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.