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.