission to hospital. ̽��ֱ��antibody test result is available within 15 minutes, but might benefit from confirmation with a second point-of-care antibody test. Importantly the study showed that the antibody tests can detect antibodies against a mutated form of SARS-CoV-2, D614G in spike protein, that has now become the dominant strain worldwide.

This approach could be particularly beneficial in low resource settings where centralised virology laboratories are scarce and the pandemic is expanding, said Professor Gupta. In addition, it removes the need for repeated nose/throat swabbing when the first test is negative and suspicion of COVID-19 is high, which may generate aerosols and lead to transmission.

̽��ֱ��research was mainly funded by Wellcome and supported by the National Institute for Health Research Cambridge Biomedical Research Centre and the Cambridge Clinical Trials Unit.

Reference
Micochova, P et al. Combined point of care SARS-CoV-2 nucleic acid and antibody testing in suspected moderate to severe COVID-19 disease. Cell Reports Medicine; 1 Sept 2020; DOI: 10.1016/j.xcrm.2020.100099

A Cambridge hospital has piloted the use of combined rapid point-of-care nucleic acid and antibody testing for SARS-CoV-2 infection after researchers at the ̽��ֱ�� of Cambridge showed that this approach was superior to virus detection alone for diagnosing COVID-19 disease.

PCR and antibody tests both have limitations because of the nature of coronavirus infection and how our body responds. But we’ve shown that if you combine them and carry out both at point of care, their reliability can be hugely increased

Ravi Gupta

U.S. Pacific Fleet

Man taking COVID-19 test

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National trial launched to test re-purposing existing drugs to treat COVID-19 patients

cjb250 — Wed, 20 May 2020 10:59:02 +0000

A new trial to prevent organ failure and death in COVID-19 patients has been launched, led by clinicians and scientists in Cambridge and London.

TACTIC, as the trial is known, will test whether re-purposing existing drugs, which target the body’s own immune response, can prevent people suffering severe organ failure or death. ̽��ֱ��trial is part of the coordinated national approach by the UK Government to support the early phase development of potential new treatments for COVID-19.

For the majority of people with COVID-19, the infection causes only mild symptoms, including a fever and cough. However, around 15% of patients develop severe disease, including serious damage to the lungs and multiple organ failure, and about two percent die.

̽��ֱ��serious symptoms appear to be mostly caused by the body’s own immune system responding to the presence of infected cells and ‘over-reacting’, destroying healthy cells as well as virus-infected ones.

Two drugs will initially be tested through TACTIC on patients at a network of hospitals across the UK, including Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH), Guy’s and St Thomas’ NHS Foundation Trust, and King’s College Hospital.

̽��ֱ��first patient was recruited onto the study at Addenbrooke’s Hospital in Cambridge on Friday 8 May.

̽��ֱ��two drugs, Ravulizumab and Baricitinib, have been carefully selected by a consortium of doctors and scientists with expertise in treating immune-response diseases. They are both thought to have a high chance of reducing the sometimes fatal over-reaction of the immune system seen in very sick patients with COVID-19.

This study is one of a number of COVID-19 studies that have been given urgent public health research status by the Department of Health and Social Care. It is supported by the National Institute for Health Research (NIHR) Biomedical Research Centres at Cambridge and Guy’s and St Thomas’ and UK Research and Innovation; the drug manufacturers , Lilly and Alexion, have each supplied the drug for up to 469 subjects as well as contributing up to £200,000 in running costs for the project.

If the trial demonstrates that a drug is effective, it will be quickly moved into NHS care pathways, to treat the patients with severe COVID-19 related disease. Similarly, if the trial reveals that a drug is not effective, it can be quickly removed so that other options can be tested.

UK Research and Innovation Chief Executive, Professor Sir Mark Walport, said: “By supporting the rapid progress of these re-purposed drugs into early clinical trials we will test whether they can prevent the development of severe COVID-19 symptoms. Trialling drugs that have the potential to suppress the severe inflammation caused by an over-reaction of the immune system is an important part of tackling the COVID pandemic.”

Dr Frances Hall, Consultant Rheumatologist, CUH, and TACTIC Chief Investigator, said: “It is striking that the severe COVID-19-related disease is associated with the person’s own immune system causing most of the damage. It seems that, while most people’s immune system attacks the virus appropriately, in those who become really sick, the immune response appears to overreact.

“We have selected the first two drugs for the TACTIC study based on their ability to ‘dial-down’, or block, two distinct types of response, each of which appear important in the immune response which causes damage to lungs and other organs in COVID-19-related disease. Baricitinib acts through the network of cytokines (soluble immune system signals running between cells); it reduces the upscaling of the cytokine response which leads to the “cytokine storm” evident in severe COVID-19-related disease. On the other hand Ravulizumab inhibits the activation of a trigger in a “tag-team” of molecules, called the complement cascade, which serves to rapidly ramp up inflammation and cell killing.”

̽��ֱ��two drugs are used routinely as treatments – Baricitinib in severe rheumatoid arthritis and Ravulizumab in blood diseases where complement activation destroys red blood cells. Dr Hall says there is good reason to believe that either or both of these strategies could help prevent severe organ failure and even death in patients with COVID-19.

Professor Ian Wilkinson, Director of the Cambridge Clinical Trials Unit, and Professor of Therapeutics at the ̽��ֱ�� of Cambridge, said: "This is a time of huge national effort in the fight against COVID-19 and I am delighted that Cambridge is playing a key role in this. TACTIC will test the effectiveness of a number of existing and new drugs in patients admitted to hospital, in a similar way to the RECOVERY trial, but with a strong focus on modulating the immune response and collecting high quality data that can be used by our partner pharmaceutical companies to seek the necessary approvals for widespread international use.”

Dr James Galloway, Senior Lecturer in Rheumatology at King’s College London, and a Co-Investigator on the TACTIC trial, said: “By testing existing drugs that we think have the best chance of working against COVID-19, we hope that we can find proven ways to treat the disease. Identifying the high risk patients taking part in this research will be key, and we’re incredibly grateful to the patients who have been so willing to take part, and their families.”

Dr Hall is a Fellow in Medical and Veterinary Science at Sidney Sussex College. Professor Wilkinson is a Fellow in Clinical Medicine at Trinity Hall.

Adapted from a press release from Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust

A new trial to prevent organ failure and death in COVID-19 patients has been launched led by clinicians and scientists in Cambridge and London.

This is a time of huge national effort in the fight against COVID-19 and I am delighted that Cambridge is playing a key role

Ian Wilkinson

Matryx

Coronavirus

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Drugs: how to pick a winner in clinical trials

lw355 — Mon, 26 Jun 2017 11:00:12 +0000

“Did not meet primary endpoint.”

Prosaic words, but they can mean a billion dollar failure has just happened.

̽��ֱ��average cost of taking a scientific discovery all the way through to a drug on a shelf is enormous – last year it was estimated at $2.6 billion by the Tufts Center for the Study of Drug Development.

One reason the figure is so high is because it also includes the cost of failure. Recent years have seen some very high-profile failures of drug candidates that either did not meet the ‘primary endpoint’ (they didn’t work) or had their trials halted owing to serious side effects.

“It’s only natural that some drugs will fail in clinical trials – the process exists to ensure that treatments are safe and effective for patients,” says Professor Ian Wilkinson, Director of the Cambridge Clinical Trials Unit (CCTU) on the Cambridge Biomedical Campus. “But what’s unexpected is the high number of drugs that fail in phase III. You’d think that by this stage the molecule would be a sufficiently good candidate to make it through.”

He explains that failures in phases I and II – when the drug is tested for safety and dosage in healthy volunteers and patients – are inevitable. However, a great many molecules don’t make it through phase III, the stage at which the drug’s effectiveness is tested in large numbers of patients before regulatory approval is given. In fact only 10–20% of drugs that enter phase I are ultimately licensed.

“ ̽��ֱ��problem with failing at phase III is it’s very expensive – a single drug trial can cost around $500m.”

He continues: “There’s a human impact for the thousands of patients who enrolled on the trial. For patients with cancer, it’s sometimes their last available treatment option,” says Wilkinson. “It’s also really unhelpful economically. Pharma companies have less money to put back into R&D, and it becomes even harder to fund drug development.”

This is why Wilkinson, along with a team of clinicians, scientists and pharmaceutical collaborators, together with statisticians at the Medical Research Council Biostatistics Unit, has been taking a hard look at the early phases of clinical trials. Their aim is to ask what can be done to get an early indication that a potential drug will make it to market.

“Traditionally, clinical trials have been organised to test safety first and efficacy last,” he explains. “It’s a cautious step-by-step approach adopted to ensure that pharma companies can satisfy regulators that the drug is safe.

“For many drugs this has worked well. But we are in a landscape where drug targets are more challenging – think for instance of conditions like psychiatric disorders and dementia. Leaving questions of whether a drug is effective to the final stages is now too risky and expensive.”

On any one day, the CCTU (one of the UK units accredited by the National Institute for Health Research) might be coordinating up to 20 trials in various phases for potential treatments for cancer, stroke, infections, dementia, heart attack, and so on.

Many of the trials are now designed with what Wilkinson calls “added value” built in at very early stages to give indications of whether the drug might work. This could include a biomarker that shows a drug for cirrhosis is reaching the liver, or a drug for heart disease is lowering cholesterol. “These are read-outs. They don’t show the drug works for the disease, but if the results are negative then there’s no point in progressing to later stages.”

̽��ֱ��trials are also run ‘adaptively’. “We look at data for each person as it comes in… once we have enough information to guide us, we make a decision that might change the trial. It’s a quite different approach to the traditional rigidity of trials. It maximises the value of information a trial can yield.”

In recent years, pharmaceutical companies like GSK and AstraZeneca (AZ) have championed the need for rigorous trial design to weed out likely failures earlier in the process.

GSK has its only trials unit in the UK in the same building as the CCTU. There, GSK researchers work alongside Cambridge clinicians and scientists on first-in-man studies. A more targeted approach to testing medicines in patients is a key component of a Strategic Partnership between GSK, the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH), which has the long-term ambition of jointly delivering new medicines to patients in the next five to ten years.

A few years ago, AZ analysed its drug pipeline before embarking on a major revision of its R&D strategy to increase the chance of successful transition to phase III and beyond. One area AZ identified as being crucial to success is to identify a causal relationship between target and disease. This might seem obvious but so-called mistaken causation has led to late failures right across the drugs industry. ̽��ֱ��usual cause is confounding – where a factor that does not itself cause a disease is associated with factors that do increase disease risk.

Professor John Danesh and colleagues at the Department of Public Health and Primary Care have pioneered a new way of finding evidence for causality before a patient is ever involved. Called ‘Mendelian randomisation’, it’s akin to a trial carried out by nature itself.

“Misinterpreting correlation as causation is a big problem,” explains Dr James Peters, who works with Danesh. “An increase in a protein biomarker in patients with atherosclerosis might suggest it’s important in the disease, but it’s not a valid drug target unless it plays a causal role. ̽��ֱ��conventional way to test this is to block the protein with a drug in a clinical trial, which is expensive, time-consuming and not always ethical.

“In phase III trials, the randomisation of participants helps to average out all differences apart from whether they are receiving the drug. Instead, we take advantage of the natural randomisation of genetic variants that occurs during reproduction.”

Some genetic variants can increase or decrease certain proteins that have been linked to a disease. If these variants can be identified – by computationally analysing enormous genetic datasets – then researchers can compare groups of people to see whether having the variant also increases the risk of a disease.

̽��ֱ��team has used this method to look retrospectively at why two phase III trials for a potential cardiovascular drug failed. “ ̽��ֱ��genetic evidence showed that the drug target was not valid,” says Peters. “We would have advised against taking this drug to a clinical trial.”

But it’s not just about predicting failures, Danesh’s team is picking winners. Evidence for the role of an inflammatory protein in atherosclerosis has now resulted in a clinical trial to see if an arthritis drug can be repurposed for atherosclerosis.

̽��ֱ��researchers are helping industrial collaborators to prioritise potential drug targets and predict side effects. They also hope to expand their capabilities to test large numbers of variants for different potential targets in an automated fashion – a high-throughput approach to therapeutic target prioritisation.

Meanwhile, Wilkinson is planning ahead to avoid a different type of limitation: expertise. “There is a lack of individuals trained to design and deliver innovative clinical trials, and this is now impacting on drug development,” he explains.

Last year, an Experimental Medicine Training Initiative was launched to train medics how to run innovative clinical trials. Wilkinson is its Director and it’s supported by the ̽��ֱ�� in partnership with CUH, Cambridge Biomedical Research Centre, and AZ/MedImmune and GSK.

“We all believe that the failure rate for drug candidates making it through phase III is unacceptably high,” he says. “Less than one in a thousand molecules discovered in the lab make it through to being a drug. We want to be sure that we can answer the billion dollar question of which are most likely to be winners.”

Read more about research on future therapeutics in Research Horizons magazine.

When a drug fails late on in clinical trials it’s a major setback for launching new medicines. It can cost millions, even billions, of research and development funds. Now, an ‘adaptive’ approach to clinical trials and a genetic tool for predicting success are increasing the odds of picking a winner.

We all believe that the failure rate for drug candidates making it through phase III is unacceptably high. We want to be sure that we can answer the billion dollar question of which are most likely to be winners.

Ian Wilkinson

Gatis Gribusts

Medication

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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