Thumbs down for sildenafil in IPF combo

Combination therapy with nintedanib and sildenafil offers no advantage over nintedanib alone in patients with IPF.

The INSTAGE trial, presented at ERS 2018 in Paris and published concurrently in the NEJM, randomised 274 patients across 13 countries to either the combination treatment or nintedanib with placebo.

Patients had relatively severe impairment of gas exchange with DLCO (diffusing capacity of the lungs for carbon monoxide) of 35% or less.

The study authors, led by Dr Martin Kolb of Ontario, said the trial was set up after a previous study suggested that sildenafil may provide benefits regarding oxygenation and gas exchange, symptoms and quality of life in patients with IPF and severely decreased DLCO.

However the study found there was no significant difference between the groups in the primary endpoint of a change in a health-related quality of life measure (St. George’s Respiratory Questionnaire) from baseline to either 12 or 24 weeks.

Similarly, there was no difference between the groups in secondary end points – adjusted mean change from baseline in the University of California, San Diego, Shortness of Breath Questionnaire (UCSD-SOBQ) or general health status as measured by the EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D).

Changes in the oxygen saturation and the DLCO at weeks 12 and 24 did not differ substantially between the two groups.

However ‘patients who had been treated with nintedanib plus sildenafil had a lower risk of reaching the prespecified composite end point of an absolute decline in the FVC of at least 5 percentage points of the predicted value or death than did those who received treatment with nintedanib alone’.

“Whether this finding is due to chance alone or represents a true treatment effect is not known, but given the likely fragility of this finding, this observation cannot be considered to be clinically directive,” the study authors said.

Both groups had similar rates of adverse events or deaths from any causes.

In other data presented at ERS 2018 and published in Lancet Respiratory Medicine, long term follow-up of patients treated with the tyrosine kinase inhibitor showed no new safety signals.

In 734 patients on nintedanib for up to 68 months, diarrhoea was the most frequent adverse event. However the most common reason for discontinuation of treatment was IPF progression.

Both studies were funded by Boehringer Ingelheim.

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