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Clinical Trial Results:
A Phase 2 Study of Galicaftor/Navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 Combination Therapies in Subjects With Cystic Fibrosis Who Are Homozygous or Heterozygous for the F508del Mutation

Summary
EudraCT number	2020-005805-25
Trial protocol	BE HU NL
Global end of trial date	05 Jun 2023

Results information
Results version number	v1(current)
This version publication date	20 Jun 2024
First version publication date	20 Jun 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

M19-771

ISRCTN number

US NCT number

NCT04853368

WHO universal trial number (UTN)

Sponsor organisation name

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation address

AbbVie House, Vanwall Business Park, Vanwall Road, , Maidenhead, Berkshire, United Kingdom, SL6 4UB

Public contact

Global Medical Services, AbbVie, AbbVie Deutschland GmbH & Co. KG , 001 8006339110, abbvieclinicaltrials@abbvie.com

Scientific contact

Global Medical Services, AbbVie, AbbVie Deutschland GmbH & Co. KG , 001 8006339110, abbvieclinicaltrials@abbvie.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

05 Jun 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

05 Jun 2023

Was the trial ended prematurely?

Yes

Main objective of the trial

The main objective of this study is to assess how safe and effective is the combination therapy of galicaftor/navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 in adult participants with CF who are homozygous or heterozygous for the F508del mutation in each arm.

Protection of trial subjects

The investigator or his/her representative explained the nature of the study to the subject and answered all questions regarding this study. Subject and/or legal guardian/representative read and understood the information provided about the study and gave written permission.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Sep 2021

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 10

Country: Number of subjects enrolled

Australia: 16

Country: Number of subjects enrolled

Hungary: 7

Country: Number of subjects enrolled

Netherlands: 3

Country: Number of subjects enrolled

New Zealand: 8

Country: Number of subjects enrolled

Slovakia: 4

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were enrolled at 41 sites in 6 countries. Cohort 1 subjects (C1), received galicaftor/navocaftor dual therapy for 28 days as a Run-in Period Cohort 1(d-29 to -1), followed by galicaftor/navocaftor/ABBV-119 triple therapy for 28 days as a Triple Combination Treatment Period.

Screening details

Subjects either homozygous or heterozygous for F508del mutation were placed in cohorts based on genotype and treatment status of ETI therapy. In Part 1, Cohort 1(d-29 to -1) (C1) completed g/n dual combo therapy for 28 days (d) and started Part 2. In Part 2, C1(d 1 – 29) and C2 received g/n/ABBV-119 triple combo, and C3 received g/n/ABBV-576 triple

Period 1 title

Study Period (Days 1 to 29) (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

Participants in Cohorts 1 and 3 will receive Open-label therapy. Participants in Cohorts 2 will receive Double-blinded therapy. Part 1 of this study includes Cohort 1 (Day -29 to -1) Dual Combination Galicaftor + Navocaftor for F508del Homozygous (n=24). Part 2 of this study includes Cohort 1 (Day 1 to 29) and Cohorts 2 and 3 (Day 1 to 29).

Are arms mutually exclusive

Yes

C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo

Arm description

F508del homozygous CF participants from Cohort 1(Day -29 to -1) who received Galicaftor/Navocaftor dual combination therapy followed by Galicaftor/Navocaftor/ABBV-119 triple combination therapy (Day 1- 29). Galicaftor: 300 mg QD, Oral capsules Navocaftor: 50 mg QD, Oral capsules ABBV-119: 210 mg BID, Oral capsules

Arm type

Experimental

Investigational medicinal product name

Galicaftor

Investigational medicinal product code

Other name

ABBV-2222

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Galicaftor: 300 mg QD, Oral capsules

Investigational medicinal product name

Navocaftor

Investigational medicinal product code

Other name

ABBV-3067

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Navocaftor: 50 mg QD, Oral capsules

Investigational medicinal product name

ABBV-119

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

210 mg BID, Oral capsules

C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete

Arm description

F508del Heterozygous CF participants received Galicaftor/Navocaftor/ABBV-119 triple combination therapy (Day 1 - 29). Galicaftor: 300 mg QD, Oral capsules Navocaftor: 50 mg QD, Oral capsules ABBV-119: 210 mg BID, Oral capsules

Arm type

Experimental

Investigational medicinal product name

Galicaftor

Investigational medicinal product code

Other name

ABBV-2222

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Galicaftor: 300 mg QD, Oral capsules

Investigational medicinal product name

Navocaftor

Investigational medicinal product code

Other name

ABBV-3067

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Navocaftor: 50 mg QD, Oral capsules

Investigational medicinal product name

ABBV-119

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

210 mg BID, Oral capsules

C2 (Day 1 - 29) Placebo F508del Heterozygous

Arm description

F508del Heterozygous CF participants received placebo (Day 1 - 29). Placebo: Oral capsules

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral capsules

C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo

Arm description

F508del Homozygous CF participants received Galicaftor/Navocaftor/ABBV-576 triple combination therapy (Day 1 - 29). Galicaftor: 300 mg QD, Oral capsules Navocaftor: 50 mg QD, Oral capsules ABBV-576: 5 mg QD, Oral capsules

Arm type

Experimental

Investigational medicinal product name

Galicaftor

Investigational medicinal product code

Other name

ABBV-2222

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Galicaftor: 300 mg QD, Oral capsules

Investigational medicinal product name

Navocaftor

Investigational medicinal product code

Other name

ABBV-3067

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Navocaftor: 50 mg QD, Oral capsules

Investigational medicinal product name

ABBV-576

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

ABBV-576: 5 mg QD, Oral capsules

C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete

Arm description

F508del Heterozygous CF participants received Galicaftor/Navocaftor/ABBV-576 triple combination therapy (Day 1 - 29). Galicaftor: 300 mg QD, Oral capsules Navocaftor: 50 mg QD, Oral capsules ABBV-576: 5 mg QD, Oral capsules

Arm type

Experimental

Investigational medicinal product name

Galicaftor

Investigational medicinal product code

Other name

ABBV-2222

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Galicaftor: 300 mg QD, Oral capsules

Investigational medicinal product name

Navocaftor

Investigational medicinal product code

Other name

ABBV-3067

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Navocaftor: 50 mg QD, Oral capsules

Investigational medicinal product name

ABBV-576

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

ABBV-576: 5 mg QD, Oral capsules

Number of subjects in period 1	C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo	C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete	C2 (Day 1 - 29) Placebo F508del Heterozygous	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete
Started	24	9	4	9	2
Completed	22	9	4	8	2
Not completed	2	0	0	1	0
Consent withdrawn by subject	-	-	-	1	-
other	2	-	-	-	-

Baseline characteristics

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Reporting group title

C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo

Reporting group description

Reporting group title

C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete

Reporting group description

Reporting group title

C2 (Day 1 - 29) Placebo F508del Heterozygous

Reporting group description

F508del Heterozygous CF participants received placebo (Day 1 - 29). Placebo: Oral capsules

Reporting group title

C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo

Reporting group description

Reporting group title

C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete

Reporting group description

Reporting group values	C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo	C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete	C2 (Day 1 - 29) Placebo F508del Heterozygous	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete	Total
Number of subjects	24	9	4	9	2	48
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	33.5 ( 8.80 )	35.2 ( 11.09 )	30.0 ( 10.55 )	34.4 ( 7.84 )	37.0 ( 5.66 )	-
Gender categorical
Units: Subjects
Female	9	3	1	2	2	17
Male	15	6	3	7	0	31
Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) (%) at Baseline (Day 1)
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Units: percent predicted FEV1 (%)
arithmetic mean (standard deviation)	57.0 ( 14.63 )	62.9 ( 18.27 )	67.3 ( 19.97 )	57.0 ( 19.77 )	51.0 ( 5.66 )	-
Sweat Chloride (SwCl) in mmol/L at Baseline (Day 1) Cohort 3
Units: mmol/L
arithmetic mean (standard deviation)	76.71 ( 13.127 )	93.61 ( 12.437 )	98.38 ( 9.978 )	42.94 ( 10.333 )	26.50 ( 4.950 )	-

End points

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Reporting group title

C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo

Reporting group description

Reporting group title

C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete

Reporting group description

Reporting group title

C2 (Day 1 - 29) Placebo F508del Heterozygous

Reporting group description

F508del Heterozygous CF participants received placebo (Day 1 - 29). Placebo: Oral capsules

Reporting group title

C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo

Reporting group description

Reporting group title

C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete

Reporting group description

Primary: Cohorts 1 and 2: Absolute Change From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

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End point title

Cohorts 1 and 2: Absolute Change From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) ^[1]

End point description

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration and is used as a measure of lung function. Mixed-effect model with repeated measures (MMRM) was used for the analyses.

End point type

Primary

End point timeframe

Day 1 (Baseline) through Day 29

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The arms as shown are aligned with the sub study and planned analysis population for this end point per protocol and statistical analysis plan.

End point values	C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo	C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete	C2 (Day 1 - 29) Placebo F508del Heterozygous
Number of subjects analysed	20 ^[2]	7 ^[3]	4
Units: percent predicted FEV1 (%ppFEV1)
arithmetic mean (standard deviation)	2.2 ( 3.68 )	2.6 ( 5.62 )	-2.0 ( 6.63 )

Attachments

C1 Absolute Change From Baseline in ppFEV1
C2 Absolute Change From Baseline in ppFEV1

Notes
[2] - 2-sided CI was calculated as 90% and 1.22 to 4.04 CI
[3] - 2-sided CI was calculated as 90% and -2.07 to 4.67 CI

C2 + PBO Absolute Change From Baseline in ppFEV1

Comparison groups

C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete v C2 (Day 1 - 29) Placebo F508del Heterozygous

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.402 ^[5]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.9

Confidence interval

level

90%

sides

2-sided

lower limit

-5.07

upper limit

6.77

Notes
[4] - Primary analysis of ppFEV1 using MMRM excludes data inconsistent with baseline in terms of the timing of bronchodilator or airway clearance regimen.
[5] - One-sided p-value; p-value <=0.05 indicates significance

Primary: Cohort 3: Absolute Change From Baseline Through Day 29 in Sweat Chloride (SwCl) in mmol/L

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End point title

Cohort 3: Absolute Change From Baseline Through Day 29 in Sweat Chloride (SwCl) in mmol/L ^[6] ^[7]

End point description

Sweat collection was performed to evaluate sweat chloride concentration. SwCl is a biomarker of cystic fibrosis transmembrane conductance regulator (CFTR) activity. Persons with CF have higher levels of chloride in their sweat. MMRM was used for the analysis.

End point type

Primary

End point timeframe

Day 1 (Baseline) through Day 29

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The arms as shown are aligned with the sub study and planned analysis population for this end point per protocol and statistical analysis plan.
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The arms as shown are aligned with the sub study and planned analysis population for this end point per protocol and statistical analysis plan.

End point values	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete
Number of subjects analysed	1	1
Units: mmol/L
arithmetic mean (full range (min-max))	24 (24 to 24)	40 (40 to 40)

No statistical analyses for this end point

Secondary: Cohorts 1 and 2: Absolute Change From Baseline Through Day 29 in Sweat Chloride (SwCl) in mmol/L

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End point title

Cohorts 1 and 2: Absolute Change From Baseline Through Day 29 in Sweat Chloride (SwCl) in mmol/L ^[8]

End point description

Sweat collection was performed to evaluate sweat chloride concentration. SwCl is a biomarker of CFTR activity. Persons with CF have higher levels of chloride in their sweat. MMRM was used for the analysis.

End point type

Secondary

End point timeframe

Day 1 (Baseline) through Day 29

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The arms as shown are aligned with the sub study and planned analysis population for this end point per protocol and statistical analysis plan.

End point values	C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo	C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete	C2 (Day 1 - 29) Placebo F508del Heterozygous
Number of subjects analysed	20 ^[9]	7	4
Units: mmol/L
arithmetic mean (standard deviation)	5.7 ( 10.78 )	-11.5 ( 16.61 )	2.5 ( 4.56 )

Attachments

C1 Absolute Change From Baseline in Sweat Chloride

Notes
[9] - 2-sided CI was calculated as 90% and 1.07 to 9.92 CI

C2+ PBO Abs Change From Baseline in Sweat Chloride

Comparison groups

C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete v C2 (Day 1 - 29) Placebo F508del Heterozygous

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.043 ^[10]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-14.1

Confidence interval

level

90%

sides

2-sided

lower limit

-27.59

upper limit

-0.62

Notes
[10] - One-sided p-value; p-value <=0.05 indicates significance.

Secondary: Absolute Change From Baseline Through Day 29 in Forced Vital Capacity (FVC)

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End point title

Absolute Change From Baseline Through Day 29 in Forced Vital Capacity (FVC)

End point description

FVC is the total amount of air exhaled during forced expiratory volume (FEV) test and is a lung function test that is measured during spirometry. MMRM was used for the analyses.

End point type

Secondary

End point timeframe

Day 1 (Baseline) through Day 29

End point values	C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo	C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete	C2 (Day 1 - 29) Placebo F508del Heterozygous	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete
Number of subjects analysed	20 ^[11]	7 ^[12]	4	3	1 ^[13]
Units: Liters (L)
arithmetic mean (standard deviation)	0.10 ( 0.256 )	0.05 ( 0.269 )	-0.07 ( 0.297 )	-0.22 ( 0.318 )	-0.28 ( 9999 )

Attachments

C1 Absolute Change From Baseline in FVC
C2 Abs Change From Baseline Through Day 29 in FVC

Notes
[11] - 2-sided CI was calculated as 90% and 0.059 to 0.219 CI
[12] - 2-sided CI was calculated as 90% and -0.162 to 0.150 CI
[13] - SD not applicable; value could not be estimated due to n=1

C2 + PBO Abs Change From BL Through Day 29 in FVC

Comparison groups

C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete v C2 (Day 1 - 29) Placebo F508del Heterozygous

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.352 ^[14]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.06

Confidence interval

level

90%

sides

2-sided

lower limit

-0.332

upper limit

0.212

Notes
[14] - One-sided p-value; p-value <=0.05 indicates significance.

Secondary: Absolute Change From Baseline Through Day 29 in Forced Expiratory Flow at Mid-Lung Capacity (FEF25-75)

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End point title

Absolute Change From Baseline Through Day 29 in Forced Expiratory Flow at Mid-Lung Capacity (FEF25-75)

End point description

FEF25-75 is a lung function test that is measured during spirometry, and is defined as the forced expiratory flow between 25% and 75% of vital capacity (mid-lung capacity). MMRM was used for analyses.

End point type

Secondary

End point timeframe

Day 1 (Baseline) through Day 29

End point values	C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo	C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete	C2 (Day 1 - 29) Placebo F508del Heterozygous	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete
Number of subjects analysed	20 ^[15]	7 ^[16]	4	3	1 ^[17]
Units: Liters/second (L/sec)
arithmetic mean (standard deviation)	0.067 ( 0.2038 )	0.134 ( 0.2506 )	-0.082 ( 0.1947 )	-0.329 ( 0.378 )	-0.263 ( 9999 )

Attachments

C1 Abs Change From BL through Day 29 in FEF25-75
C2 Abs Change From BL Through Day 29 in FEF25-75

Notes
[15] - 2-sided CI was calculated as 90% and 0.0209 to 0.1568 CI
[16] - 2-sided CI was calculated as 90% and -0.1814 to 0.2880 CI
[17] - SD not applicable; value could not be estimated due to n=1

C2+PBO Abs Change From BL Through D29 in FEF25-75

Statistical analysis description

Cohort 2 (Day 1 - 29) Triple Combination Galicaftor+ Navocaftor + ABBV-119 for F508del Heterozygous, Cohort 2 (Day 1 - 29) Placebo F508del Heterozygous

Comparison groups

C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete v C2 (Day 1 - 29) Placebo F508del Heterozygous

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

= 0.23 ^[19]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.136

Confidence interval

level

90%

sides

2-sided

lower limit

-0.1809

upper limit

0.4527

Notes
[18] - The LS mean is estimated using the mixed-Effect model repeat measurement method.
[19] - One-sided p-value; p-value <=0.05 indicates significance

Secondary: Relative Changes From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Top of page

End point title

Relative Changes From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

End point description

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration and is used as a measure of lung function. MMRM was used for the analyses. Note: The primary analysis of ppFEV1 using MMRM excludes data that are inconsistent with baseline in terms of the timing of bronchodilator or airway clearance regimen.

End point type

Secondary

End point timeframe

Day 1 (Baseline) through Day 29

End point values	C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo	C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete	C2 (Day 1 - 29) Placebo F508del Heterozygous	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete
Number of subjects analysed	20 ^[20]	7 ^[21]	4	3	1 ^[22]
Units: % ppFEV1
arithmetic mean (standard deviation)	3.8 ( 6.07 )	3.3 ( 8.15 )	-4.9 ( 12.25 )	-9.1 ( 5.12 )	-19.1 ( 99999 )

Attachments

C1 Relative Changes From Baseline in ppFEV1
C2 Relative Changes From Baseline in ppFEV1

Notes
[20] - 2-sided CI was calculated as 90% and 2.04 to 6.78 CI
[21] - 2-sided CI was calculated as 90% and -4.42 to 6.97 CI
[22] - SD not applicable; value could not be estimated due to n=1

C2 + PBO Relative Changes From Baseline in ppFEV1

Statistical analysis description

Cohort 2(Day 1 - 29) Triple Combination Galicaftor+ Navocaftor + ABBV-119 for F508del Heterozygous, Cohort 2 (Day 1 - 29) Placebo F508del Heterozygous

Comparison groups

C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete v C2 (Day 1 - 29) Placebo F508del Heterozygous

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.412 ^[23]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

1.3

Confidence interval

level

90%

sides

2-sided

lower limit

-8.75

upper limit

11.34

Notes
[23] - Comments One-sided p-value; p-value <=0.05 indicates significance.

Secondary: Relative Changes From Baseline Through Day 29 in Forced Vital Capacity (FVC)

Top of page

End point title

Relative Changes From Baseline Through Day 29 in Forced Vital Capacity (FVC)

End point description

FVC is the total amount of air exhaled during FEV test and is a lung function test that is measured during spirometry. MMRM was used for the analyses.

End point type

Secondary

End point timeframe

Day 1 (Baseline) through Day 29

End point values	C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo	C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete	C2 (Day 1 - 29) Placebo F508del Heterozygous	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete
Number of subjects analysed	20 ^[24]	7 ^[25]	4	3	1 ^[26]
Units: Liters (L)
arithmetic mean (standard deviation)	3.75 ( 7.006 )	1.07 ( 6.524 )	-2.06 ( 8.004 )	-6.01 ( 8.782 )	-16.91 ( 99999 )

Attachments

C1 Relative Changes From Baseline in FVC
C2 Relative Changes From Baseline in FVC

Notes
[24] - 2-sided CI was calculated as 90% and 2.190 to 6.524 CI
[25] - 2-sided CI was calculated as 90% and -4.449 to 3.268 CI
[26] - SD value could not be estimated due to n=1

C2 + PBO Relative Changes From Baseline in FVC

Statistical analysis description

Cohort 2(Day 1 - 29) Triple Combination Galicaftor+ Navocaftor + ABBV-119 for F508del Heterozygous, Cohort 2 (Day 1 - 29) Placebo for F508del Heterozygous

Comparison groups

C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete v C2 (Day 1 - 29) Placebo F508del Heterozygous

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.305 ^[27]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2

Confidence interval

level

90%

sides

2-sided

lower limit

-8.724

upper limit

4.732

Notes
[27] - One-sided p-value; p-value <=0.05 indicates significance.

Secondary: Relative Changes From Baseline Through Day 29 in Forced Expiratory Flow at Mid-Lung Capacity (FEF25-75)

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End point title

Relative Changes From Baseline Through Day 29 in Forced Expiratory Flow at Mid-Lung Capacity (FEF25-75)

End point description

End point type

Secondary

End point timeframe

Day 1 (Baseline) through Day 29

End point values	C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo	C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete	C2 (Day 1 - 29) Placebo F508del Heterozygous	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete
Number of subjects analysed	20 ^[28]	7 ^[29]	4	3	1 ^[30]
Units: Liters/second (L/sec)
arithmetic mean (standard deviation)	4.553 ( 13.2453 )	8.701 ( 12.9781 )	-6.449 ( 25.1954 )	-8.288 ( 24.409 )	-25.784 ( 99999 )

Attachments

C1 Relative Change from BL through D29 in FEF25-75
C2 Relative Change from BL through D29 in FEF25-75

Notes
[28] - 2-sided CI was calculated as 90% and 1.4443 to 11.5056 CI
[29] - 2-sided CI was calculated as 90% and -7.1464 to 19.1844 CI
[30] - SD value could not be estimated due to n=1

C2+PBO Rel Change from BL through D29 in FEF25-75

Statistical analysis description

Cohort 2(Day 1 - 29) Triple Combination Galicaftor+ Navocaftor + ABBV-119 for F508del Heterozygous, Cohort 2 (Day 1 - 29) Placebo for F508del Heterozygous

Comparison groups

C2 (Day 1 - 29) Placebo F508del Heterozygous v C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.286 ^[31]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

7.29

Confidence interval

level

90%

sides

2-sided

lower limit

-15.186

upper limit

29.766

Notes
[31] - One-sided p-value; p-value <=0.05 indicates significance.

Secondary: Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline.

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End point title

Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline.

End point description

The CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score is designed for use in participants with a diagnosis of cystic fibrosis and is designed to measure impact on overall health, daily life, perceived well-being, and symptoms. CFQ-R has a total of 50 questions. Questions 40, 41, 42, 44, 45, 46, scored 1, 2, 3, or 4, from worst to best, were used to calculate the respiratory domain score. The scaled score for the domain is calculated as 100 × (mean scores of all non-missing questions – 1) / 3, ranging from 0 to 100. If more than 3 questions in the domain have missing scores, the scaled score was set as missing. Note: The LS mean is estimated using the linear regression on the change in CFQ-R from baseline to day 29.

End point type

Secondary

End point timeframe

Day 1 (Baseline) through Day 29

End point values	C1 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Homo	C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete	C2 (Day 1 - 29) Placebo F508del Heterozygous	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete
Number of subjects analysed	19 ^[32]	7 ^[33]	4	3	1 ^[34]
Units: score on a scale
arithmetic mean (standard deviation)	5.56 ( 15.930 )	10.32 ( 19.092 )	-5.56 ( 21.754 )	-9.26 ( 22.453 )	-22.22 ( 99999 )

Attachments

C1 Absolute Change in CFQ-R Score From Baseline
C2 Absolute Change in CFQ-R Score From Baseline

Notes
[32] - 2-sided CI was calculated as 90% and -0.26 to 11.37 CI
[33] - 2-sided CI was calculated as 90% and -2.18 to 19.40 CI
[34] - ] value could not be estimated due to n=1

C2 + PBO Abs Change in CFQ-R Score From Baseline

Statistical analysis description

Cohort 2(Day 1 - 29) Triple Combination Galicaftor+ Navocaftor + ABBV-119 for F508del Heterozygous, Cohort 2 (Day 1 - 29) Placebo for F508del Heterozygous

Comparison groups

C2 (Day 1 - 29) Placebo F508del Heterozygous v C2 (Day 1 - 29) Triple Combo G + N + ABBV-119 for F508del Hete

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.142 ^[35]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

11.2

Confidence interval

level

90%

sides

2-sided

lower limit

-6.9

upper limit

29.25

Notes
[35] - One-sided p-value; p-value <=0.05 indicates significance.

Secondary: Cohorts 3: Absolute Change From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

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End point title

Cohorts 3: Absolute Change From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) ^[36]

End point description

End point type

Secondary

End point timeframe

Day 1 (Baseline) through Day 29

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The arms as shown are aligned with the sub study and planned analysis population for this end point per protocol and statistical analysis plan.

End point values	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Homo	C3 (Day 1 - 29) Triple Combo G + N + ABBV-576 for F508del Hete
Number of subjects analysed	3	1
Units: % ppFEV1
arithmetic mean (full range (min-max))	-5.7 (-9.0 to -3.0)	-9.0 (-9.0 to -9.0)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All-cause mortality is reported from enrollment to the end of study, median time on follow up in Part 1 was 28d for C1. In Part 2, was 28d for C1; 28, 28d for C2;14, 20.5, and 14d for C3. AEs were collected from first dose until 30d after last dose.

Adverse event reporting additional description

For Cohort 1 - Triple Combination Treatment arm, a TEAE was collected through day 56 and within 30 days after the last dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Cohort_1_Dual_Run-in_Galicaftor_Navocaftor_Homozygous

Reporting group description

Reporting group title

Cohort_1_Triple_Galicaftor_Navocaftor_ABBV-119_Homozygous

Reporting group description

Reporting group title

Cohort_3_Triple_Galicaftor_Navocaftor_ABBV-576_Heterozygous

Reporting group description

Reporting group title

Cohort_2_Placebo_Heterozygous

Reporting group description

Reporting group title

Cohort_3_Triple_Galicaftor_Navocaftor_ABBV-576_Homozygous

Reporting group description

Reporting group title

Cohort_2_Triple_Galicaftor_Navocaftor_ABBV-119_Heterozygous

Reporting group description

Serious adverse events	Cohort_1_Dual_Run-in_Galicaftor_Navocaftor_Homozygous	Cohort_1_Triple_Galicaftor_Navocaftor_ABBV-119_Homozygous	Cohort_3_Triple_Galicaftor_Navocaftor_ABBV-576_Heterozygous	Cohort_2_Placebo_Heterozygous	Cohort_3_Triple_Galicaftor_Navocaftor_ABBV-576_Homozygous	Cohort_2_Triple_Galicaftor_Navocaftor_ABBV-119_Heterozygous
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 24 (0.00%)	1 / 24 (4.17%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Congenital, familial and genetic disorders
CYSTIC FIBROSIS
subjects affected / exposed	0 / 24 (0.00%)	1 / 24 (4.17%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
INFECTIVE EXACERBATION OF BRONCHIECTASIS
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cohort_1_Dual_Run-in_Galicaftor_Navocaftor_Homozygous	Cohort_1_Triple_Galicaftor_Navocaftor_ABBV-119_Homozygous	Cohort_3_Triple_Galicaftor_Navocaftor_ABBV-576_Heterozygous	Cohort_2_Placebo_Heterozygous	Cohort_3_Triple_Galicaftor_Navocaftor_ABBV-576_Homozygous	Cohort_2_Triple_Galicaftor_Navocaftor_ABBV-119_Heterozygous
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 24 (16.67%)	10 / 24 (41.67%)	2 / 2 (100.00%)	2 / 4 (50.00%)	7 / 9 (77.78%)	4 / 9 (44.44%)
Investigations
SPIROMETRY ABNORMAL
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0
FORCED VITAL CAPACITY DECREASED
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0
FORCED EXPIRATORY VOLUME DECREASED
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0
Injury, poisoning and procedural complications
NASAL INJURY
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1
Nervous system disorders
HEADACHE
subjects affected / exposed	1 / 24 (4.17%)	2 / 24 (8.33%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	1	5	0	0	1	0
LETHARGY
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0
POST-TRAUMATIC HEADACHE
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1
General disorders and administration site conditions
FATIGUE
subjects affected / exposed	1 / 24 (4.17%)	2 / 24 (8.33%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	1	3	0	0	1	0
INFLUENZA LIKE ILLNESS
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0
CHEST DISCOMFORT
subjects affected / exposed	1 / 24 (4.17%)	0 / 24 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	1	0	0	1
NON-CARDIAC CHEST PAIN
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0
PAIN
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastrointestinal disorders
ABDOMINAL PAIN LOWER
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0
CONSTIPATION
subjects affected / exposed	0 / 24 (0.00%)	1 / 24 (4.17%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	1	0
DIARRHOEA
subjects affected / exposed	0 / 24 (0.00%)	2 / 24 (8.33%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0	0
DYSPEPSIA
subjects affected / exposed	2 / 24 (8.33%)	1 / 24 (4.17%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	1	0	0	0	0
DISTAL INTESTINAL OBSTRUCTION SYNDROME
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1
ABDOMINAL PAIN UPPER
subjects affected / exposed	0 / 24 (0.00%)	2 / 24 (8.33%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0	0
VOMITING
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0
STEATORRHOEA
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0
NAUSEA
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	1 / 2 (50.00%)	1 / 4 (25.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	1	0	0
FLATULENCE
subjects affected / exposed	0 / 24 (0.00%)	1 / 24 (4.17%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	1	0
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	0 / 24 (0.00%)	2 / 24 (8.33%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0	0
Respiratory, thoracic and mediastinal disorders
RESPIRATORY TRACT CONGESTION
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0
CATARRH
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0
COUGH
subjects affected / exposed	0 / 24 (0.00%)	1 / 24 (4.17%)	2 / 2 (100.00%)	2 / 4 (50.00%)	4 / 9 (44.44%)	0 / 9 (0.00%)
occurrences all number	0	1	2	2	5	0
DYSPNOEA
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	2 / 2 (100.00%)	0 / 4 (0.00%)	3 / 9 (33.33%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	3	0
DYSPNOEA EXERTIONAL
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0
EPISTAXIS
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1
HAEMOPTYSIS
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0
UPPER-AIRWAY COUGH SYNDROME
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0
SPUTUM INCREASED
subjects affected / exposed	0 / 24 (0.00%)	2 / 24 (8.33%)	1 / 2 (50.00%)	0 / 4 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)
occurrences all number	0	2	1	0	2	0
RHINORRHOEA
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0
Skin and subcutaneous tissue disorders
NIGHT SWEATS
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0
RASH
subjects affected / exposed	0 / 24 (0.00%)	2 / 24 (8.33%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	2	0	0	0	1
Musculoskeletal and connective tissue disorders
BACK PAIN
subjects affected / exposed	0 / 24 (0.00%)	1 / 24 (4.17%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	1	0	0	0	1
Infections and infestations
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 24 (4.17%)	0 / 24 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	1	0
INFECTIVE PULMONARY EXACERBATION OF CYSTIC FIBROSIS
subjects affected / exposed	0 / 24 (0.00%)	0 / 24 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0
COVID-19
subjects affected / exposed	0 / 24 (0.00%)	4 / 24 (16.67%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	4	0	0	0	0
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	0 / 24 (0.00%)	1 / 24 (4.17%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	1	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

24 Mar 2021

The purpose of this version is to correct minor clerical errors for consistency throughout the protocol in addition to the following: • Clarified that home spirometry will be performed by subjects based on availability of devices at the site(s)

04 Jun 2021

The purpose of this version is to update the ABBV-119 final dose and dosing regimen, and add Cohort 3 for participating countries with access to ETI, in addition to the following: • Updated the risk sections based on preliminary Phase 1 data and nonclinical data, including updates to LFT requirements including the following: o Added additional safety monitoring for LFTs considering the ABBV-119 Phase 1 data, including new Day 21 visit for all 3 cohorts o Updated eligibility criteria to better exclude patients with underlying conditions that may increase risk of hepatic AEs: Excluded subjects with cirrhosis with or without portal hypertension or history of clinically significant liver disease • Added language to allow subjects to have LFTs done in a local laboratory if a subject cannot return to the site for testing and provide guidance on handling and reporting elevations in LFTs at the local laboratory • Updated statistical methods to o Describe that analysis of each cohort may be performed separately o Update the definition of the PP Population o Add the sample size and power calculation for Cohort 3 o Correct typos in the statistical analysis section o Clarify that AbbVie team will be blinded to the post-first-dose spirometry and SwCl data for Cohort 2 only o Update the definition of SAR and SUSAR to align with the current AbbVie template language

22 Oct 2021

The purpose of this version is to make the following changes: • Removed the SCR SwCl cutoff for Cohort 3 (Rationale: SwCl cutoff is not applicable to ETI treated subjects) • Added flexible language regarding MF mutations (Rationale: MF mutation table is not exhaustive) • Added prespecified interim analysis plan • Corrected error in Operations Manual • Added COVID-19 Pandemic-Related Vaccination Guidance • Added safety language on sun protection

02 Mar 2022

The purpose of this version is to make the following changes: • Grammatical updates to clarify language regarding timing of events occurring prior to study start • Updated the timing for the primary analysis and added clarity about which endpoints will be analyzed for the primary analysis to clarify appropriate timing for primary and secondary endpoint analyses. • Increased the number of subjects to have completed the triple combination treatment period or prematurely discontinue study drug treatment in Cohort 1 for the planned interim analysis from 10 to at least 15 • Clarified expectations of subjects to return the home spirometers and associated smart phones to the site after the completion of their participation in the study in the Operations Manual • Elaborated and clarified the medical management of rash and clarified that options including study drug interruption and/or resumption of study drug after interruption (if clinically appropriate) will be at the investigator's discretion, in the Operations Manual

30 Jun 2022

The purpose of this version is to make the following changes: • Added target engagement as one of the primary objectives of the study. Changed SwCl from secondary endpoint to primary endpoint and changed ppFEV1 from primary endpoint to secondary endpoint (Rationale: update study objectives and endpoint plan for the added investigational drug, ABBV-576) • Removed washout periods in Cohort 3 and added Day 4 phone call and Day 8 (Rationale: to minimize the risk of withdrawal syndromes and strengthen safety monitoring for the first week of the treatment period) • Changed spirometry assessment to be pre-bronchodilator use for all study visits, except for screening visit (Rationale: Minimize the potential impact of bronchodilator use on spirometry measurements) • Removed protocol language regarding 'Discontinuation of Study Drug Due to COVID-19 Infection' (Rationale: Update safety measure based on the evolving COVID-19 landscape) • Added DMC review of ABBV-576 Phase 1 safety data (Rationale: Update DMC review plan for the added investigational drug, ABBV-576) • Added interim analysis for Cohort 3 (Rationale: Added interim analysis for Cohort 3 to help AbbVie's internal decision making) • Removed Day 21 visit, ocular exam and neurologic examinations for Cohort 3 in Activity Schedule (Rationale: Update safety measures based on the safety profile of ABBV-576)

26 Aug 2022

The purpose of this version is to correct minor clerical errors for consistency throughout the protocol in addition to the following changes: • Added that Cohorts 1 and 2 were terminated based on efficacy results of an interim analysis (Rationale: To provide further details on the reason for changing the study regimen) • Added 'with and without other CFTR modulators (such as ABBV-119)' (Rationale: To provide further information to clarify the safety profile of the study Regimen) • Added further information on hepatobiliary events (Rationale: To provide further information to clarify the safety profile of the study regimen) • Added HDRS and the GAD-7 as exploratory safety endpoints for Cohort 3. Further details regarding the assessment have been included (Rationale: To update safety measure based on clinical reports for marketed CFTR modulator therapy) • Added 'and all study subjects can resume their ETI therapy after all of the study related procedures are completed on Day 29' (Rationale: To improve clarity regarding the timing of study activities at Day 29) • Clarified the eligibility criteria regarding the type of cirrhosis that must be absent for subjects to participate in the study under each cohort • Removed withdrawal criteria related to the use of triazole antimicrobial due to redundancy with the prohibited medications listed in protocol appendix • Added 'as well as mental health outcome measures' to protocol to incorporate exploratory measurements of mental health parameters in order to inform future trials. • Added recording of 'Date and time of last dose of ETI' to the Day 1 visit for Cohort 3 in protocol appendix and Operations Manual Appendix (Rationale: To update schedule of activity based on the updated Cohort 3 design) • Added criteria definition for minimal function mutations based on regulatory agency feedback • Added amylase and lipase laboratory tests to the Operations Manual (Rationale: To incorporate additional safety monitoring para

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Study prematurely ended early due to business decision.

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Clinical trials

Clinical Trial Results:
A Phase 2 Study of Galicaftor/Navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 Combination Therapies in Subjects With Cystic Fibrosis Who Are Homozygous or Heterozygous for the F508del Mutation

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Cohorts 1 and 2: Absolute Change From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Primary: Cohorts 1 and 2: Absolute Change From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Primary: Cohort 3: Absolute Change From Baseline Through Day 29 in Sweat Chloride (SwCl) in mmol/L

Primary: Cohort 3: Absolute Change From Baseline Through Day 29 in Sweat Chloride (SwCl) in mmol/L

Secondary: Cohorts 1 and 2: Absolute Change From Baseline Through Day 29 in Sweat Chloride (SwCl) in mmol/L

Secondary: Cohorts 1 and 2: Absolute Change From Baseline Through Day 29 in Sweat Chloride (SwCl) in mmol/L

Secondary: Absolute Change From Baseline Through Day 29 in Forced Vital Capacity (FVC)

Secondary: Absolute Change From Baseline Through Day 29 in Forced Vital Capacity (FVC)

Secondary: Absolute Change From Baseline Through Day 29 in Forced Expiratory Flow at Mid-Lung Capacity (FEF25-75)

Secondary: Absolute Change From Baseline Through Day 29 in Forced Expiratory Flow at Mid-Lung Capacity (FEF25-75)

Secondary: Relative Changes From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Secondary: Relative Changes From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Secondary: Relative Changes From Baseline Through Day 29 in Forced Vital Capacity (FVC)

Secondary: Relative Changes From Baseline Through Day 29 in Forced Vital Capacity (FVC)

Secondary: Relative Changes From Baseline Through Day 29 in Forced Expiratory Flow at Mid-Lung Capacity (FEF25-75)

Secondary: Relative Changes From Baseline Through Day 29 in Forced Expiratory Flow at Mid-Lung Capacity (FEF25-75)

Secondary: Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline.

Secondary: Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline.

Secondary: Cohorts 3: Absolute Change From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Secondary: Cohorts 3: Absolute Change From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
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Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase 2 Study of Galicaftor/Navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 Combination Therapies in Subjects With Cystic Fibrosis Who Are Homozygous or Heterozygous for the F508del Mutation

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Cohorts 1 and 2: Absolute Change From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Primary: Cohorts 1 and 2: Absolute Change From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Primary: Cohort 3: Absolute Change From Baseline Through Day 29 in Sweat Chloride (SwCl) in mmol/L

Primary: Cohort 3: Absolute Change From Baseline Through Day 29 in Sweat Chloride (SwCl) in mmol/L

Secondary: Cohorts 1 and 2: Absolute Change From Baseline Through Day 29 in Sweat Chloride (SwCl) in mmol/L

Secondary: Cohorts 1 and 2: Absolute Change From Baseline Through Day 29 in Sweat Chloride (SwCl) in mmol/L

Secondary: Absolute Change From Baseline Through Day 29 in Forced Vital Capacity (FVC)

Secondary: Absolute Change From Baseline Through Day 29 in Forced Vital Capacity (FVC)

Secondary: Absolute Change From Baseline Through Day 29 in Forced Expiratory Flow at Mid-Lung Capacity (FEF25-75)

Secondary: Absolute Change From Baseline Through Day 29 in Forced Expiratory Flow at Mid-Lung Capacity (FEF25-75)

Secondary: Relative Changes From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Secondary: Relative Changes From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Secondary: Relative Changes From Baseline Through Day 29 in Forced Vital Capacity (FVC)

Secondary: Relative Changes From Baseline Through Day 29 in Forced Vital Capacity (FVC)

Secondary: Relative Changes From Baseline Through Day 29 in Forced Expiratory Flow at Mid-Lung Capacity (FEF25-75)

Secondary: Relative Changes From Baseline Through Day 29 in Forced Expiratory Flow at Mid-Lung Capacity (FEF25-75)

Secondary: Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline.

Secondary: Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline.

Secondary: Cohorts 3: Absolute Change From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Secondary: Cohorts 3: Absolute Change From Baseline Through Day 29 in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2 Study of Galicaftor/Navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 Combination Therapies in Subjects With Cystic Fibrosis Who Are Homozygous or Heterozygous for the F508del Mutation