Worldwide outcomes
Real world studies, collected outside of randomized studies, may give added information about CFTR modulators in populations that are not identical to those in whom the randomized clinical trial was performed, such as in different countries or ethnic populations. One retrospective observational study done in Greece, looked at lum/iva, to see if the population had similar improvements in lung function compared to initial RCTs52. In this study, 52 patients eligible for lum/iva were studied in an observational, retrospective study over 12 months. The FEV1pp increased by 2.3%, and using a multivariate longitudinal model there was an improvement in the rate of decline of lung function. The increase in FEV1pp was similar to the rate seen in the lum/iva pivotal phase 3 study published in 2015.
PwCF clinically prescribed lum/iva in 2016 were studied in a “real world” manner in 47 centers in France, examining differences in outcomes between those who took continuous treatment, intermittent therapy, or discontinued therapy53. In a total of 845 patients, over age 12 years, who were started on lum/iva, 12% of the patients did not start at full dose, due to suspected drug interactions (n=74) or other miscellaneous reasons (n=26), which were not specifically described in the paper. The average FEV1pp improvement at 12 months was 2.7%±8.86% (n=821, p<0.001). Those with continuous usage (n=631) had increased FEV1pp 3.67±8.62% (p<0.001), and a more robust increase was seen in adolescents. For those with intermittent usage of lum/iva (stopped and restarted, n=45), FEV1pp trended toward improvement (+2.36±8.47, p=0.09). For those who discontinued treatment, FEV1pp trended down (-1.36±9.03%, p=0.07). Additional outcomes with lum/iva included: increases in weight and BMI, decreases in use of IV antibiotics, no changes in vitamin A, E or D levels, and no changes in HbA1C (hemoglobin A1C) in those with CFRD. Despite differential patterns of taking the lum/iva therapy, the improvements in FEV1pp were similar to the initial phase 3 studies.
The Italian CF registry was reviewed in a study looking at clinical parameters in patients with gating mutations (GM) compared to F508del homozygotes; GMs were found in 186 (3.3%) compared to 1005 (21.5%) F508del homozygotes among 5552 patients in the registry54. Only 0.06% (n=7) of the Italian CFTR mutations were G551D, which is substantially lower than other populations. In the study, there was an improvement from 2012 to 2017 in patients with GMs in terms of lung function (FEV1pp increased from 73.6% (SD 26.6%) to 79.8% (SD 27.3%), compared to no change in the F508del homozygotes (FEV1 pp 77.1% (SD24.1%) compared to 75.2% (SD 24.7%). In those with GMs, BMI improved and there was decreased diabetes, while these parameters did not improve in the F508del homozygotes. However, the Italian CF registry itself does not have documentation of whether or not the patients were on iva. Therefore, as part of the study, a survey of CF Centers in Italy on modulator use was performed after 2014/2015, when iva first became available in Italy. The percentage of patients treated with iva steadily increased from 4% in January 2014 to 75% at the end of 2017, and the authors suggest this likely led to the changes seen in the GM patients in the Italian CF registry.