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Table 2 Clinical trials supporting regulatory decisions for the Marketing Authorization and the extensions of indication of CFTR modulators

From: The impact of FDA and EMA regulatory decision-making process on the access to CFTR modulators for the treatment of cystic fibrosis

 

FDA

EMA

Phase

Study

Control

Study Population

Treatment Duration

Primary Endpoint

Primary Outcome

Ref

IVA—Kalydeco

1

31/01/12

23/07/12

III

VX08-770-102 (NCT00909532) STRIVE

Placebo (parallel)

 ≥ 12 years—G551D Sample size: 161

48 weeks

Absolute mean change from baseline in ppFEV1 through wk 24

LS mean absolute change IVA vs placebo (95% CI): + 10.6 (+ 8.6, + 12.6)

[36]

2

III

VX08-770-103 (NCT00909727) ENVISION

Placebo (parallel)

6 to 11 years—G551D Sample size: 52

48 weeks

Absolute mean change from baseline in ppFEV1 through wk 24

LS mean absolute change IVA vs placebo (95% CI): + 12.5 (+ 6.6, + 18.3)

[57]

3

Not approved

Not approved

II

VX08-770-104 (NCT00953706) DISCOVER

Placebo (parallel)

 ≥ 12 years—F508del/F508del Sample size: 140

16 weeks

Aabsolute mean change from baseline in ppFEV1 through wk 16

LS mean absolute change IVA vs placebo (95% CI): + 1.7 (-0.6, + 4.1)

[58]

4

21/02/14

28/07/14

III

VX12-770-111 (NCT01614470) KONNECTION

Part A: Placebo (crossover) Part B: open-label

 ≥ 6 years—non-G551D gating mutation (*) Sample size: 39 (Part A: 39 Part B: 36)

24 weeks Part A: 8 wk Part B: 16 wk extension

(A) absolute change from baseline in ppFEV1 through wk 8

(A) LS mean difference IVA vs placebo (95% CI): + 10.7 (+ 7.3, + 14.1)

[32]

(B) Absolute change from baseline in ppFEV1 through wk 24

(B) LS mean absolute change IVA vs placebo (95% CI): + 13.5 (-6.9, + 36.5)

5

29/12/14

16/11/15

09/06/20

III

VX11-770-110 (NCT01614457) KONDUCT

Placebo (parallel)

 ≥ 6 years—R117H, non-gating mutation Sample size: 69

24 weeks

Absolute change from baseline in ppFEV1 through wk 24

LS mean difference IVA vs placebo (95% CI): + 2.11 (-1.13, + 5.35)

[33]

6

17/03/15

16/11/15

III

VX11-770-108 (NCT01705145) KIWI

Open-label

2 to 5 years—gating mutation (G551D, *) Sample size: 34 (Part A: 9 Part B: 33)

Part A: 4 days Part B: 24 weeks

(A) pharmacokinetic (A, B) safety: number of participants with AEs, SAEs and related AEs

(A) safety: 8 subj had AEs (88.9%), no SAEs, 4 subj (44.4%) had related AEs (B) safety: 33 subj had AEs (97.1%), 6 subj (17.6%) had SAEs, 11 subj had related AEs (32.4%)

[59]

7

31/07/17

Not approved

III

VX14-661108 (NCT02392234) EXPAND

Placebo (crossover)

 ≥ 12 years—F508del/RF Sample size: 244

8 weeks crossover

Absolute change from baseline in ppFEV1 at average of wk 4 and 8

LS mean difference IVA vs placebo (95% CI): + 4.7 (+ 3.7, + 5.8)

[14]

8

15/08/18

22/11/18

III

VX15-770-124 (NCT02725567) ARRIVAL

Open-label

 < 24 months—gating mutation (G551D, *) or R117H Sample size: Part A (Cohort 1): 7 Part B (Cohort 5): 19

Part A: 4 days Part B: 24 weeks

(A) pharmacokinetic (A, B) safety: number of participants with AEs, SAEs and related AEs

(A) safety: 3 subj had AEs (42.9%), no SAEs, no related AEs (B) safety: 18 subj had AEs (94.7%), 2 subj (10.5%) had SAEs, 7 subj (36.8%) had related AEs

[60]

29/04/19

09/12/19

Open-label

 < 24 months—gating mutation (G551D, *) or R117H Sample size: Part A (Cohort 2): 6 Part B (Cohort 6): 11

(A) safety: 4 subj had AEs (66.7%), no SAEs (B) safety: 10 subj had AEs (90.9%), 3 subj (27.3%) had SAEs, 2 subj (18.2%) had related AEs

[61]

24/09/20

03/11/20

Open-label

 < 24 months—gating mutation (G551D, *) or R117H Sample size: Part A (Cohort 3): 6 Part B (Cohort 7): 6

(A) safety: 3 subj had AEs (50.0%), 1 subj (16.7%) had SAEs, no related AEs (B) safety: 6 subj had AEs (100%), 1 subj (16.7%) had SAEs, no related AEs

[61]

LUM/IVA—Orkambi

9

02/07/15

19/11/15

III

VX12-809-103 (NCT01807923) TRAFFIC

Placebo (parallel)

 ≥ 12 years—F508del/F508del Sample size: 549

24 weeks

Absolute change from baseline in ppFEV1 through wk 24

LS mean difference LUM/IVA vs placebo (pooled analysis) (95% CI): + 3.3 (+ 2.3, + 4.3) for LUM 600 mg + 2.8 (+ 1.8, + 3.8) for LUM 400 mg

[62]

10

VX12-809-104 (NCT01807949) TRANSPORT

Placebo (parallel)

 ≥ 12 years—F508del/F508del Sample size: 559

24 weeks

11

28/09/16

08/01/18

III

VX14-809-109 (NCT02514473)

Placebo (parallel)

6 to 11 years—F508del/F508del Sample size: 204

24 weeks

Absolute change in LCI2.5 through wk 24

LS mean LUM/IVA vs placebo (95% CI): − 1.1 (− 1.4, − 0.8)

[39]

12

07/08/18

15/01/19

III

VX15-809-115 (NCT02797132)

Open-label

2 to 5 years—F508del/F508del Sample size: 62 (Part A: 12 Part B: 60)

Part A: 15 days Part B: 24 weeks

(A) pharmacokinetic (A, B) safety: number of participants with AEs and/SAEs

(B) safety: 59 subj had AEs (98%), 4 subj (7%) had SAEs

[63]

TEZ/IVA—Symdeko (Symkevi)

13

12/02/18

31/10/18

III

VX14-661-106 (NCT02347657) EVOLVE

Placebo (parallel)

 ≥ 12 years—F508del/F508del Sample size: 504

24 weeks

Absolute change from baseline in ppFEV1 through wk 24

LS mean difference TEZ/IVA vs placebo (95% CI): + 4.0 (+ 3.1, + 4.8)

[64]

7

III

VX14-661-108 (NCT02392234) EXPAND

Placebo (crossover)

 ≥ 12 years—F508del/RF Sample size: 244

8 weeks

Absolute change from baseline in ppFEV1 at average of wk 4 and 8

LS mean difference TEZ/IVA vs placebo (95% CI): + 6.8 (+ 5.7, + 7.8)

[14]

14

21/06/19

25/11/20

III

VX16-661-115 (NCT03559062)

Placebo (parallel)

6 to 11 years—F508del/RF + F508del/F508del Sample size: 67

8 weeks

Absolute change in LCI2.5 through wk 8

LS mean TEZ/IVA vs placebo (95% CI): − 0.51 (-0.74, − 0.29)

[65]

15

Not approved

Not approved

III

VX14-661-107 (NCT02516410)

Placebo (parallel)

 ≥ 12 years—F508del/MF Sample size: 168

12 weeks

Absolute change from baseline in ppFEV1 through wk 12

LS mean difference TEZ/IVA vs placebo (95% CI): + 1.2 (-0.3, + 2.6)

[12]

ELX/TEZ/IVA—Trikafta (Kaftrio)

16

21/10/19

21/08/20

III

VX17-445-102 (NCT03525444)

Placebo (parallel)

 ≥ 12 years—F508del/MF Sample size: 403

24 weeks

Absolute change in ppFEV1 from baseline at wk 4

LS Mean difference ELX/TEZ/IVA vs control (95% CI): + 13.8 (+ 12.1, + 15.4)

[34]

17

III

VX17-445-103 (NCT03525548)

Active (parallel)

 ≥ 12 years—F508del/F508del Sample size: 107

4 weeks

Absolute change in ppFEV1 from baseline at wk 4

LS Mean difference ELX/TEZ/IVA vs control (95% CI): + 10 (+ 7.4, + 12.6)

[66]

18

N/A

26/04/21

III

VX18-445-104 (NCT04058353)

Active (parallel)

 ≥ 12 years—F508del/RF + F508del/Gating Sample size: 258

8 weeks

Absolute change in ppFEV1 from baseline at wk 8

LS Mean difference ELX/TEZ/IVA vs control (95% CI): + 3.7 (+ 2.8, + 4.6)

[35]

19

08/06/21

07/01/22

III

VX18-445-106 (NCT03691779)

Open-label

6 to 11 years—F508del/MF + F508del/F508del Sample size: 66 (Part A: 16 Part B: 66)

Part A: 15 days Part B: 24 weeks

(A) pharmacokynetic (A, B) safety: number of participants with TEAEs and SAEs

(A) safety: 12 subj had AEs (75%), no SAEs (B) safety: 65 subj had AEs (98.5%), 1 subj (1.5%) had SAEs

[67]

  1. Bold style has been used only to highlight the results of the studies
  2. Definitions: * = G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P or G1349D; RF = residual function CFTR mutation according to the clinical trial list [14]; MF minimal function CFTR mutation according to the clinical trial list [68], IVA ivacaftor (VX-770), LUM lumacaftor (VX-809), TEZ tezacaftor (VX-661), ELX elexacaftor (VX-445), RCT Randomized Controlled Trial; SID = once daily, BID twice daily, ppFEV1 percentage of predicted forced expiratory volume in 1 s, LCI2.5 Lung Clearance Index 2.5: its decrease indicates improvement in lung function; AEs Adverse Events, SAEs Serious Adverse Events, LS Means Least Squares Means, CI confidence interval
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Orphanet Journal of Rare Diseases

ISSN: 1750-1172