First author [ref.] | Subject n and type | Intervention | Basal potential p-value | Δ amiloride p-value | Δ low chloride + isoproterenol p-value | Sweat chloride | Statistic |
The total chloride response (low chloride + isoproterenol) improves during treatment with ataluren t.i.d. in phase-II open label trials in children and adults with CF carrying at least one nonsense mutation | |||||||
Sermet-Gaudelus 19 | 30 CF with nonsense mutation | Ataluren 4, 4, 8 mg (14 d) | NS | NS | 0.04 (-4.6 mV) | ND | Paired t-test (mean change) |
Ataluren 10, 10, 20 mg (14 d) | NS | NS | 0.05 (-3.9 mV) | ND | |||
Kerem 18 | 53 CF with nonsense mutation | Ataluren 4, 4, 8 mg (14 d) | NS | NS | 0.0001 (-7.1 mV) | NS | Paired t-test (mean change) |
Ataluren 10, 10, 20 mg (14 d) | NS | NS | 0.03 (-3.7 mV) | NS | |||
Inconsistent findings whether systemic administration of aminoglycoside changes NPD or sweat chloride values in patients with CF Local administration of gentamycin nose drops improves NPD read-out in CF patients carrying at least one nonsense mutation 15 d intravenous gentamycin treatment | |||||||
Sermet-Gaudelus 46 | 9 CF with Y122X mutation | NS | 0.09 (20 to 15 mV) | 0.04 (-0.8 to -4.6 mV) | 0.03 (109 to 85 mmol·L−1) | Wilcoxon (mean before and after) | |
4 CF with other nonsense mutation | NS | NS | NS | ||||
5 CF without nonsense mutation | NS | NS | NS | ||||
15 d nasal aminoglycoside treatment | |||||||
Clancy 47 | 11 CF with nonsense mutation | NS | NS | NS | NA | Paired t-test | |
18 CF without nonsense mutation | NS | NS | NS | NA | |||
7 d intravenous gentamycin treatment | |||||||
Clancy 48 | 5 CF with nonsense mutation | NS | NS | NS (4/5) | NS | GLM for repeat measures (number of patients with ≥1 reading ≥5 mV) | |
5 CF without nonsense mutation | NS | NS | NS (0/5) | NS | |||
14 d gentamycin nose drops t.i.d. | |||||||
Wilschanski 17 | 11 CF homozygous nonsense mutation | 0.008 (-48 to -34 mV) | 0.05 (33 to 24 mV) | 0.001 (0.4 to -5.5 mV) | NA | t-test/MWU p-value (mean before and after) | |
8 CF heterozygous nonsense mutation | NS | NS | 0.04 (-05 to -4.8 mV) | NA | |||
5 CF homozygous F508del | NS | NS | NS | NA | |||
14 d gentamycin nose drops t.i.d. | |||||||
Wilschanski 49 | 9 CF with nonsense mutation | NS | NS | <0.001 (-0.6 to -10 mV) | NA | MWU (mean before and after) | |
Systemic administration of VX-770 to CF adults and children carrying at least one G551D mutation is associated with large drop in sweat chloride and a moderate improvement of total chloride response measured by NPD | |||||||
Accurso 20 | 20 CF with G551D mutation | VX-770 75 mg b.i.d. 14 d | ND | ND | 0.003 (-4.7 mV) | <0.001 (-40 mEq·L−1) | Paired t-test (mean change from baseline) |
VX-770 150 mg b.i.d. 14 d | ND | ND | 0 .01 (-5.3 mV) | <0.001 (-42 mEq·L−1) | |||
VX-770 150 mg b.i.d. 28 d | ND | ND | 0.02 (-3.5 mV) | 0.008 (-60 mEq·L−1) | |||
VX-770 250 mg b.i.d. 28 d | ND | ND | 0.05 (-5.5 mV) | 0.02 (-38 mEq·L−1) | |||
Ramsey 50 | 161 CF with G551D mutation | 83 VX-770 150 mg b.i.d. 48 wks | ND | ND | ND | <0.0001 (-49 mEq·L−1) | MMRM (mean change from baseline through 24 wks) |
78 placebo | ND | ND | ND | NS (-0.8 mEq·L−1) | |||
Aherns 51 | 52 CF (6–11 yrs) with G551D mutation | 26 VX-770 150 mg b.i.d. 24 wks | ND | ND | ND | <0.0001 (-56 mEq·L−1) | MMRM (mean change from baseline through 24 wks) |
26 placebo | ND | ND | ND | NS (-1.2 mEq·L−1) | |||
Systemic administration of VX-809 to CF patients homozygous for F508del is associated with a small, dose-dependent drop in sweat chloride | |||||||
Clancy 21 | 89 CF homozygous F508del mutation | VX-809 25 mg q.d. 28 d | ND | ND | NS | NS | Paired t-test (mean change from baseline); linear trend test p=0.0013 |
VX-809 50 mg q.d. 28 d | ND | ND | NS | NS | |||
VX-809 100 mg q.d. 28 d | ND | ND | NS | <0.05 (-6 mEq·L−1) | |||
VX-809 200 mg q.d. 28 d | ND | ND | NS | <0.01 (-8 mEq·L−1) | |||
After treating patients homozygous for F508del with VX-809 for 14 days, the addition of ivacaftor 250 mg b.i.d. for 7 days is associated with a further small but statistically significant drop in sweat chloride | |||||||
Boyle 52 | 61 CF homozygous F508del mutation | VX-809 200 mg q.d. 14 d | ND | ND | ND | <0.01 (-4.2 mEq·L−1)# | Paired t-test mean change from day 14 or baseline# |
+VX-770 150 mg b.i.d. 7 d | ND | ND | ND | NS (-2.2 mEq·L−1) | |||
+VX-770 250 mg b.i.d. 7 d | ND | ND | ND | p<0.001(-9.1 mEq·L−1) | |||
NPD parameters detect effect of treatment in phase-II trials of various modes of gene therapy | |||||||
Konstan 53 | 12 CF | Compacted DNA nanoparticles in saline 0.8 mg, 2.67 mg or 8.0 mg, single dose | No change | NR | 8 out of 12 subjects showed partial to complete response | NA | Descriptive |
Noone 54 | 11 CF | EDMPC cholesterol complexed with CFTR cDNA 0.4375 mg, 1.3 mg or 4 mg total dose | NS | NS | NS | NA | Paired t-test |
Alton 55 | 16 CF | pCF1-CFTR cDNA complexed with 229 mg GL-67/DOPE/DMPE-PEG5000 single dose | NS | NS | NS | NA | MWU and Wilcoxon rank sum |
Zabner 56 | 9 CF | pCF1-CFTR plasmid 1.25 mg, single dose | NS | NS | p<0.05 (3 mV to -3 mV) | NA | Not reported (mean before and after) |
pCF1-CFTR plasmid 1.25 mg complexed with 2 mg GL-67:DOPE, single dose | NS | NS | p<0.05 (3 mV to 0.5 mV) | NA | |||
Porteous 57 | 16 CF | 400 μg pCMV-CFTR complexed with 2.4 mg DOTAP cationic liposome, single dose | NS for group 2/8 treated patients demonstrated partial correction | NS for group 2/8 treated patients demonstrated partial correction | NS for group 2/8 treated patients demonstrated partial correction | NA | Not reported |
Zabner 58 | 6 CF | CFTR cDNA via adenovirus vector, single dose | Sign rank statistic | ||||
2×109 IU | NS | NS | p=0.04 (2 to -2 mV) (terbutaline) | NA | |||
6×109 IU | NS | NS | p=0.03 (2 to -0.5 mV) (terbutaline) | NA | |||
Gill 59 | 12 CF | CFTR cDNA via DC-Chol/DOPE | NS | NS | NS | NA | Not reported |
Caplen 60 | 9 CF | CFTR cDNA | NS | p<0.05 (+4 mV) | NS | NA | Not reported |
Hay 61 | 9 CF | AdCFTR cDNA via adenovirus vector, single dose | p=0.01 (-53 to -35 mV) | p=0.02 (37 to 20 mV) | p=0.05 (-5 to -9 mV) | NA | Paired t-test |
Middleton 29 | 3 CF | DC-Chol:DOPE | NS | NS | NS | NA | Not reported |
No observed effect of single dose of CPX on either NPD or sweat chloride parameters | |||||||
McCarty 62 | 37 CF | CPX, single dose | NS | NS | NS | NS | ANOVA |
NPD total chloride response detects effect of Moli1901 (activator of alternative chloride channels) | |||||||
Zeitlin 63 | 4 CF | Moli1901 (1, 3 and 10 μmol·L−1) | NA | NA | <0.05 for all doses | NA | Paired t-test versus vehicle |
NPD total chloride response detects effect of CFTR activation in patients homozygous for F508del mutation | |||||||
Rubenstein 64 | 10 CF homozygous F508del mutation | Sodium 4-phenylbuturate 6, 6, 7 g (7 d) | NS | NS | p=0.0055 (5.2 to 0.6) | NS | Paired t-test (mean before and after) |
Basal NPD detects effect of aerosolised sodium channel blockers | |||||||
Rodgers 65 | 10 CF | Amiloride nasal spray | p<0.0001 (+20 mV) | NA | NA | NA | Two way ANOVA |
Benzamil nasal spray | p<0.0001 (+21 mV) | ||||||
Hofmann 66 | 12 CF | Aerosolised amiloride | p<0.05 | NA | NA | NA | Independent t-test |
Hofmann 67 | 41 CF | Aerosolised amiloride (10−3 M) (n=16) | +35 mV | NA | NA | NA | No statistics |
Aerosolised benzamil (7×10−3 M) (n=5) | +35 mV | ||||||
NPD detects effect of flavonoids on CFTR function | |||||||
Pyle 68 | 12 non-CF | Quercetin 20 μg:mL single dose | NR | p<0.05 (-7 mV) | p<0.05 (-15 mV) | NA | ANOVA |
Illek 69 | 25 non-CF | Quercetin (n=15), genistein (n=3), kaempferol (n=3), apigenin (n=4) | p<0.05 (-3 mV) | ND | ND | ND | Paired t-test |
NPD detects effect of hypertonic saline | |||||||
Middleton 70 | 7 non-CF | 150 mM | p<0.05 (6.6 mV) | ND | ND | ND | Paired t-test |
250 mM | p<0.05 (7.6 mV) | ||||||
500 mM | p<0.05 (10.0 mV) | ||||||
1200 mM | p<0.05 (13.1 mV) | ||||||
2000 mM | p<0.05 (14.8 mV) | ||||||
NPD detects effect of fluticasone propionate on epithelial sodium absorption | |||||||
Graham 71 | 6 non-CF | Fluticasone propionate | ND | p=0.03 (1.8 to 3.3 mV) | NS | NA | Paired t-test |
NPD detects effect of milrinone on epithelial sodium absorption | |||||||
Smith 72 | 6 CF | Milrinone (perfused during NPD) | p<0.05 (52 to 57 mV) | NS | NS | NA | MWU |
Total chloride response increases in response to increased temperature | |||||||
Boyle 73 | 32 non-CF | NS | NS | 0.01 (-4.4 mV) | NA | Paired t-test | |
PD recorded at the end of Ringers (i.e. basal) and at the end of isoproteronol were more polarised when using agar catheter versus perfusion method | |||||||
Solomon 74 | 26 non-CF | p<0.05 (-15.9 versus -14.0 mV) | NS | p<0.05 (-31.2 versus -24.8 mV) | NA | Paired t-test | |
Basal NPD and amiloride response detects effect of moderate exercise | |||||||
Alsuwaidan 75 | 7 CF | Cycle ergometer exercise at 80% HRpeak | p<0.05 | ND | ND | ND | Paired t-test |
Hebestreit 76 | 9 CF | Cycle ergometer exercise at 85% of VT | p<0.01 (-34 to -7 mV) | p<0.01 (+26 to +16 mV) | NS | ND | Paired t-test |
CF: cystic fibrosis; NS: nonsignificant; ND: no data; NA: not applicable; GLM: generalised linear model; MWU: Mann–Whitney U-test; MMRM: mixed-effects models for repeated measurements; NR: not reported; HRpeak: peak heart rate, VT: ventilatory threshold. Subject type: CF subjects with a specific mutation can be homozygous or heterozygous for this mutation unless specifically stated.