"The MRINZ now has the capability to act autonomously as the trial coordinating centre in New Zealand for large scale pivotal multicentre, multi-national trials in intensive care and respiratory medicine."
"The MRINZ is the most productive independent medical research organisation in New Zealand."
"Despite its relatively small size the MRINZ produces about one peer-reviewed publication every week, which is a remarkable output."
The MRINZ is part of an international collaborative group which has proposed a paradigm shift in the approach to the management of asthma and COPD. It is based on the concept that asthma and COPD represent a continuum of different diseases that share biological mechanisms and present with distinct clinical, pathophysiological and psychosocial features that can be observed and which require individualised treatment. This allows treatments to be targeted to the needs of individual patients on the basis of such clinical characteristics that distinguish a given patient from other patients. This ‘precision medicine’ approach has been adopted in the Asthma Foundation (New Zealand) Adult Asthma Guidelines to be released in 2016.
Comment: Recognition of ‘treatable traits’ will allow an individualised approach to the management of asthma and COPD.
A ‘State of the Art’ review, ‘Risk factors for asthma: Is prevention possible?’ was published in the Lancet. This review presented the stark reality that the prevalence of asthma is increasing globally, yet the causes of the global increase are unknown. Furthermore, none of the intervention strategies to reduce the risk of developing asthma, that have undergone scrutiny in randomised controlled trials, has provided sufficient evidence to lead to their widespread use in clinical practice. In the review it is proposed that it is necessary to ‘think outside of the box’, not only in terms of risk factors that cause asthma, but also the type of novel primary prevention strategies that are developed and the research methods used to provide the evidence base required for their implementation.
Comment: If progress is to be made in developing strategies to reduce asthma risk, it will be necessary to ‘think outside the box’.
Management of high risk asthma
Further analyses were undertaken of the huge database from our study of the SMART regimen, (the Single combination budesonide/ formoterol inhaler as Maintenance And Reliever Therapy), published in the Lancet Respiratory Medicine. These analyses, funded by the Health Research Council of New Zealand, provided useful insights into the circumstances leading to delay in obtaining medical review in association with high beta agonist use in patients presenting to hospital with severe exacerbations of asthma. The SMART regimen reduced non-adherence with inhaled corticosteroid (ICS) therapy, which together with the increased administration of ICS therapy in the setting of worsening asthma is likely to be responsible for the reduction in severe exacerbations with its use.
It also provided much needed data on the efficacy of management regimens in asthma patients who smoke, a high risk group with a substantial burden of disease. It was shown that the SMART regimen has a favourable risk/benefit profile in smokers, reducing the risk of severe asthma attacks by half, compared with standard management.
Comment: The priority now is to ensure that doctors and other health professionals in New Zealand are familiar with the SMART regimen and prescribe it to adults with high risk asthma, including smokers.
Combination Asthma Therapy
The MRINZ has an important leadership role in major international multicentre randomised controlled trials of novel medications in respiratory and intensive care medicine. This study investigated the safety and efficacy of QMF149, a once daily fixed dose combination of the long acting b2-agonist (LABA) indacaterol maleate and inhaled corticosteroid mometasone furoate for the treatment of persistent asthma. The clinical trial studied 1519 adolescents and adults with asthma from 174 research centres in nine countries. It showed that QMF149 had a favourable efficacy/safety profile, reducing the rate of severe exacerbations requiring systemic steroids by 29% compared with mometasone furoate therapy.
Comment: The findings are reassuring, not only in terms of the efficacy/safety profile of QMF149, but also the safety of LABA’s in asthma.
An important priority for the MRINZ is supporting the New Zealand biotechnology industry by undertaking randomised controlled trials of novel therapies or devices. In 2015 we undertook a randomised controlled trial of the effectiveness and safety of Honevo, a medical grade kanuka honey preparation in the treatment of rosacea, a common skin disorder which affects up to 10% of adults. This landmark study showed that Honevo was both safe and effective, with sufferers being over four times more likely to have complete resolution of their rosacea than those who used a control skin cream, despite having had rosacea for 15 years on average and the use of previous treatments. The findings offer new hope for rosacea sufferers. There is currently a range of treatment options for rosacea including several topical and oral antibiotics, however these are only partially effective and side effects may limit their use. Also, there are global concerns about the increasing rates of antibiotic resistance resulting from the widespread use of antibiotics, particularly with long term use in chronic conditions.
Comment: It is not often that clinician researchers have the opportunity to discover a novel, effective and safe treatment for a common medical condition – that the treatment has been developed by a research-based New Zealand biotechnology company makes the discovery even more special.
Chronic obstructive pulmonary disease (COPD)
The chronic breathlessness of COPD is physically limiting, socially isolating and associated with depression and anxiety. Pulmonary rehabilitation improves quality of life, exercise tolerance and breathlessness in patients with COPD. Adding to and sustaining these benefits are much needed topics of research. Singing has reported health benefits, and some data suggest beneficial effects on hyperinflation and mood in patients with COPD. We conducted a study to evaluate the potential health benefits of a community singing group in patients with COPD who had previously completed a pulmonary rehabilitation programme. This 12 month study has demonstrated that participation in a weekly community singing group is feasible for patients with COPD of varying severity, resulting in statistically significant and clinically important improvements in respiratory function and mood. Patients themselves reported enjoyment, purpose and connectedness.
Comment: This community singing group is an example of a low-cost, community-based, patient-centred, non-pharmacological intervention for COPD.
Dr Fingleton’s Health Research Council of New Zealand Clinical Training Fellowship and PhD Thesis investigated the different overlapping disorders that make up the syndromes of asthma and COPD. It was a huge undertaking, initially including a post-out to a random population sample of 16,459 adults in the greater Wellington region, with 451 who reported current wheeze and breathlessness then being studied in detail. Through utilisation of an epidemiological technique called cluster analysis, 5 phenotypes (separate disorders) of symptomatic airflow obstruction were identified: an asthma/COPD overlap group, two groups of childhood onset atopic asthma distinguished by severity, and two adult onset groups, one distinguished by the presence of obesity and comorbidities while the other had mild intermittent symptoms. The novel finding of inhaled corticosteroid responsiveness in the asthma/COPD overlap and obesity/comorbid groups is of particular interest as it suggests that these patients may benefit from treatment along asthma pathways.
Comment: The current ‘one size fits all’ approach to the management of asthma and COPD might be outdated. It may be preferable to work out which type of asthma or COPD a patient might have, and tailor their treatment accordingly.
Alongside our strong programmes of investigator led research, the MRINZ has a stream of research supporting clinical trials of new therapeutic agents developed by industry. A particular focus is on new monoclonal antibodies which may offer a chance for personalised therapy for patients with severe asthma or COPD. Over the last year we have been recruiting participants in three studies exploring the short and medium term benefits offered by these new agents.
Comment: These novel medicines represent the future of respiratory medicine for many patients with severe disease and in some cases participation in clinical research can provide access to new treatments for people who have not responded to current funded therapies.
The MRINZ is committed to improving medical practice through the development and implementation of evidence-based management guidelines. A key initiative in 2015 was the drafting of guidelines for the use of oxygen therapy in adults, responding to concerns that the common practice of administering high flow oxygen to patients regardless of need may pose real risks and lead to bad outcomes. A team from the MRINZ took a senior role with colleagues from Australia in drafting these guidelines on behalf of the Thoracic Society of Australia and New Zealand. The guidelines promote the titration of oxygen therapy to achieve a target level of oxygen saturation rather than the current practice of routine administering high flow oxygen regardless of need. This approach recognises that there are potential risks, not only associated with not enough oxygen, but also with too much oxygen.
Comment: This ‘swimming between the flags’ concept guides doctors, nurses and other health professionals to prescribe oxygen only if required, and within a target oxygen saturation range.
Medication to reduce fever (antipyretic treatment) is recommended in the management of influenza infection, yet in animal models antipyretic treatment increases mortality from influenza. In a Health Research Council of New Zealand-funded study we investigated the effects of paracetamol on viral and clinical outcomes in adults with influenza infection. Utilising the Wellington Regional Hospital Clinical Trials Unit and in collaboration with Canterbury Health Laboratories, we studied 80 participants with influenza and/or an influenza-like illness. We found that regular paracetamol had no effect on viral shedding, temperature, or clinical symptoms in patients with confirmed influenza infection.
Comment: There remains an insufficient evidence-base for paracetamol use in influenza infection.
Paracetamol is one of the world’s most widely used medicines and is commonly given to Intensive Care Unit (ICU) patients with infections. The findings of a randomised controlled trial of paracetamol in the treatment of fever in critically ill patients with sepsis were published in the world’s most prestigious medical journal, the New England Journal of Medicine. This study was undertaken in response to concern amongst doctors that the common practice of suppressing fever in ICU patients with serious infections might make them worse. The clinical trial, which was funded by the Health Research Council of New Zealand, and led by the MRINZ, studied 700 critically ill patients with serious infections in 23 ICUs across New Zealand and Australia. It showed that paracetamol was safe to use and did not make outcomes worse. The observation that patients who survived spent less time in ICU if they were given paracetamol, yet patients who died spent more time in ICU before death if given paracetamol, was intriguing and worthy of further study.
Comment: The findings are of major significance for global public health, because they provide reassurance about the safety of paracetamol, the most commonly used medication worldwide.
Acutely ill patients are commonly treated with intravenous fluids. A randomised controlled trial of commonly used intravenous fluids in ICU which was led by the MRINZ and conducted in four ICU’s in New Zealand was published in the prestigious Journal of the American Medical Association. The study, funded by the Health Research Council of New Zealand, was undertaken because doctors were troubled by the emerging evidence suggesting that using saline might increase the risk of kidney failure in critically ill patients, yet struck by the lack of data from clinical trials of the safety of newer intravenous fluids such as PlasmaLyte. The cluster randomised controlled trial showed that outcomes for patients who received saline and PlasmaLyte were similar. Importantly, there was no evidence that using saline increased the risk of developing kidney failure.
Comment: These findings provide reassurance about the safety of intravenous saline, which is administered to around one million patients in the world every day.
Nutrition therapy is an essential standard of care for all ICU patients who require life support and remain in ICU for more than a few days. There is a substantial and well established dissociation between the recommended calorie requirement and calories actually delivered to ICU patients. Nevertheless, while it remains logical that energy delivery should match energy consumption, the benefits of such matching remain to be confirmed by a robust, high quality clinical trial. With funding from the Health Research Council of New Zealand, we are currently undertaking the TARGET study in collaboration with Australian and other New Zealand investigators to determine if delivery of the full recommended calorie (energy) requirement to critically ill patients improves 90-day survival when compared to standard practice.
Comment: The TARGET study will include patients from nearly every New Zealand ICU and will enrol 4,000 ICU patients overall. We expect that the study TARGET study will be completed in 2019.
Stress ulcer prophylaxis
The administration of stress ulcer prophylaxis (SUP), either with a Proton Pump Inhibitor (PPI) or a Histamine-2 Receptor Blocker (H2RB) is recommended in international guidelines and incorporated into quality-oriented checklists for care of ICU patients. Our recent data show that PPIs and H2RBs are routinely used for SUP in Australia and New Zealand with the choice of medication probably not based on patient factors, but instead dependent on clinician preference or unit policy. This practice variation reflects the lack of definitive evidence comparing PPIs to H2RBs in the ICU setting. Although data suggest PPIs are more effective at reducing upper GI bleeding risk in ICU patients than H2RBs, it also appears that using PPIs in ICU patients is associated with an increase in pneumonia risk compared to H2RBs, and that PPI use but not H2RB use is associated with increased risk of Clostridium difficile infection. The overall influence of the opposing risks of upper GI bleeding and SUP-related infectious complications on in-hospital mortality is unknown. We are currently leading the PEPTIC study, a Health Research Council of New Zealand funded study which is a multicentre, multi-national trial comparing the safety and efficacy of PPIs vs. H2RBs in 40,000 mechanically ventilated ICU patients.
Comment: The PEPTIC study will be the largest clinical trial ever undertaken in critically ill patients.
The MRINZ has a long-standing collaboration with researchers from the University of Auckland and Otago University, working to identify associations between various lifestyle factors and obesity in children and adolescents. The collaboration utilises data on over 250,000 children from 71 centres in 35 countries, from the ISAAC programme. In 2015 three studies were published; the association of paracetamol treatment in infancy and BMI in children, the association between breastfeeding and BMI in children, and the association between parental smoking and BMI of children and adolescents. The findings of the analyses of parental smoking and childhood obesity were particularly interesting. We found that both maternal and paternal smoking in childhood is associated with greater BMIs in children.
Comment: In addition to the major health risks already recognised, the increase in the risk of their children becoming obese is yet another reason for parents not to smoke.
Oxygen therapy has been demonstrated to place patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) at risk of carbon dioxide retention and poor clinical outcomes. This has led to a change in practice with more careful use of oxygen given to such patients transferred by ambulance to hospital. However an audit of management in Wellington has shown that while oxygen is more carefully controlled, its use to drive bronchodilator nebulisers still leads to inappropriately excessive delivery of oxygen. This has led to a Health Research Council of New Zealand funded study of the use of air versus oxygen bronchodilator nebulisation in acute exacerbations of COPD, the results of which will be due in 2016.
Comment: This study is an example of how clinical research is guided by the findings of audits of clinical practice.
High Flow Delivery Devices
MRINZ has also been investigating the use of a device from Fisher & Paykel Healthcare called AIRVO which delivers high flow humidified air through nasal prongs to patients with respiratory conditions. We commenced studies observing its effect on patients with COPD, and are underway with a new study to observe whether these patients may find it beneficial to take a device home after admission with an exacerbation.
Another study has determined the maximum airway pressure effects generated by nasal high flow therapy. Current practice is to use flows over a range of 30 to 60 L/min however it is technically possible to apply higher flows. In this study airway pressure measurements and electrical impedance tomography were employed to assess the relationship between flows of up to 100 L/min and changes in lung physiology with the use of the Optiflow (Fisher & Paykel Healthcare, NZ) system. A cumulative and linear increase in end expiratory lung impedance was observed with increasing gas flows as well as a decrease in the respiratory rate. Airway pressures observed were in the range used clinically with facemask-delivered noninvasive ventilation.
Comment: Developments in delivery systems may result in this nasal high flow therapy being an acceptable alternative to noninvasive ventilation.
AMPLE is the first multinational randomised controlled trial in pleural disease that is investigator-led from within Australasia. It is a multinational trial investigating the best way to manage patients with malignant pleural effusions (a cancer-induced collection of fluid between the lung and chest wall). This is a common problem for people with cancer. Usually this is managed by undertaking a ‘talc pleurodesis’ procedure, where a tube is inserted to drain the fluid and the remaining space is reduced by using a chemical that promotes adhesion between the lung and the chest wall. AMPLE compares the standard procedure of talc pleurodesis with the use of a new device called an Indwelling Pleural Catheter (IPC), from which fluid can be drained by the patient at home. The study has now been completed and the results will be available by early 2016.
Comment: Through this study a strong network of trial centres in pleural disease has been built in Australia, New Zealand, and Singapore, and this will facilitate ongoing research.
2015 was a significant year for the Stroke/Rehabilitation programme. The Heath Research Council has funded a randomised controlled trial (Taking Charge after Stroke – the TaCAS study), run by the MRINZ, seeking to test whether the ‘Take Charge session’, developed in a previous clinical trial by MRINZ, is effective for a wide range of stroke-affected individuals. This multi-centre study based in 7 DHBs in New Zealand will recruit 400 people discharged to community living after stroke over the next 18 months and follow them up for 12 months. The first patients have been recruited in Wellington and other centres (Hutt Valley DHB, Counties-Manukau DHB, Auckland DHB, Hawkes Bay DHB, MidCentral DHB, Canterbury DHB) are ready to start recruiting in February. Discussions are under way about a ‘Take Charge’ study in Australia.
Comment: If the results of this study back up the previously positive randomised controlled trial of the ‘Take Charge session’ in Māori; and Pacific people with stroke (the MaPSS study, also run by MRINZ), this simple, cheap, safe intervention could make a very significant impact on stroke outcomes in New Zealand and elsewhere.
Research from the MRINZ has recently shown that prolonged seated immobility at work is an important yet previously unrecognised risk factor for venous thromboembolism, comprising deep vein thrombosis and/or pulmonary embolism (aka blood clots). The focus has now turned to preventive measures to reduce this risk. In early 2015, we started evaluating a small floor based foot-rest called the Legflow® with the intention of seeing whether it would improve blood flow in the legs of workers sitting at office desks for long periods of time. We found that the venous flow in a user’s leg was about 15 times greater when using the Legflow® compared to having feet flat on the floor. We are now undertaking a feasibility study of 200 office-based workers to see whether the Legflow® is a feasible option for improving circulation in the sedentary workforce without impacting on workplace productivity. A feasibility study is also being conducted, assessing patient use of a pump-like device under a leg cast to improve blood flow in patients with lower limb injuries.
Comment: Through this research programme, we aim to develop a comprehensive package of interventions for the prevention of venous thromboembolism in situations in which prolonged seated immobility cannot be avoided.