Lung clearance index
Lung clearance index (LCI) is an alternative research measure to FEV1pp.
LCI is a measure of ventilation inhomogeneity. It can be found most
easily using nitrogen washout from the lungs, and it is defined as the
total sum of gas expired during the washout (cumulative expired volume),
divided by the function residual capacity (FRC). Practically, it is the
number of times the resting or end-tidal lung volume has to be “turned
over” to clear or washout nitrogen (N2) with 100%
O2. LCI is usually reported as LCI2.5,
or washout until 1/40th of the starting
N2 end tidal concentration is reached. Normal LCI is
less than 7.5 “turnovers”15. Shaw M et
al evaluated LCI2.5 in 49 subjects who were F508del
homozygotes, over 6 years of age, pre/post lum/iva
treatment16. Although FEV1pp did not change with
treatment, LCI2.5 decreased, which is evidence of
clinical improvement in this measure. LCI2.5 decreased
by 0.81, demonstrating a 5.3% improvement at 1 month, with sustained
decreases at 3 months and 6 months (cumulative decrease 0.77(5.9%
improvement) and 0.67(5.9% improvement), respectively.
LCI2.5 decrease was attenuated at 12 months with
cumulative decrease 0.55 (4.3% improvement) from baseline. Male gender,
higher baseline LCI2.5 , and younger age were
independent predictors of initial improvement in LCI2.5. The clinical applicability of such a change is unknown as there is no
acknowledged clinically significant difference for
LCI2.5, however the authors state the improvement is
similar to treatment effect seen with inhaled hypertonic saline in the
preschool trial 16,17.
Three other studies in 2020 studied LCI2.5 as an
endpoint for CFTR modulator trials. A randomized, placebo-controlled,
crossover study of 38 subjects with either the 3849+10kbCT or D1152H
mutation compared LCI2.5 in those treated with iva
versus placebo for 8 weeks18. In these subjects with
mean baseline FEV1pp of 74 (SD 16.9), baseline LCI 13(SD 4.7), and
89.5% of whom were adults, the difference in LCI2.5between iva and placebo groups was -0.66 (95% CI, -1.10 to -0.21) at 8
weeks. There was one study dropout due to pregnancy in the placebo to
iva treatment sequence. Otherwise, adverse events were similar in iva
versus placebo, sweat chloride difference was -9.2mmol/L (-12.4 to
-5.9), and FEV1pp improvement was 2.7 (0.6-4.7) in iva versus placebo
groups.
Nick JA et al contributed a phase 2, randomized, double-blind,
placebo controlled, within patient crossover study using iva in 24 CF
subjects ≥ 12 years (mean age 37.3 (SD 13.9) years) with residual
function mutations19. Residual function in this study
was defined as any one of the following: age ≥ 12 years at diagnosis,
having ≥ 1 CFTR missense or splicing (not gating) mutation, screening
sweat Cl ≤ 80 mmol/L, or fecal elastase (FE) >200 ug/g
(indicating residual pancreatic exocrine function). Subjects were
randomized to receive iva or placebo, followed by an 8 week open label
period. The baseline mean FEV1pp of these subjects was 67.8% (SD 22.6),
and baseline mean LCI was 10.6 (SD 3.1). After 2 weeks, there was an
insignificant LCI difference of -0.42 (0.22) (p=0.686) for iva versus
placebo, and a significant increase in FEV1pp of 2.3 (SD 1) (95% CI
0.4-4.1) for iva versus placebo. As part of the phase 3 open label
extension part of this study, with iva compared to baseline, there was a
-1.6 (SD 2.3) decrease in LCI, 4.7 (4.2) increase in FEV1pp
(p<0.0001), -15.7mmol/L decrease in sweat Cl,
0.5kg/m2 increase in BMI, and 1.8kg increase in
weight.
A phase 3, double blind, parallel group, 8 week study of tez/iva in
fifty-four 6-11 year olds with CF, homozygous for F508del or
heterozygous for F508del/residual function mutations, showed a
significant decrease in LCI2.5 of 0.51 from baseline of
9.56 (95% CI, -0.74 to 0.29, p<0.0001)15.
FEV1pp increased by 2.8 from baseline of 86.5 in the tez/iva group (95%
CI, 1.0-4.6). There were no SAEs in the study and only 3 subjects
(5.6%) in the tez/iva group had transaminase elevation ≥ 3x normal.
Sweat chloride decreased by 12.3mmol/L, and CFQ-R increased
non-significantly by 2.3 points in the tez/iva group.
In these studies, LCI2.5 appeared to show some, but
sometimes insignificant, improvements with iva, and tez/iva compared to
placebo. LCI2.5 may be a useful parameter in future CFTR
modulator studies, but further research is needed.