Can CFTR therapy SIMPLIFY the treatment burden in CF?

Cystic fibrosis

By Dave Levitan

2 Feb 2021

Two concurrent new clinical trials will examine the feasibility of discontinuing the chronic therapies hypertonic saline or dornase alfa in patients with cystic fibrosis who have begun therapy with the elexacaftor/tezacaftor/ivacaftor (ETI) combination.

The combination CF transmembrane regulator (CFTR) modulator therapy is set to greatly change the treatment of CF. Clinical trials showed it can offer unparalleled clinical benefit in patients with at least one F508del mutation, meaning it may be appropriate for as many as 90% of patients.

“The impactful clinical benefits of ETI provides new motivation to address the pressing question of whether certain chronic therapies targeted at managing symptoms and sequelae of the disease can now be withdrawn without clinical consequence after establishment of ETI therapy,” wrote study authors led by Prof Nicole Mayer Hamblett, of the University of Washington in Seattle.

SIMPLIFY is a master protocol comprising two concurrent clinical trials. They are randomised, controlled trials, designed to evaluate the short-term effects of discontinuing hypertonic saline or dornase alfa.

It will include both paediatric patients ages 12-17 years with a ppFEV1 of at least 70, and those 18 years and older with ppFEV1 of at least 60. All participants will need to have been on ETI and either or both of the mucolytic therapies for at least 90 days prior to screening.

Each study will enrol about 400 participants, randomised evenly to either discontinue hypertonic saline or dornase alfa, or to continue those therapies. Patients on both those agents can participate sequentially in both of the studies, according to the protocol published in Annals of the American Thoracic Society.

The studies will evaluate clinical and safety outcomes after six weeks including ppFEV1, antibiotic use, pulmonary exacerbations, adverse events, and patient-reported outcomes across 90 study sites.

“SIMPLIFY is the largest medication withdrawal study in CF to date, motivated by the increasing availability of effective CFTR modulator therapy to a majority of the CF population,” the authors wrote.

In the UK, where over 10,000 people per year are affected by CF, the CF STORM trial is set to begin soon. This will be a randomised, registry-based open label study, comparing respiratory function outcomes in patients on established ETI who either continue or reduce their daily treatment burden by removing hypertonic saline and/or dornase alfa from daily care.

“As transformative therapies emerge for CF and other conditions it is important we evaluate rigorously the impact on the patient journey,” wrote the leaders of that trial. “CF STORM presents an innovative registry-based approach to achieve this and provide a framework for future stopping studies.”

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