Lumacaftor/ Ivacaftor improves exercise tolerance in patients with Cystic Fibrosis and severe airflow obstruction

Abstract

Background: Treatment of patients with Cystic Fibrosis homozygous for the Phe508del gene, with Lumacaftor /Ivacaftor (LUM/IVA) improves outcomes in patients with FEV1 > 40% predicted. We set out to observe the most sensitive clinical measure that would change with treatment in terms of exercise capacity or lung function in adults with severe lung disease as defined by an FEV1 < 40% predicted when clinically stable.

Methods: 10 adults homozygous for the Phe508del received LUM/IVA. We assessed; six minute walk test (6MWT), spirometry, gas transfer (DLCO), plethysmography, and nitrogen multiple breath washout (MBW) at baseline, 4, 12, 24 and 52 weeks. Comparison was made with 10 matched historical controls that had been observed over 12 months.

Results: There was a significant improvement in 6MWT by 4 weeks of treatment; with a mean increase of 78 m (SD 62.3) and this increased to 118.1 m (SD 80.9) (ANOVA p = 0.006) by 52 weeks. Significant improvements were also seen in the resting heart rate and the oxygen saturation (SaO2) after 6 min walking. A significant improvement was not seen in FEV1 though until 24 weeks, though this was maintained at 52 weeks (ANOVA, p = 0.0004). There were no significant differences seen in the MBW or DLCO. After 12 months treatment with LUM/IVA, in comparison to historical controls; the 6MWT increased by 118 m (SD 80.9), but fell in the controls - 61.3 m (SD 31.1). FEV1; LUM/IVA led to an increase of 0.398 L/min, compared to a fall in the controls - 0.18 (SD 0.2).

Conclusion: In adults homozygous for Phe508del with severe disease, treatment with LUM/IVA results in a clinically significant improvement in 6MWT that was evident at 4 weeks and maintained at 52 weeks. Improvement in exercise tolerance is an important outcome to consider in those with more severe airways disease.

Trial registration: This was an observational trial conducted on individuals who became eligible to receive LUM/IVA. All investigations were carried out as part of routine clinical care. The trial was registered in retrospect on the 13/5/2019 on the Australian New Zealand Clinical Trials registry; ACTRN12619000708156 .

Keywords: Cystic fibrosis; Ivacaftor; Lumacaftor; Lung transplantation; Six minute walk test; Spirometry.

Fig. 1

Data on the 6MWT. The data relates to the 10 subjects treated with LUM/IVA over 12 months. Individual data points are represented as well as the median and interquartile range. Analysis was done using one-way ANOVA with Dunnett’s multiple comparisons test. The overall ANOVA p value is given. The groups that are different from baseline (p < 0.05) are represented by *

Fig. 2

Data on FEV1 and FVC. The data relates to the 10 subjects treated with LUM/IVA over 12 months. Individual data points are represented as well as the median and interquartile range. Analysis was done using one-way ANOVA with Dunnett’s multiple comparisons test. The overall ANOVA p value is given. The groups that are different from baseline (p < 0.05) are represented by *

Fig. 3

Data on the Nitrogen MBW. The data relates to the 10 subjects treated with LUM/IVA over 12 months. Individual data points are represented as well as the median and interquartile range. Analysis was done using one-way ANOVA with Dunnett’s multiple comparisons test. The overall ANOVA p value is given. No values are given for the y axis as these changes are without dimension

Fig. 4

Comparison in the change seen over 12 months of treatment in 10 subjects treated with LUM/IVA. This is compared to the change seen in 10 age matched historical controls over a 12 month period of review. Data is represented as mean and standard deviation. Comparison made using Student’s T test