Dr André Shultz has good reason to smile. The BEAT CF study, a multicentre clinical trial over five years of which he is clinical lead, was funded more than $3.4 million from the Future Fund. In line with Perth’s innovative thinking, the 400 or so Cystic Fibrosis (CF) patients in WA (in the US >30,000) will benefit from this and other CF initiatives. This includes: slower-than-expected gene therapy in the UK, Iowa and Adelaide; and about 8 drugs in advanced stages of envelopment that includes phase 2 and 3 trials.

Dr Andre Schultz

It is also hoped the Pharmaceutical Benefits Advisory Committee (PBAC) will approve the combination drug (lumacaftor-ivacaftor) for people homozygous for the most common CF mutation (ΔF508).

“These patients constitute 50% of the CF population, so we are all hoping for a positive result. Ivacaftor, alone, in those with class III mutations – about 7% of the CF population – seems to significantly slow the decline in lung function, which translates into improved quality of life and increased survival,” André said.

Of the recognised CFTR gene mutations (and there are many, with about 200 definitely linked to Cystic Fibrosis Transmembrane Regulator [CFTR] gene expression), the classes of mutations look at six protein-making errors affecting things like transcription, protein folding, gating and synthesis.

Getting on top of infection

In a nutshell, the CFTR gene mutations affect ion conduction, airway surfaces become dehydrated, and secretions are not cleared. The clearance of pathogens from the lung is impaired..

“Infections are important in CF – they are one of the main reasons why lung function deteriorates. It’s about optimising management of exacerbations of CF because about 25% of those affected by exacerbations don’t regain their previous lung function,” he said.

With emerging resistance, the choice of antibiotics is changing and clinicians have their preferences, some of them not well informed by evidence, according to André. With about 2000 hospitalisations in Australia for CF a year and a Cochrane review in 2015 showing different antibiotic choices for the treatment of exacerbations, the burning question is how to get the best evidence ‘on the fly’ without spending lots of money. Research would be aimed at a rare disease, which needs multicentre studies that take a long time.

Head-to-head clinical trials would take many decades. Enter the “Bayesian statistics informed adaptive platform trial, which allows more flexibility in randomisation, recruitment and efficiency in getting results quicker.” This is a relatively new statistical method in clinical trials, using a complex interpretation of probability requiring enormous amounts of computing power, which enables better treatments as time goes by.

“By participating in the BEAT CF trial, patients are more likely to be allocated to treatments that are performing better in the trial, partly because of the uncertainty about which conventional treatment is the best – you get to the answers quicker.”

Collaboration the key

Of course, this needs to be imbedded in clinical practice, which requires a huge buy-in from clinicians around Australia, which André says they have and are now collaborating with clinicians in Boston who lead the world in this kind of trial. Apparently, there are currently only four or five trials that use statistics in this way. Dr Tom Snelling leads the investigation.

We talked more of the importance of maintaining a consumer focus in their research, his excitement that about eight disease-modifying drugs some of which are in phase III clinical trials, the work of Steve Stick, the increasing survival median age of 40-50 years for those with CF, the mental health of CF patients, and research into non-antibiotic ways to fight infection.

In this regard, gene therapy is the Holy Grail. But as André says, “the lung is designed to keep things out”. Getting the right vector to deliver the genetic payload to affected cells and the right animal model to do the research are difficult. Adelaide researchers apparently have a rat model with milder lung disease; the animals live longer so it’s more suited to studying the effects of gene therapy.

Combat CF study is a phase 3 multi-centre randomised placebo-controlled study of azithromycin in the primary prevention of radiologically-defined bronchiectasis in infants with cystic fibrosis. It seeks to see if azithromycin, with both an anti-inflammatory and antibiotic action, can prevent lung disease in very young children with CF. The children diagnosed with cystic fibrosis by newborn screening can be enrolled in the study by six months of age.

“If the study of infants doesn’t show good effect we have shown we can conduct multi-centred clinical trials across the world and have set up networks to do it.”

On a more personal level, he knows many of the 400 or so CF patients in WA and says it is not all doom and gloom. “I know many adults with CF and although it is tough they have meaningful lives typically characterised by incredible resilience.”

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