Clinical trial NCT04853368
Conditions: Cystic Fibrosis (CF)
Keywords: Cystic Fibrosis (CF) Galicaftor Navocaftor ABBV-119 ABBV-576
Sponsor: AbbVie
Start date: 2021-09-20; Completion date: 2023-06-05
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Cystic Fibrosis (CF) is a rare, life-threatening, genetic disease that affects the lungs and digestive system, significantly impairing the quality of life, with those affected having a median age of death at 40. 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.

Galicaftor/Navocaftor/ABBV-119 combination therapy and Galicaftor/Navocaftor/ABBV-576 is being developed as an investigational drug for the treatment of CF. Study doctors place participants in 1 of the 4 groups, called treatment arms. Each group receives a different treatment. Around 90 adult participants with a diagnosis of CF will be enrolled in the study around approximately 35 sites worldwide.

Participants in arm 1 will receive oral capsules of galicaftor/navocaftor dual combination for 28 days followed by galicaftor/navocaftor/ABBV-119 triple combination for 28 days. Participants in arms 2 and 3 will receive the galicaftor/navocaftor/ABBV-119 triple combination or placebo for 28 days. Participants in arm 4 will receive galicaftor/navocaftor/ABBV-576 triple combination therapy for 28 days. For all study arms, ABBV-576, galicaftor, navocaftor, will be given once daily and ABBV-119 twice a day.

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

Detailed description:
Participants in Cohorts 1 and 3 will receive Open-label therapy. Participants in Cohorts 2 will receive Double-blinded therapy.

Arms: arm 1: F508del homozygous cystic fibrosis (CF) participants receive galicaftor/navocaftor dual combination (28 days) followed by galicaftor/navocaftor/ABBV-119 triple combination therapy (28 days). arm 2: F508del heterozygous CF participants receive galicaftor/navocaftor/ABBV-119 combination therapy (28 days). arm 3: F508del heterozygous CF participants receive placebo (28 days). arm 4: F508del homozygous and heterozygous CF participants receive galicaftor/navocaftor/ABBV-576 triple combination therapy for 28 days.
Interventions: intervention 1: ABBV-576 intervention 2: Galicaftor intervention 3: Placebo intervention 4: Navocaftor intervention 5: ABBV-119
Intervention descriptions: intervention 1: Oral capsules intervention 2: Oral capsules intervention 3: Oral capsules intervention 4: Oral capsules intervention 5: Oral capsules

Protocol documents:
Prot_000.pdf: 


  
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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO SUBJECTS
8
3
OBJECTIVES AND ENDPOINTS
11
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
11
3.2
PRIMARY ENDPOINT
12
3.3
SECONDARY ENDPOINTS
12
3.4
EXPLORATORY EFFICACY ENDPOINT
13
3.5
SAFETY ENDPOINTS
13
3.6
EXPLORATORY SAFETY ENDPOINTS
13
3.7
PHARMACOKINETIC ENDPOINTS
13
3.8
BIOMARKER RESEARCH ENDPOINTS
13
4
INVESTIGATIONAL PLAN
14
4.1
OVERALL STUDY DESIGN AND PLAN
14
4.2
DISCUSSION OF STUDY DESIGN
17
5
STUDY ACTIVITIES
19
5.1
ELIGIBILITY CRITERIA
19
5.2
CONTRACEPTION RECOMMENDATIONS
23
5.3
PROHIBITED MEDICATIONS AND THERAPY
25
5.4
PRIOR AND CONCOMITANT THERAPY
25
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
27
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
29
5.7
STUDY DRUG AND STUDY DEVICES
29
5.8
RANDOMIZATION/DRUG ASSIGNMENT
32
5.9
PROTOCOL DEVIATIONS
32
5.10
DATA MONITORING COMMITTEE
33
6
SAFETY CONSIDERATIONS
33
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6.1
COMPLAINTS AND ADVERSE EVENTS
33
6.2
TOXICITY MANAGEMENT
39
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
39
7.1
STATISTICAL AND ANALYTICAL PLANS
39
7.2
DEFINITION FOR ANALYSIS POPULATIONS
40
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND KEY SECONDARY ENDPOINTS
40
7.4
STATISTICAL ANALYSES FOR EFFICACY
41
7.5
STATISTICAL ANALYSES FOR SAFETY
42
7.6
PHARMACOKINETIC AND EXPOSURE-RESPONSE ANALYSES
42
7.7
INTERIM ANALYSIS
43
7.8
OVERALL TYPE I ERROR CONTROL
43
7.9
SAMPLE SIZE DETERMINATION
43
8
ETHICS
44
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
44
8.2
ETHICAL CONDUCT OF THE STUDY
44
8.3
SUBJECT CONFIDENTIALITY
45
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
45
10
DATA QUALITY ASSURANCE
45
11
START AND COMPLETION OF THE STUDY
45
12
REFERENCES
45
LIST OF TABLES
TABLE 1.
IDENTITY OF INVESTIGATIONAL PRODUCTS
31
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
16
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
47
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
51
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
52
APPENDIX D.
ACTIVITY SCHEDULE
53
APPENDIX E.
EXAMPLES OF PROHIBITED MEDICATIONS AND THERAPY
60
APPENDIX F.
CFTR MINIMAL FUNCTION MUTATIONS ELIGIBLE FOR COHORT 2 AND COHORT 3
61
APPENDIX G.
PROTOCOL SUMMARY OF CHANGES
63
APPENDIX H.
OPERATIONS MANUAL
65
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Cystic fibrosis (CF) is caused by mutations in the gene that encodes for the CF transmembrane 
conductance regulator (CFTR) protein, a cyclic adenosine monophosphate (cAMP)-regulated anion 
channel expressed primarily at the apical plasma membrane of secretory epithelia.  The F508del 
mutation is the most common mutation globally, which is present on at least one allele in more than 
80% of CF patients.  The F508del mutation causes significantly reduced expression and function of the 
CFTR protein in various tissues (e.g., lung, pancreas), which leads to CF disease manifestations.
CFTR modulators are compounds designed to increase the cell surface expression and restore the 
function of CFTR.  Triple combination therapy of CFTR modulators (i.e., elexacaftor/tezacaftor/ivacaftor, 
or ETI) has been recently approved and marketed as Trikafta® or Kaftrio® to treat CF patients harboring 
at least one F508del mutation.  Although ETI demonstrated significant improvement in lung function in 
clinical studies, there is still a need for the development of treatment options for CF patients.  Therefore, 
additional CFTR modulators have been investigated as combination therapy to restore F508del CFTR
expression and function, including galicaftor (ABBV-2222), navocaftor (ABBV-3067), and ABBV-119 or 
ABBV-576.
In the cultivated human bronchial epithelial cells (HBEs) from F508del/F508del homozygous patients, 
the triple combinations of galicaftor/navocaftor/ABBV-119 and galicaftor/navocaftor/ABBV-576 showed 
more significant restoration of F508del CFTR expression and function than the combination of galicaftor 
and navocaftor.  This study is designed to evaluate the safety, tolerability, target engagement, and 
efficacy for galicaftor/navocaftor/ABBV-119 and galicaftor/navocaftor/ABBV-576 combination therapies 
in adult subjects with CF who are homozygous or heterozygous for the F508del mutation.
2.2 Benefits and Risks to Subjects
Benefits
Galicaftor has been evaluated as either single-agent therapy (GLPG2222-CL-202) or part of combination 
therapy (GLPG2737-CL-105) in subjects with CF who are homozygous for the F508del mutation.  The 
completed Phase 2 study (GLPG2222-CL-202) showed that 4-week treatment of galicaftor significantly 
reduced sweat chloride (SwCl) in CF subjects.  The completed Phase 1 study (GLPG2737-CL-105) also 
showed that the dual combination of galicaftor and GLPG2451 (another potentiator with a similar 
mechanism of action as navocaftor) further reduced SwCl and increased ppFEV1 in CF subjects.  In the 
cultivated human bronchial epithelial cells (HBEs) from F508del/F508del homozygous patients, the triple 
combinations of galicaftor/navocaftor/ABBV-119 and galicaftor/navocaftor/ABBV-576 showed more 
significant restoration of F508del CFTR expression and function than the dual combination of galicaftor 
and navocaftor.  Therefore, it is anticipated that the triple combination of 
galicaftor/navocaftor/ABBV-119 or galicaftor/navocaftor/ABBV-576 has the potential to improve 
F508del CFTR function in patients with CF who carry at least one copy of the mutation, as well as their 
lung function measured by ppFEV1.
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An interim analysis for Cohort 1 of the study was conducted after 15 subjects in Cohort 1 had completed 
the galicaftor/navocaftor/ABBV-119 triple combination treatment or prematurely discontinued study 
drug treatment (Section 7.7).  The galicaftor/navocaftor dual combination treatment was safe and well 
tolerated and resulted in a mean decrease in SwCl concentration (-14.2 mmol/L) from baseline at the 
end of 28-day run-in period.  The addition of ABBV-119 in the following triple combination treatment 
period was also well tolerated but did not result in further decrease in SwCl concentration. Therefore, 
Cohort 1 and Cohort 2 of the study were terminated based on the efficacy results following the interim 
analysis, and the design of Cohort 3 is modified to replace ABBV-119 with ABBV-576, a structurally 
differentiated modulator with improved safety and pharmacokinetic profiles that is hypothesized to 
deliver the therapeutic benefit of the triple combination therapy.
Risks
ABBV-119 was being characterized in two healthy-volunteer Phase 1 studies, M19-775 and M20-065, 
when the M19-771 study was initiated in 2021.  Based on preliminary pharmacokinetics (PK) and safety 
data from the single ascending dose (SAD) and multiple ascending dose (MAD) portions of the ongoing 
Study M19-775, a dose of 210 mg BID was selected for ABBV-119 in Study M19-771.  An independent 
data monitoring committee (DMC, see Section 5.10) reviewed the complete safety and PK data from the 
Phase 1 study prior to initiation of Study M19-771, and confirmed that it was safe to proceed with the 
planned 210 mg BID dose for ABBV-119.
ABBV-576 is currently being characterized in a Phase 1 study (Study M21-054, in healthy volunteers).  
Based on preliminary PK and safety data from the SAD and MAD portions of the ongoing Study M21-054, 
a dose of 5 mg QD has been selected for ABBV-576 in Study M19-771.  An independent DMC (see 
Section 5.10) will review the safety and PK data from ABBV-576 Phase 1 studies prior to the initiation of 
Cohort 3 and confirm that it is safe to proceed with the planned 5 mg QD dose for ABBV-576.
The safety results from the completed and ongoing Phase 1 studies demonstrated that ABBV-119,
ABBV-576, galicaftor, and navocaftor were generally well tolerated in healthy volunteers, either as single 
agents or combination regimen.  The following paragraphs describe the main safety issues that are 
potentially associated with repeated doses of the combination of ABBV-119, ABBV-576, galicaftor, and 
navocaftor.
Rash
Nonserious events of generalized rash of mild to moderate severity leading to study drug 
discontinuation have been observed following multiple dose treatment when galicaftor and navocaftor 
were co-administered with and without other CFTR modulators (such as ABBV-119).  Rash was 
considered possibly related to study drug by the investigator and resolved after treatment 
discontinuation.
There were also reports of mild rash occurring among subjects who received galicaftor or navocaftor 
given as monotherapy, but none led to study drug discontinuation.
As a result of these rash occurrences, enhanced safety monitoring and specific guidance to the 
investigator is described in the Operations Manual (Appendix H).  Rash is considered an adverse event of 
special interest (AESI) (see Section 6.1).
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Hepatobiliary Events 
Elevated liver function tests (LFTs) are adverse reactions associated with marketed products with a 
similar mechanism of action.  In the MAD part of the navocaftor first-in-human (FIH) study 
(GLPG3067-CL-101), one healthy volunteer who received navocaftor at the highest dose 500 mg BID 
temporarily interrupted treatment for a total of 2 doses because of alanine transaminase (ALT) elevation 
~3.8 × upper limit of normal (ULN) without concurrent bilirubin elevation.
In the Phase 1 and 2 studies for ABBV-119, 3 asymptomatic healthy volunteers (2 subjects in M20-065; 
1 subject in M19-775) and 1 CF subject in Cohort 1 of M19-771 experienced ALT elevations (peak value 
~4.8 - 8 × ULN) associated with milder increases in aspartate aminotransferase (AST) and gamma 
glutamyl transferase (GGT) with no concurrent rise in bilirubin.1  LFT elevations were observed 
14-19 days after multiple dosing with ABBV-119 (300 mg BID or 210 mg BID) given alone or in 
combination with galicaftor and navocaftor.  The events led to drug discontinuation in 2 subjects.  
Transaminases levels returned to normal in the follow-up period.  No severe or life-threatening
outcomes have been reported.
As a result of the hepatobiliary events, enhanced safety monitoring and specific guidance to the 
investigator is described in Section 6.1.  Hepatobiliary events are considered an AESI. A Day 21 visit was
added to Cohorts 1 and 2 (Appendix D) for clinical laboratory testing and monitoring for hepatobiliary 
adverse events (AEs).
Taken together, the safety and efficacy data from the Phase 1 and Phase 2 programs and the specific risk 
management activities to address the potential risks support further development of ABBV-576, 
galicaftor, and navocaftor in Phase 2 studies in subjects with CF, with the DMC review and monitoring 
plan (Section 5.10) in place to safeguard the study subjects.
Potential Risks based on Nonclinical Data
There is a potential risk of testicular toxicity based on adverse testicular changes that have been 
observed in dogs following navocaftor administration with a no-observed effect level (NOEL) at 3-fold of 
the observed exposure at the anticipated clinical dose (50 mg once daily [QD]).  The findings were 
reversible after a 13-week treatment-free period.  The triple combination toxicology studies with 
galicaftor/navocaftor/ABBV-119 resulted in new findings in the epididymis (adverse sperm granuloma) 
that were not reversible after a 4-week treatment-free period.  The findings and associated risks have 
been described in the Informed Consent.  Contraceptive guidance for males has been specified in 
Section 5.2.  To participate in the study, males must not be planning to father a child or donate sperm 
during the study and for 90 days after the last dose of study drug.  In the triple combination toxicology 
studies with galicaftor/navocaftor/ABBV-576, non-adverse gallbladder epithelial vacuolation occurred in 
the dog at doses of 300/10/3 mg/kg (galicaftor/navocaftor/ABBV-576) for 4 weeks.  A similar gallbladder 
effect was previously observed in dogs administered ABBV-576 for 4 weeks at 100 mg/kg (current ABBV-
5762 IB, Repeat-Dose Toxicity).  These changes were low grade and without correlating effects indicative 
of cellular or tissue injury.
No phototoxicity assessments have been conducted for ABBV-119 or ABBV-576 and the risk for 
phototoxicity is unknown.  Study subjects must comply with requirements to limit sun exposure and 
avoid UV beds and to use sun and UV-light protection (i.e., use of broad-spectrum sunscreen ≥SPF30, 
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protective clothing, hats and/or sunglasses) if there will be exposure to sunlight while participating in 
this study.
For further details, please see findings from completed studies, including safety data in the current 
galicaftor3, navocaftor4, ABBV-1195, and ABBV-5762 Investigator's Brochures (IBs).
COVID-19 Pandemic-Associated Risks
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects participating in this 
study has been re-evaluated.  The marketed CFTR modulator combination therapy ETI has been shown 
to improve pulmonary function1,6 and reduce sputum pathogen density in patients with CF.7  Since the 
combination of galicaftor/navocaftor/ABBV-119 or galicaftor/navocaftor/ABBV-576 is anticipated to 
have an analogous biological effect, participation in this study is not expected to increase COVID-19-
associated risk among study participants.
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Primary
The primary objective is to evaluate the safety, tolerability, target engagement, and efficacy for 
galicaftor/navocaftor/ABBV-119 and galicaftor/navocaftor/ABBV-576 combination therapies in adult 
subjects with CF who are homozygous or heterozygous for the F508del mutation in each cohort.
Clinical Hypotheses
1.
Galicaftor/navocaftor/ABBV-119 and galicaftor/navocaftor/ABBV-576 combination therapies are
safe and well-tolerated in adults with CF.
2.
Galicaftor/navocaftor/ABBV-119 combination therapy will result in significant improvement 
from baseline pharmacodynamic markers of CFTR function (lung function and SwCl) in CF 
subjects who are homozygous or heterozygous for the F508del mutation, and not receiving ETI 
therapy.
3.
Galicaftor/navocaftor/ABBV-119 and galicaftor/navocaftor/ABBV-576 combination therapies
will be able to maintain and/or improve CFTR function (lung function and SwCl) in CF subjects 
who have been receiving ETI therapy.
Baseline for efficacy endpoints in this protocol refers to the last non-missing observations before the 
first dose of galicaftor/navocaftor/ABBV-119 or galicaftor/navocaftor/ABBV-576 triple combination 
therapies on Study Day 1.
The statistical hypothesis for the primary efficacy objective is that the absolute change from Baseline 
through Day 29 in ppFEV1 (Cohorts 1 and 2) or SwCI (Cohort 3) is statistically significantly greater than 
zero in subjects treated with galicaftor/navocaftor/ABBV-119 (Cohorts 1 and 2) or 
galicaftor/navocaftor/ABBV-576 (Cohort 3) combination therapies.  This hypothesis will be tested 
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separately for each cohort and for the homozygous and heterozygous CF subjects at 1-sided type I error 
of 5%.
The estimand corresponding to the primary efficacy objective is the mean estimate of the absolute 
change from Baseline through Day 29 in ppFEV1 (Cohorts 1 and 2) or SwCI (Cohort 3) for subjects with CF 
who are homozygous (Cohorts 1 and 3) or heterozygous (Cohorts 2 and 3) for the F508del mutation and 
received at least one dose of galicaftor/navocaftor/ABBV-119 or galicaftor/navocaftor/ABBV-576 
combination treatment.  Subjects who do not have both Baseline and at least one post-baseline ppFEV1
or SwCl value from the triple combination treatment period will be excluded.  Subject's post-baseline 
ppFEV1 data that are collected with inconsistent bronchodilator or airway clearance status at Baseline or 
after a subject starts another CFTR modulator therapy will be excluded from the analysis.
3.2 Primary Endpoint
Cohorts 1 and 2: Absolute change from Baseline through Day 29 in percent predicted forced expiratory 
volume in 1 second (ppFEV1).
Cohort 3:  Absolute change from Baseline through Day 29 in SwCl.
3.3 Secondary Endpoints
Cohorts 1 and 2: 
1.
Absolute change from Baseline through Day 29 in SwCl
2.
Absolute change from Baseline through Day 29 in forced vital capacity [FVC]
3.
Absolute change from Baseline through Day 29 in forced expiratory flow at mid-lung capacity 
[FEF25-75]
4.
Relative changes from Baseline through Day 29 in ppFEV1
5.
Relative changes from Baseline through Day 29 in FVC
6.
Relative changes from Baseline through Day 29 in FEF25-75
7.
Absolute change in CF Questionnaire-Revised (CFQ-R) respiratory domain score from Baseline 
through Day 29
Cohort 3:
8.
Absolute change from Baseline through Day 29 in ppFEV1
9.
Absolute change from Baseline through Day 29 in FVC
10. Absolute change from Baseline through Day 29 in FEF25-75
11. Relative changes from Baseline through Day 29 in ppFEV1
12. Relative changes from Baseline through Day 29 in FVC
13. Relative changes from Baseline through Day 29 in FEF25-75
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14. Absolute change in CFQ-R respiratory domain score from Baseline through Day 29
3.4 Exploratory Efficacy Endpoint
The exploratory endpoint is ppFEV1 change over time monitored via home spirometer.
3.5 Safety Endpoints
Safety evaluations are AE monitoring, AESIs, weight, physical examinations (including neurologic 
examination for Cohorts 1 and 2 only), vital sign measurements, electrocardiogram (ECG) variables, 
clinical laboratory testing (hematology, chemistry, and urinalysis), pulse oximetry, and spirometry as 
measures of safety and tolerability for the entire study duration.
3.6 Exploratory Safety Endpoints
Cohort 3 will include mental health outcome measures as exploratory safety endpoints that are 
monitored via the Hamilton Depression Rating Scale (HDRS) and the 7-item Generalized Anxiety Disorder 
scale (GAD-7).
3.7 Pharmacokinetic Endpoints
Plasma galicaftor, navocaftor, and ABBV-119 or ABBV-576 concentrations will be obtained at the visits 
indicated in Appendix D.  A nonlinear mixed effects modeling approach will be used to estimate the 
population central values and the empirical Bayesian estimates of the individual values of galicaftor, 
navocaftor, and ABBV-119 or ABBV-576 oral clearance (CL/F) and volume of distribution (V/F).  
Additional parameters may be estimated if useful in the interpretation of the data.
3.8 Biomarker Research Endpoints
Optional samples (whole blood) will be collected at specific time points as described in the Activity 
Schedule (Appendix D) to evaluate known and/or novel disease-related or drug-related biomarkers.  
Types of biomarkers may include nucleic acids, proteins, lipids, and/or metabolites.  The objective of this 
research is to analyze samples for biomarkers that will help to understand CF, related conditions, and 
the subject's response to galicaftor/navocaftor/ABBV-119 or galicaftor/navocaftor/ABBV-576
combination therapies.  Genes of interest may include those associated with PK (drug metabolizing 
enzymes, drug transport proteins), genes within the target pathway, or genes related to CF (e.g., CFTR).  
This research is exploratory in nature and the results may not be included with the clinical study report.
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4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a multicenter, multi-country, Phase 2, three parallel-cohort study of galicaftor, navocaftor, and 
ABBV-119 or ABBV-576 combination therapy for 28 days in adult CF subjects who are homozygous or 
heterozygous for the F508del mutation, including subjects already on stable CFTR modulator therapy. 
This study is designed as a proof-of-concept study to evaluate the safety, tolerability, target 
engagement, and efficacy for galicaftor/navocaftor/ABBV-119 and galicaftor/navocaftor/ABBV-576
combination therapies administered at fixed doses.
This study will enroll subjects with a confirmed clinical diagnosis of CF who carry at least one copy of the 
F508del mutation.  In Cohort 2, randomization will be stratified by ppFEV1 at Screening (< 70% versus 
[vs.] ≥ 70%).  See Section 5.1 for detailed information regarding eligibility criteria.
Cohort 1 included adult CF subjects who are homozygous for the F508del mutation and are not receiving 
ETI treatment, with a single arm, open-label design.  Approximately 20 subjects were enrolled in this 
cohort.  Subjects received the galicaftor/navocaftor dual combination therapy for 28 days as the run-in 
period, followed by galicaftor/navocaftor/ABBV-119 triple combination therapy for 28 days.  Differences 
in endpoint values between the dual combination run-in period and the triple combination treatment 
period will demonstrate the contribution of ABBV-119 to the efficacy of the triple combination.
For subjects on stable treatment of other CFTR modulator therapy (i.e., ivacaftor/tezacaftor; or 
Symkevi), 2 brief washout periods of 5 days were included to allow for elimination of the previous 
modulator drugs.  The 5-day washout period was based on the mean effective half-lives (t1/2) of ivacaftor 
and tezacaftor, which are 13.7 h and 15.0 h, respectively.8 The first washout period occurred before the 
start of the dual combination run-in period, and the second washout period occurred after the triple 
combination treatment period.  These subjects could resume their stable modulator treatment after the 
second washout period.
Cohort 2 included adult CF subjects who are heterozygous for the F508del mutation and a minimal 
function mutation (Appendix F) and are not receiving ETI treatment, with a double-blind, placebo-
controlled, parallel-arm design.  Approximately 30 subjects were enrolled in this cohort and were
randomized to 2 parallel treatment arms at a 2:1 treatment to placebo ratio.  Subjects received
galicaftor/navocaftor/ABBV-119 triple combination therapy, or placebo treatment for 28 days.  
Differences in endpoint values from Baseline to the end of the triple combination treatment period will 
demonstrate the efficacy of the triple combination.
For Cohort 2, study sites and subjects will remain blinded for the duration of the study.
Cohort 1 and Cohort 2 have been terminated based on the efficacy results of the Cohort 1 interim 
analysis (see Section 2.2). Cohort 3 is modified to replace ABBV-119 with ABBV-576, a structurally 
differentiated modulator with improved safety and pharmacokinetic profiles.
Cohort 3 will include adult CF subjects who are homozygous or heterozygous for the F508del mutation 
receiving stable treatment of ETI at the time of screening, with a single arm, open-label design. Up to 
40 subjects will be enrolled in this cohort, including approximately 20 F508del homozygous subjects and 
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up to 20 F508del heterozygous subjects.  Subjects will receive galicaftor/navocaftor/ABBV-576 triple 
combination therapy for 28 days.  Differences in endpoint values from Baseline to the end of the triple 
combination treatment period will be used to evaluate target engagement and the efficacy of the triple 
combination.
For subjects on stable treatment of ETI, no washout period is planned to minimize the risk of withdrawal 
syndromes.9 In order to better monitor patient safety during the first week of the treatment period 
when ETI elimination is taking place, a phone call on Day 4 and a study visit on Day 8 are added for 
safety evaluation.  In addition, considering the potential impact of ETI carry-over effect on ppFEV1
response by Day 2910, the primary endpoint for Cohort 3 has been changed to SwCl (Section 3.2), a 
biomarker that reflects target engagement, and is less susceptible to carry-over effect as shown in 
Cohort 1 interim analysis results.
To ensure the safety and integrity of the study data, an independent DMC consisting of independent 
experts convened before the study to review the unblinded safety data from ABBV-119 or ABBV-576 
Phase 1 study and provided a recommendation on study initiation (see Section 5.10).  The DMC will also
periodically review the accumulating unblinded safety data for the study and provide recommendations 
on study continuation or early termination.  The DMC charter will outline the specific responsibilities 
and composition of the DMC and will contain the details of outputs provided for the meetings, as well as 
the meeting schedule.
The total duration of a subject's participation in each part of this study (including all periods) is up to 
approximately 4 months for Cohort 1 and 3 months for Cohort 2 and Cohort 3, consisting of the 
following study periods:

Screening Period:  up to approximately Day –60 (Cohort 1) or approximately Day –30 (Cohort 2 
and Cohort 3)

Dual Combination Run-in Period (Cohort 1 only):  28 days (± 2 days)

The first dose of study drugs (as galicaftor/navocaftor dual combination) will be 
administered at the site on Study Day –28

Dose of study drugs (as galicaftor/navocaftor dual combination) on Day –15 will be 
administered at the site

Triple Combination Treatment Period:  28 days (± 2 days)

Dose of study drugs (as galicaftor/navocaftor/ABBV-119 triple combination [or matching 
placebo in Cohort 2 only] or galicaftor/navocaftor/ABBV-576 triple combination) will be 
administered at the site on Day 1

Dose of study drugs (as galicaftor/navocaftor/ABBV-119 triple combination [or matching 
placebo in Cohort 2 only] or galicaftor/navocaftor/ABBV-576 triple combination) will be 
administered at the site on Day 15

Subjects will not dose on day of Day 29 Visit, and all study subjects can resume their ETI 
therapy after all of the study related procedures are completed on Day 29

Follow-Up Period:  30 days (± 7 days) following the last dose of study drug
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The schematic of the study is shown in Figure 1.  Details regarding study procedures are located in the 
Operations Manual (Appendix H).
See Section 5 for information regarding eligibility criteria.
Figure 1.
Study Schematic
ETI = elexacaftor/tezacaftor/ivacaftor; QD = once daily
Retesting and Rescreening
Retesting of individual screening assessments that did not meet eligibility criteria is allowed once for the 
following parameters provided results can be obtained and it is possible to randomize the subject within 
the same screening period.  Otherwise, subjects who do not meet one or more eligibility criterion will be 
considered screen failures.

If the initial sweat collection has insufficient volume for chloride analysis, then the sweat
collection may be repeated once.
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
If there is clear evidence of a laboratory error (e.g., hemolyzed sample) or equipment 
malfunction, collection of a repeat sample for the appropriate laboratory test or assessment 
may be permitted.

Exclusionary hepatic function test levels may be retested within 14 days of the original screening 
date.

Spirometry may be retested once if the screening spirometry measurement failed to meet the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria for acceptability 
and/or repeatability.  Spirometry may also be retested once for subjects who usually have a 
ppFEV1 within 40% to 90% of predicted value but have a first screening spirometry result just 
outside the eligibility range.
Subjects may be rescreened only after approval of the sponsor's study physician or delegate.  If a subject 
is rescreened, all screening assessments will be repeated, with the exception of CFTR genotyping, SwCl, 
and follicle-stimulating hormone (FSH) (if applicable).  Rescreened subjects will keep the same subject 
identification number.  If a subject is rescreened, the screening window will begin once the first 
rescreening assessment has been initiated.
4.2 Discussion of Study Design
Choice of Control Group
Cohort 1 and Cohort 2 of this study will mainly be conducted in countries that are not anticipated to 
have access to ETI throughout the study duration.  Cohort 3 will mainly be conducted in countries that 
currently have access to ETI. 
Some of these Cohort 1 and Cohort 2 countries have access to dual modulator combination therapies as 
standard of care for CF subjects who are homozygous for the F508del mutations.  Therefore, Cohort 1 of 
the study will be conducted with an open-label, single arm design.  Cohort 1 also includes a dual 
combination run-in period before the triple combination treatment period (Figure 1), where endpoint 
value from the dual combination run-in period can also serve as within subject control.  Differences in 
endpoint values between the dual combination run-in period and the triple combination treatment 
period will demonstrate the contribution of ABBV-119 to the efficacy of the triple combination therapy 
(Figure 1).
Dual modulator combination therapies are not approved to treat CF subjects who are heterozygous for 
the F508del mutation and minimal function mutation (Appendix F).  Therefore, Cohort 2 of the study will 
be conducted with a double-blind, placebo-controlled design.  The control group consists of subjects 
randomly assigned to receive placebo.
In countries that currently have access to ETI as standard of care for CF subjects who are homozygous or 
heterozygous for the F508del mutations, Cohort 3 will be conducted with an open-label single arm 
design.
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Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be used.  All efficacy and safety-related 
measurements are standard for assessing disease activity in subjects with CF.  All clinical and laboratory 
procedures are standard and generally accepted.
Suitability of Subject Population
This study was designed to enroll subjects with a confirmed clinical diagnosis of CF who also carry at 
least one copy of the F508del CFTR mutation because galicaftor, navocaftor, ABBV-119, and ABBV-576
are CFTR modulators designed to restore the expression and function of F508del CFTR.  This population 
is the most likely to demonstrate a significant change in SwCl and ppFEV1 when given a triple 
combination of galicaftor/navocaftor/ABBV-119 or galicaftor/navocaftor/ABBV-576.
Selection of Doses in the Study
For Cohort 1 and Cohort 2, galicaftor, navocaftor, and ABBV-119 were evaluated at fixed doses of 
300 mg (QD), 50 mg (QD) and 210 mg BID, respectively.  The ABBV-119 dose and dosing regimen were 
selected based on the safety and PK data from the ongoing Phase 1 studies in healthy volunteers. For 
Cohort 3, galicaftor, navocaftor, and ABBV-576 will be evaluated at fixed doses of 300 mg (QD), 50 mg 
(QD) and 5 mg QD, respectively.  The ABBV-576 dose and dosing regimen were selected based on the 
safety and PK data from the ongoing Phase 1 study in healthy volunteers.
Galicaftor has been evaluated in CF subjects who are homozygous for the F508del mutation in a Phase 2 
study GLPG2222-CL-202, at dosages ranging from 50 mg to 400 mg QD.  Galicaftor was generally 
well-tolerated in all of the regimens tested.  In that 28-day study, a trend of dose-dependent decrease in 
SwCl was observed between 50 mg and 200 mg doses on Day 14 and Day 28, with maximum decrease in 
SwCl observed in the 200 mg dose group. 
 
 
 Considering the totality of the data from galicaftor Phase 1 and Phase 2 studies, a 
dose range of 10 mg to 300 mg is being evaluated in an ongoing Phase 2 dose ranging Study M19-530.  
The highest dose of galicaftor (300 mg QD) will be used to evaluate the galicaftor/navocaftor/ABBV-119 
combination therapy in this study.
 
 
 
 
 
 
In addition, the completed Cohort 1 interim analysis showed that galicaftor/navocaftor dual 
combination treatment at the selected doses 300 mg QD/50 mg QD was safe and well tolerated and 
resulted in a decrease in SwCl concentration (-14.2 mmol/L) from baseline at the end of the 28-day 
run-in period, which further supports the doses selected for these two components of the triple 
combination.
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Demographic and Laboratory Assessments
2. Adult male or female, at least 18 years old on the day of signing the ICF.
3. Are willing and able to comply with procedures required in this protocol (per investigator's 
judgment).
4. Weight ≥35 kg at Screening and Day -28 for Cohort 1 or Day 1 for Cohort 2 and Cohort 3.
5. No clinically significant laboratory values at Screening that would pose undue risk for the 
subject or interfere with safety assessments (per the investigator).
6. The following laboratory values must be in the defined range at Screening:

Liver function test (LFT) (AST, ALT, alkaline phosphatase) < 3 × the upper limit of normal 
(ULN), and total bilirubin < 1.5 × ULN.

Estimated creatinine clearance ≥ 50 mL/minute using Cockcroft-Gault equation.

Hemoglobin ≥ 10 gm/dL.

Negative tests for human immunodeficiency virus infection (HIV-1 and HIV-2 antibodies), 
hepatitis B virus infection (hepatitis B virus surface antigen [HBsAg]) and active Hepatitis C 
virus (HCV) infection (HCV RNA).
7. Absence of clinically significant abnormality detected on ECG regarding rate, rhythm, or 
conduction (e.g., QT interval corrected for heart rate using Fridericia's formula [QTcF] should be 
< 450 msec for males and < 460 msec for females).
Disease Activity
8. Confirmed clinical diagnosis of CF, and genotype homozygous for the F508del CFTR mutation 
for Cohort 1 and Cohort 3, heterozygous for F508del CFTR mutation and a minimal function 
mutation (see Appendix F for the list of minimal function mutations) for Cohort 2 and Cohort 3 
(documented in the subject's medical record or CF patient registry).

Subjects may be enrolled based on prior documentation of CFTR genotype, but if the 
genotype determined at Screening from the central laboratory does not confirm study 
eligibility, the subject must be discontinued from the study.

For subjects who participated in Study M19-530, it is acceptable to use the CFTR genotype 
that the central lab provided in Study M19-530 to establish eligibility.

The list of minimal function mutation (Appendix F) may not include every eligible mutation, 
and the investigator should contact the medical monitor regarding other mutations that 
may also meet study eligibility criteria.
9. ppFEV1 ≥40% and ≤ 90% of predicted normal for age, gender, and height (Global Lung 
Function Initiative [GLI] equations) at Screening.
10. SwCl at screening visit must be ≥ 60 mmol/L for Cohort 1 and Cohort 2, and this criterion 
does not apply to Cohort 3.  For subjects who participated in Study M19-530, it is acceptable to 
use a SwCl value that the central lab provided in Study M19-530 to establish eligibility.
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Subject History
11. Stable pulmonary status, i.e., no respiratory infections or exacerbations requiring a change 
in therapy (including antimicrobials) or causing an acute decline in ppFEV1 of >10% from usual 
ppFEV1 level within 4 weeks before Day –28 in Cohort 1 or Day 1 in Cohort 2 and Cohort 3 (first 
dose of study drug).
12. Absence of co-morbidities and medical history listed below, or in the opinion of the 
investigator, may pose additional risk by participating in the study, or may confound the results 
of the study.

For Cohort 1 and Cohort 2, cirrhosis with or without portal hypertension (e.g., 
splenomegaly, esophageal varices) or history of clinically significant liver disease.  For 
Cohort 3, cirrhosis with portal hypertension (e.g., splenomegaly, esophageal varices).

Past or present positive sputum culture for organisms that are often associated with a faster
decline in pulmonary status (e.g., Mycobacterium abscessus, Burkholderia cenocepacia or 
B. dolosa, Aspergillus fumigatus infection or allergic bronchopulmonary aspergillosis [ABPA]) 
is allowed if, in the opinion of the investigator, clinical stability has not been adversely 
affected.  Subjects with these organisms can remain on chronic treatment for them if 
applicable, as long as the medications are not prohibited in this study (see Appendix E).  To 
assure clinical stability, treatment for these organisms should start at least 8 weeks before 
screening, and the subjects will be expected to continue the treatment through the final 
study visit.

History of malignancy within past 5 years (except for excised basal cell carcinoma of the skin 
with no recurrence or treated carcinoma in situ of the cervix with no recurrence).

Recent (within the past 6 months) history of drug or alcohol abuse that might preclude 
adherence to the protocol, in the opinion of the investigator.

Smoking or vaping tobacco or cannabis products within 1 year before Screening.

History of solid organ or hematopoietic transplantation.

History of known sensitivity to any component of the study drug.

Need for supplemental oxygen while awake, or > 2 L/minute while sleeping.
13. Subjects can be on stable treatment with chronic use of oral corticosteroids provided that 
the daily dose of prednisone (or equivalent) is ≤ 10 mg.  For example, 20 mg taken every other 
day is permissible.
14. No concurrent participation in another interventional drug study.  Prior participation in 
investigational drug studies is allowed, provided that 30 days or a washout period of at least 
5 terminal half-lives of the investigational drug (whichever is longer) has elapsed before 
Screening.
15. Subjects receiving Orkambi (i.e., lumacaftor/ivacaftor) are not allowed to participate in this 
study.  Subjects receiving Symkevi (i.e., tezacaftor/ivacaftor) at the time of screening are 
allowed to participate in Cohort 1.  Subjects not receiving any CFTR modulator therapy at the 
time of screening are allowed to participate in either Cohort 1 or Cohort 2.
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16. Only subjects on stable treatment of ETI for at least 3 months at the time of screening can 
participate in Cohort 3, and subjects on stable treatment of ETI cannot participate in either 
Cohort 1 or Cohort 2.
17. For Cohorts 1 and 2, no evidence of active SARS-CoV-2 infection.  If a subject has 
signs/symptoms suggestive of SARS-CoV-2 infection, they should undergo molecular (e.g., 
polymerase chain reaction [PCR]) testing to rule out SARS-CoV-2 infection.  Subjects who do not 
meet SARS-CoV-2 infection eligibility criteria must be screen failed and may only rescreen after 
they meet the following SARS-CoV-2 infection viral clearance criteria:

At least 14 days since first PCR test result have passed in asymptomatic patients or 14 days 
since recovery, defined as resolution of fever without use of antipyretics and improvement 
in symptoms.
18. For Cohort 3, no known active SARS-CoV-2 infection.  If a subject has signs/symptoms 
suggestive of SARS-CoV-2 infection, the subject must have a negative molecular (e.g., PCR) test 
or 2 negative antigen test results at least 24 hours apart.  Note: SARS-CoV2 diagnostic tests 
should be applied following local requirements/recommendations.  Subjects who do not meet 
SARS-CoV-2 infection eligibility criteria must be screen failed and may only rescreen for the 
study after they meet the following SARS-CoV-2 infection viral clearance criteria:

At least 10 days since first PCR test result have passed in asymptomatic patients or at least 
10 days since recovery, defined as resolution of fever without use of antipyretics and 
improvement in symptoms.
19. No history of diseases aggravated or triggered by ultraviolet radiation and no history of 
abnormal reaction photosensitivity or photoallergy to sunlight, or artificial source of intense 
light, especially ultraviolet light.
Contraception
20. For all females of childbearing potential:  a negative serum pregnancy test at the Screening 
Visit and a negative urine pregnancy test on Day –28 visit for Cohort 1 or Day 1 visit for Cohort 2 
and Cohort 3, before the first dose of study drug.
21. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control that is effective from Study Day –28 for Cohort 1 or Day 1 for Cohort 2 and 
Cohort 3 through at least 30 days after the last dose of study drug.  Female subjects of non-
childbearing potential do not need to use birth control.
22. Female subject who is not pregnant, breastfeeding, or considering becoming pregnant
during the study or within 30 days after the last dose of study drug.
23. If male, and subject is sexually active with female partner(s) of childbearing potential, he 
must agree, from Study Day –28 for Cohort 1 or Day 1 for Cohort 2 and Cohort 3 through 
approximately 90 days after the last dose of study drug to practice protocol-specified 
contraception.
24. Male subject who is not considering fathering a child or donating sperm during the study or 
for approximately 90 days after the last dose of study drug.
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Concomitant Medications
25. Stable concomitant medication and airway clearance regimen for at least 4 weeks before the 
first dose of study drug and willing to continue the same regimen for the duration of the study.
26. No use of any strong inhibitor(s) or inducer(s) of CYP3A4 within 4 weeks before the first dose 
of study drug or during the study period (see Appendix E).
27. No use of drugs that are CYP2C8 substrates within 4 weeks before the first dose of study 
drug or during the study period (e.g., paclitaxel, torasemide, amodiaquine, cerivastatin, 
repaglinide).
28. No use of drugs that are strong CYP2C9 inducers within 4 weeks before the first dose of 
study drug or during the study period (e.g., enzalutamide, rifampin, carbamazepine, dabrafenib).
29.No use of oral cannabis products within 4 weeks before the first dose of study drug and 
during the study period due to potential interaction with the study drugs.
5.2 Contraception Recommendations
Contraception Requirements for Females
Highly effective contraceptive measures for females of childbearing potential must be documented in 
the source documents (i.e., hormonal, surgical, or lifestyle decision).
Subjects must follow the following contraceptive guidelines as specified:

Females, Non-Childbearing Potential

Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:
1.
Postmenopausal female

Age > 55 years with no menses for 12 or more months without an alternative medical 
cause.

Age ≤ 55 years with no menses for 12 or more months without an alternative medical 
cause AND a follicle-stimulating hormone (FSH) level ≥ 30 IU/L.
2.
Premenopausal female with permanent sterility or permanent infertility due to one of the 
following:

Permanent sterility due to a hysterectomy, bilateral oophorectomy, bilateral 
salpingectomy.

Non-surgical permanent infertility due to Mullerian agenesis, androgen insensitivity, or 
gonadal dysgenesis; investigator discretion should be applied to determining study entry 
for these individuals.

Females, of Childbearing Potential

Females of childbearing potential must avoid pregnancy while taking study drug(s) and for 
at least 30 days after the last dose of study drug.
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
Females must commit to one of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation plus a 
barrier method* initiated at least 30 days before the first dose of study drugs.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation plus a barrier method* initiated at least 30 days before the first 
dose of study drugs.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS) plus a barrier method*.

Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject).

Practice true abstinence, defined as:  Refraining from heterosexual intercourse when 
this is in line with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable).
* As there are no current clinical data available regarding potential interactions between the study drugs 
and hormonal contraceptives, female subjects who use hormonal contraception should supplement 
this with one of the effective barrier methods described below (preferably male condom):

Male or female condom with or without spermicide.

Cap, diaphragm, or sponge with spermicide.
Contraception recommendations related to use of concomitant therapies prescribed should be based on 
the local label.
Contraception Requirements for Males
Note:  Most CF males are infertile due to absence of the vas deferens.  However, sperm can be 
harvested for in vitro fertilization purposes.  Males must not have sperm harvested for the purpose of 
fertility during the study or for approximately 90 days after the last dose of study drug.
Male subjects who are sexually active with a female partner of childbearing potential, must agree to use 
condoms, from the first dose of study drugs through approximately 90 days after the last dose of study 
drug unless the subject meets one of the criteria below.
Contraception requirement for the male subject is not required for the following:

Vasectomized male subjects or male subjects with complete bilateral absence of vas deferens 
are not required to use additional form of contraception providing documented azoospermia by 
semen analysis or demonstration of the absence of vas deferens by ultrasound.
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
Male subjects who have undergone bilateral orchiectomy.
5.3 Prohibited Medications and Therapy
Throughout the study, strong inhibitors and inducers of CYP3A4, or strong inducers of CYP2C9, or 
substrates of CYP2C8 and other investigational drugs are prohibited.  Examples of such compounds are 
shown in Appendix E.  The use of topical treatments of CYP3A4 inhibitors/inducers or CYP2C9 inducers
would not be expected to impact study drug.  Consult with the AbbVie medical contact with questions 
regarding administration of an excluded concomitant therapy before administration.
5.4 Prior and Concomitant Therapy
Concomitant CF medications and other long-term medications for other conditions that are not 
expressly prohibited are allowed.  The concomitant medication regimen must be stable for at least 
4 weeks before the first dose of study drug (as specified in Section 5.1, Eligibility Criteria) and should be 
continued with minimal variation of dose or frequency for the study duration.  Subjects who take 
inhaled antibiotics for suppression of chronic airway infection must be on a stable regimen for at least 
8 weeks before the first study drug administration and remain on that regimen for the study duration.  
Examples of therapeutic regimens for pulmonary health are antibiotics; corticosteroids (inhaled or oral); 
inhalation of bronchodilators, hypertonic saline, mannitol or dornase alfa; ibuprofen, and airway 
clearance techniques.

Inhaled antibiotics:  Subjects who are on cycling inhaled antibiotics (including "on/off" cycling) 
must continue on the same schedule.  The timing of the first dose of study drug should be 
synchronized as closely as possible to the first day of the inhaled antibiotic in the cycle.  The 
timing of the first dose in a cycle also applies to subjects who are alternating 2 different inhaled 
antibiotics each month.

Bronchodilators and airway clearance:  Bronchodilator medications and airway clearance 
techniques are frequently used in CF and may affect lung function measurements in the short 
term.  At each study visit, subjects will be asked about the medication name and timing of their 
last bronchodilator use (if applicable).  There are several bronchodilators available, including 
salbutamol (albuterol), salmeterol, formoterol, arformoterol, indacaterol, vilanterol, 
ipratropium, tiotropium, glycopyrronium, umeclidinium, and aclidinium.  In some cases, 
bronchodilators are combined with a second bronchodilator, an inhaled corticosteroid, or both 
into a single inhaler.  If a subject uses a combination product, the information captured in the 
source documents should include the combination and not just the bronchodilator component.

During the Screening Period, spirometry assessments may be performed before or after 
bronchodilator use. At all other study visits, all spirometry assessments should be performed 
before bronchodilator use. On Days –28, –15, 1 and 15 for Cohort 1 and Days 1 and 15 for 
Cohort 2 and Cohort 3, spirometry will be performed twice, before and after taking study drug.  
Bronchodilators should not be given between the 2 spirometry measurements.

Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have
withheld their short-acting bronchodilators (e.g., albuterol) for more than 4 hours before the 
spirometry assessment; withheld their long-acting bronchodilator (e.g., salmeterol) for more 
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than 12 hours before the spirometry assessment; and withheld their once-daily, long-acting 
bronchodilator (e.g., tiotropium bromide) for more than 24 hours before the spirometry 
assessment.

In the event that a subject does not withhold bronchodilator(s), spirometry assessment should 
be performed as follows: 

If a subject's Day 1 spirometry is performed before bronchodilator use, but the subject does 
not withhold bronchodilator use at a subsequent visit, then a post-bronchodilator 
spirometry assessment will be obtained for that visit only, and the visit will not be 
rescheduled.

If a subject does not withhold bronchodilator use on Day 1, then Day 1 spirometry should be 
performed post-bronchodilator, and spirometry assessment on all subsequent visits should 
be performed post-bronchodilator.  Each spirometry assessment will be recorded in the 
source documents as pre- or post-bronchodilator.
Any medication or vaccine (including over the counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving at the time of enrollment or receives during the study 
must be recorded through the final post-treatment visit (30 days after the last dose of study drug).  Any 
questions regarding concomitant or prior therapy should be raised to the AbbVie emergency contact.
Information regarding potential drug interactions with galicaftor, navocaftor, ABBV-119, or ABBV-576 is 
located in the galicaftor3, navocaftor4, ABBV-1195, or ABBV-5762 IBs.
Subjects must be able to safely discontinue any prohibited medications 5 half-lives or 4 weeks before 
first dose of study drug, whichever is longer.  Subjects must be consented for the study before 
discontinuing any prohibited medications for the purpose of meeting study eligibility.
Cohort 1 subjects who do not tolerate the 5-day washout period before the dual run-in period will be 
discontinued from the study and allowed to resume their standard of care CFTR modulator therapy.
COVID-19 Pandemic-Related Vaccination Guidance
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., mRNA, non-replicating viral 
vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be administered during screening, 
the treatment period, or follow up, as long as components of the vaccine are not contraindicated.
The decision to receive a locally available vaccine should be based on local guidance and an individual 
discussion between the treating physician and the subject.
The potential impact of study drug(s) on SARS-CoV-2 vaccination is unknown.  Therefore, study drug 
should be administered as follows:

The first dose of study drug(s), when possible, is preferred to be given at least ± 7 days from the 
SARS-CoV-2 vaccine administration.
Note: The above guidance applies to all SARS-CoV-2 vaccine doses given as part of the complete 
treatment course.
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These recommendations may be subject to change based on the evolving knowledge around the use of 
SARS-CoV-2 vaccines in patients with CF and as more data are collected in real-world scenarios and 
clinical trials.
Any SARS-CoV-2 vaccine information must be documented on the SARS-CoV-2/COVID-19 vaccine eCRF.  
Refer to the Operations Manual for instructions on reporting any adverse events associated with the 
SARS-CoV-2/COVID-19 vaccine.
5.5 Withdrawal of Subjects and Discontinuation of Study
Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:

The investigator believes it is in the best interest of the subject.

The subject requests withdrawal from the study.

Subject is significantly noncompliant with study procedures, which would put the subject at risk 
for continued participation in the trial.
Withdrawal of Study Drug Therapy

The medical monitor should be notified of an interruption of study drug that lasts > 72 hours for 
any reason and of the resumption of study drug after such interruption.  

Discontinuation of study drug therapy does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated in Section 5.6
Study drug therapy must be discontinued if a subject meets any of the following criteria:

Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the AbbVie Therapeutic Area Medical Director.

Life-threatening AE or a serious adverse event (SAE) that places the subject at immediate risk.

Eligibility criteria violation after the subject started study drug and continuation of the study 
drug would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.

The subject becomes pregnant while on study drug.

Maculopapular rash or other clinical manifestation of allergic drug reaction, for which the 
severity is categorized as Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0 
or most recent version) Grade 3 or higher.
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
Worsening pulmonary status that, in the investigator's opinion, is likely to respond to an 
approved and commercially available CFTR modulator therapy or that requires a significant 
change to the existing therapeutic regimen.

Serious infections (e.g., requiring parenteral antimicrobial therapy and/or hospitalization).

Arrhythmia or conduction abnormality, including, but not limited to prolonged QT interval 
corrected for the heart rate (HR) using Fridericia's formula (QTcF), where the severity is 
categorized as CTCAE (Version 5.0 or most recent version) Grade 3 or higher (QTc ≥501 ms on at 
least 2 separate ECGs) [at least 2 minutes apart] obtained within 10 minutes of the initial 
recording.

If any of the following hepatic function test criteria are met, study drug must be discontinued 
immediately, the medical monitor must be notified, and a supplemental hepatic case report 
form must be completed (see Section 6.1):

AST and/or ALT elevations > 5 × ULN

AST and/or ALT elevations > 3 × ULN, and (total bilirubin > 2 × ULN or confirmed 
international normalized ratio [INR] > 1.5)

AST and/or ALT elevations > 3 × ULN, accompanied by clinical signs or symptoms suggestive 
for hepatic injury (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia [> 5%])
A thorough investigation of potential etiologies for elevated transaminases should be conducted (e.g., 
trauma, acetaminophen use, viral hepatitis, alcohol ingestion), and the subject should be followed 
closely for clinical progression.
Subjects for whom treatment is discontinued for elevated hepatic function tests should have 
transaminases and bilirubin levels repeated by the central laboratory within 48 to 72 hours after the 
initial finding if possible, and then monitored closely until levels normalize or return to baseline.  If a 
subject cannot return to the site for liver function testing, a local laboratory may be used.  Elevations in 
LFTs at the local laboratory must be reported immediately to the medical monitor, and the subject must 
have the tests repeated and sent to the central laboratory as soon as possible (ideally within 48 to 
72 hours).
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix H.
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The investigator should contact the sponsor medical contact before discontinuing a subject from the 
study for a reason other than "planned per protocol," to ensure all acceptable mitigation steps have 
been explored.
Refer to the Operations Manual in Appendix H for details on how to handle study activities/procedures.
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed at a Premature Discontinuation visit (PD visit) and 
30-day follow-up visit after the last dose of study drug to ensure that all treatment-emergent AEs/SAEs 
have been resolved, unless subjects have decided to discontinue study participation entirely (withdrawal 
of informed consent).  Subjects should be advised on the continued scientific importance of their data 
even if they discontinue treatment with study drug early.
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory result that is 
significantly outside of the reference range, the investigator will attempt to provide follow-up until a 
satisfactory clinical resolution of the AE or laboratory result is achieved.
If a subject prematurely discontinues study participation, the procedures outlined for the PD visit should 
be completed as soon as possible, preferably within 2 weeks.
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed the subject has 
withdrawn and no longer wishes biomarker research to continue, samples will not be analyzed, no new 
biomarker analysis data will be collected for the withdrawn subject or added to the existing data or 
database(s), and the samples will be destroyed.  A subject may withdraw consent for optional biomarker 
research at any time and remain in the clinical study.  Data generated from clinical study and/or optional 
biomarker research, before subject withdrawal of consent, will remain part of the study results.
5.7 Study Drug and Study Devices
Galicaftor, navocaftor, ABBV-119, ABBV-576, or matching placebo manufactured by AbbVie will be taken 
orally beginning on Day –28 for Cohort 1 and Day 1 for Cohort 2 and Cohort 3 and should be taken at 
approximately the same time each day.  Study drug should be taken within 1 hour after a meal.  If 
subjects forget to take their galicaftor, navocaftor, ABBV-576 or matching placebo dose at their regularly 
scheduled time, they should take the forgotten dose as soon as they remember as long as it is at least 
10 hours before the next scheduled dose.  If subjects forget to take their ABBV-119 dose at their 
regularly scheduled time, they should take the forgotten dose as soon as they remember as long as it is 
at least 4 hours before the next scheduled dose.  Otherwise, they should take the next dose at the next 
scheduled dosing time.
The subject will be instructed to return all drug containers (even if empty) to the study site personnel at 
each study visit.  The study site personnel will document compliance.
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AbbVie will provide study drug for galicaftor, navocaftor, and ABBV-119 or ABBV-576, and their 
matching placebos (Cohort 2 only).  Study drug provided by AbbVie should not be substituted or 
alternately sourced unless otherwise directed by AbbVie.  If a subject is unable to come to the study site 
to pick up their study drug due to COVID-19-related restrictions, a direct-to-patient (DTP) study drug 
shipment can be made from the study site to the subject if allowed by local laws and regulations.  
AbbVie will submit any required notifications to the regulatory authority as applicable.  Refer to the 
Operations Manual in Appendix H for details on DTP shipment of study drug.
Study drug will be packaged in blister cards with quantities sufficient to accommodate study design.  
Each kit will be labeled per local requirements and this label must remain affixed to the kit.  Upon 
receipt, study drug should be stored as specified on the label and kept in a secure location.  Each kit will 
contain a unique kit number.  This kit number is assigned to a subject via interactive response 
technology (IRT) and encodes the appropriate study drug to be dispensed at the subject's corresponding 
study visit.  Site staff will complete all blank spaces on the label before dispensing to subjects.  Study 
drug will only be used for the conduct of this study.
Upon completion of or discontinuation from study treatment, all original study drug units (containing 
unused study drugs)/devices will be returned to the Sponsor (or designee) or destroyed on site.  All 
return or destruction procedures will be according to instructions from the Sponsor and according to 
local regulations following completion of drug/device accountability procedures.
Information about the drug formulations to be used in this study is presented in Table 1.
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Digital Health Tools Accountability
The investigator or his/her representative will verify that the digital health tools are received intact and 
in the correct amounts.  A proof of receipt or similar document will be kept in the site files as a record of 
what was received.
In addition, sites will maintain records of traceability, accountability, and return including but not limited 
to date received/dispensed/returned, subject number, and the identification of the person 
dispensing/returning the digital health tools.
5.8 Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  For Cohort 2, IRT will assign a randomization number that will encode the subject's treatment 
group assignment according to the randomization schedule generated by the statistics department at 
AbbVie.
Cohort 1 was open-label.  In Cohort 2, randomization to galicaftor/navocaftor/ABBV-119 triple vs. 
placebo was stratified by ppFEV1 at screening (< 70% vs ≥70% of predicted value).  Cohort 3 is 
open-label.
For Cohort 2, all AbbVie personnel with direct oversight of the conduct and management of the trial 
(with the exception of AbbVie Drug Supply Management Team), the investigator, study site personnel, 
and the subject remained blinded to each subject's treatment throughout the study.  To maintain the 
blind, the galicaftor, navocaftor, and ABBV-119 capsules and placebo capsules provided for the study 
will be identical in appearance. The IRT will provide access to unblinded subject treatment information 
in the case of a medical emergency.
Also, to minimize the potential for unblinding and/or bias, the AbbVie study team will not have access to 
the post-first-dose spirometry or SwCl results for Cohort 2 subjects until after the study database is 
locked for analysis.  For all cohorts, site personnel and subjects will not be informed of the subjects'
study-related post-first-dose SwCl results until the end of the cohort.  Subjects will not be informed of 
their study-related spirometry results until the end of the study.
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws and regulations regarding protocol 
deviations.  If a protocol deviation occurs (or is identified, including those that may be due to the 
COVID-19 pandemic), the investigator is responsible for notifying independent ethics 
committee/institutional review board (IEC/IRB), regulatory authorities (as applicable), and AbbVie.
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5.10 Data Monitoring Committee
To enhance the safety and integrity of the study data, an external DMC composed of clinicians and 
statisticians independent of AbbVie and with relevant expertise in their field reviewed the unblinded 
data from the Phase 1 studies for ABBV-119 (e.g., Study M19-775) before the start of Study M19-771 
and provided a recommendation on the start of Study M19-771.  DMC recommendation, including the 
DMC approved final dose and dosing regimen for ABBV-119 was documented in DMC meeting minutes.
The DMC will also review all of the safety and PK data from ABBV-576 Phase 1 studies before the start of 
Cohort 3 and provide a recommendation on the start of Cohort 3.  DMC recommendation, including the 
DMC final approval of the start of Cohort 3 will be documented in DMC meeting minutes.
The DMC will also periodically review the accumulating unblinded safety data for the study, as well as 
monitor the integrity and interpretability of the study.  The DMC will provide recommendations to the 
sponsor regarding ongoing study conduct or modifications to the study as described in a separate DMC 
Charter.
In order to maintain sponsor blinding, an independent statistical data analysis center (SDAC) is 
responsible for performing the analyses described in the DMC charter as well as additional analyses 
requested by the DMC and facilitating interpretation and answering questions that arise before, during 
or after DMC review.
A separate DMC charter will be prepared outside of the protocol and will further describe the roles and 
responsibilities of the DMC members, frequency and scope of the data reviews, and expectations for 
blinded communications.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
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Clinically Significant Assessments
A laboratory value that is Grade 4 will not automatically be an SAE.  A Grade 4 laboratory value will be 
an SAE if the clinical status of the subject indicates a life-threatening AE.
Study assessments including laboratory tests, ECGs, physical examinations, and vital signs will be 
assessed, and those deemed a clinically significant worsening from baseline will be documented as an 
AE.  When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia).  In the absence of a diagnosis, the 
abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine, decreased hemoglobin).
An abnormal study assessment is considered clinically significant if the subject has one or more of the
following:

Concomitant signs or symptoms related to the abnormal study assessment

Further diagnostic testing or medical/surgical intervention

A change in the dose of study drug or discontinuation from the study
Repeat testing to determine whether the result is abnormal, in the absence of any of the above criteria, 
does not necessarily meet clinically significant criteria.  The investigator will determine whether the 
study assessment results are clinically significant.  All study assessments deemed "clinically significant"
based on the investigator's medical judgment will be managed and followed to a satisfactory clinical 
resolution.
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance or CRO (as appropriate) as an SAE within 24 hours of the 
site being made aware of the SAE (refer to Section 4.3 of the Operations Manual for reporting details 
and contact information [Appendix H]):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
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Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based on 
medical judgment, may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.
All AEs reported from the time of study drug administration until 30 days or 5 half-lives, whichever is 
longer, after discontinuation of study drug administration will be collected, whether solicited or 
spontaneously reported by the subject.  In addition, study procedure-related serious and nonserious AEs 
will be collected from the time the subject signs the study-specific informed consent.
The following definitions will be used for Serious Adverse Reactions (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR):
SAR
Defined as all noxious and unintended responses to an IMP related to any dose 
administered that result in an SAE as defined above.
SUSAR
Refers to individual SAE case reports from clinical trials where a causal 
relationship between the SAE and the IMP was suspected by either the sponsor 
or the investigator, is unexpected (not listed in the applicable Reference Safety 
Information) and meets one of the above serious criteria.
AbbVie will be responsible for SUSAR reporting for the Investigational Medicinal Product (IMP) in 
accordance with global and local requirements.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Adverse Events of Special Interest
The following adverse events of special interest will be monitored during the study:

Rash

Hepatobiliary events
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Rash
Definition and Diagnosis
Maculopapular rash is a disorder characterized by the presence of macules (flat) and papules (elevated).  
Also known as morbilliform rash, it is one of the most common cutaneous AEs, frequently affecting the 
upper trunk, spreading centripetally and associated with pruritus.
Nonserious events of generalized rash of mild to moderate severity leading to study drug 
discontinuation have been observed following multiple dose treatment when galicaftor and navocaftor 
were co-administered with or without other CFTR modulators (such as ABBV-119).  Rash was considered 
possibly related to study drug by the investigator and resolved after treatment discontinuation.
Rash is to be graded according to the CTCAE (CTCAE version 5.0 or current version).11   Refer to the 
Operations Manual Section 4.2 (Appendix H) for additional guidance on the management of these 
events.  All rash cases have to be reported within 24 hours from the time of knowledge of the event 
using a study-specific rash questionnaire (Operations Manual Section 7.1).
Hepatobiliary Events
Elevated LFTs are adverse reactions associated with marketed products with a similar mechanism of 
action.  Preclinical toxicology studies with ABBV-119 identified reversible hepatobiliary effects 
accompanied by increased serum liver enzymes and bilirubin that were dose responsive and adverse at 
the highest dose (150 mg/kg) (see ABBV-1195 IB).  In the MAD part of the navocaftor FIH study 
(GLPG3067-CL-101), one healthy volunteer who received navocaftor at the highest dose (500 mg BID) 
temporarily interrupted treatment for 2 doses because of ALT elevation approximately 3.8 × ULN 
without concurrent bilirubin elevation.  Transaminase elevations have been noted in Phase 1 and 2 
studies in healthy volunteers and CF subject who received multiple doses of ABBV-119, given alone or 
coadministered with galicaftor and navocaftor, with onset approximately 14-19 days after the start of 
dosing (see Section 2.2 under Risks; see also the navocaftor4 IB and the ABBV-1195 IB). 
Management
Subjects with new treatment-emergent LFT elevations must be followed closely including confirmatory 
testing within 48 to 72 hours after the initial finding and subsequent close monitoring of LFT levels, as 
clinically indicated.  If any of the laboratory criteria defined in Section 5.4 are met, study drug must be 
discontinued immediately, the medical monitor must be notified, and a supplemental hepatic case 
report must be completed.  A thorough investigation of potential etiologies for the elevated 
transaminases should be conducted (e.g., trauma, acetaminophen use, viral hepatitis, alcohol ingestion), 
and the subject should be followed closely for clinical progression.
Subjects for whom treatment is discontinued for elevated hepatic function tests should have 
transaminases and bilirubin levels repeated by the central laboratory within 48 to 72 hours after the 
initial finding if possible, and then monitored closely until levels normalize or return to baseline.
If a subject cannot return to the site for liver function testing, a local laboratory may be used.  Elevations 
in LFTs at the local laboratory must be reported immediately to the medical monitor, and the subject 
must have the tests repeated and sent to the central laboratory as soon as possible (ideally within 48 to 
72 hours).
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A supplemental case report form should be completed for the following:

Discontinuation or interruption of study drug due to a hepatic-related AE

A hepatic-related SAE

Laboratory criteria defined in Section 5.5
Adverse Event Severity and Relationship to Study Drug
The investigator will rate the severity of each AE according to the National Cancer Institute (NCI) CTCAE 
(NCI CTCAE Version 5.0 or current version).
For AEs not captured by the NCI CTCAE, the following severity grading system should be used (Note: a 
semicolon indicates "or" within the description of the grade):
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADLa
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADLb
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
ADL = Activities of Daily Living; AE = adverse event
a.
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
b.
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
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Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (Section 5.4).  If a pregnancy occurs in a study subject or in the partner of a study subject, 
information regarding the pregnancy and the outcome will be collected.
In the event of pregnancy occurring in a subject's partner during the study, written informed consent 
from the partner must be obtained before collection of any such information.  AbbVie will provide a 
separate consent form for this purpose.  Pregnancy in a subject's partner(s) will be collected from the 
date of the first dose through 90 days following the last dose of study drug.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered an SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
6.2 Toxicity Management
The management of specific AEs (including AESI of rash) and laboratory parameters is described in the 
Operations Manual (Appendix H).  Specific management for elevated hepatic function tests and 
hepatobiliary AESI is described in this protocol in Section 5.4 and Section 6.1.
Adverse corneal findings with neutrophilic inflammation were noted on histopathology in dogs 
administered ABBV-119 after 4 weeks of dosing.  These occurred only at the highest dose (150 mg/kg) 
and were reversible after 4 weeks of recovery.  No other eye findings were noted in histopathology 
examinations.  For Cohorts 1 and 2 only: If any subject experiences an ocular AE, it is recommended to 
consult an ophthalmologist for examination as clinically indicated.  All subjects should be assessed for 
alternative causes and treated as appropriate.  All findings related to an AE will be captured on the 
appropriate eCRF page.  Deidentified results of consultations should be forwarded to AbbVie as soon as 
they are available.
Adverse minimal to mild peripheral nerve degeneration was present in dogs administered 150 mg/kg 
ABBV-119 for 4 weeks.  The finding was not reversible after a 4-week post-dose recovery period.  A brief 
neurologic examination will be performed with the physical examination at time points designated in 
the activity schedule (for Cohorts 1 and 2 only).  See Operations Manual Section 3.12 on neurologic 
examination for further details (Appendix H).
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods provided in this protocol will be focused on primary and key secondary analyses.  
Complete and specific details of the statistical analysis will be described in the Statistical Analysis Plan 
(SAP).
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The final analysis for each cohort will be conducted after all subjects in that cohort have completed the 
study or prematurely discontinued from the study.  If the timing of the completion of each cohort differs 
significantly, the analysis may be performed separately for each cohort.
7.2 Definition for Analysis Populations
For each cohort, these analysis populations will be defined and used for the analysis:

The Full Analysis Set (FAS) includes all enrolled subjects (randomized subjects for Cohort 2) who 
received at least 1 dose of study drug as dual or triple combination (or corresponding placebo).  
The FAS will be used for demographics and baseline characteristics analyses.

A Per-Protocol (PP) Population includes all enrolled subjects (randomized subjects for Cohort 2) 
who carry the intended CFTR mutation based on central lab report and received at least 1 dose 
of triple combination of study drug (or corresponding placebo).  The PP Population will be used 
for all efficacy analyses as well as the summary of demographics and baseline characteristics.

The Safety Analysis Set consists of all enrolled subjects (randomized subjects for Cohort 2) who 
received at least 1 dose of study drug.
7.3 Handling Potential Intercurrent Events for the Primary and Key 
Secondary Endpoints
The primary efficacy endpoint of ppFEV1 (Cohorts 1 and 2) and SwCI (Cohort 3) (defined in Section 3.2) 
will be analyzed based on PP population to address the following potential intercurrent events:

Enrolled subjects who do not carry the intended CFTR mutation based on central lab report will 
be excluded from the primary analysis.

Enrolled subjects who did not receive any dose of study drug as triple combination (or 
corresponding placebo) will be excluded from the primary analysis.

Subjects who did not have a baseline data measurement or did not have at least one valid 
post-baseline data measurement during triple combination treatment period with respect to the 
corresponding endpoint will be excluded from the primary analysis.

A valid post-baseline ppFEV1 data measurement refers to ppFEV1 data collected at a 
post-baseline visit for which spirometry data were collected pre-dose and consistently with 
the baseline bronchodilator or airway clearance regimen status, and subjects has not started 
another CFTR modulator treatment.

A valid post-baseline SwCI data measurement refers to SwCI data collected at a 
post-baseline visit for a subject who has not started another CFTR modulator treatment.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The secondary efficacy endpoints related to spirometry evaluation (e.g., relative change in ppFEV1, 
absolute change in forced vital capacity [FVC], FEV25-75, defined in Section 3.3) will be analyzed based on 
PP Population with the following potential intercurrent events being addressed:

Enrolled subjects who do not carry the intended CFTR mutation based on central lab report will 
be excluded from the analysis.

Enrolled subjects who did not receive any dose of study drug as triple combination (or 
corresponding placebo) will be excluded from the analysis.

Subjects who did not have a baseline data or did not have at least one valid post-baseline data 
during triple combination treatment period with respect to the corresponding spirometry 
endpoint will be excluded from the analysis.

A valid post-baseline spirometry endpoint data refers to data collected at a post-baseline 
visit for which it was collected pre-dose and consistently with the baseline bronchodilator or 
airway clearance regimen status, and subjects has not started another CFTR modulator 
treatment.
The secondary efficacy endpoints related to SwCl and CFQ-R (defined in Section 3.3) will be analyzed 
based on PP population with the following potential intercurrent events being addressed:

Enrolled subjects who do not carry the intended CFTR mutation based on central lab report will 
be excluded from the analysis.

Enrolled subjects who did not receive any dose of study drug as triple combination (or 
corresponding placebo) will be excluded from the analysis.

Subjects who did not have a baseline data or did not have at least one valid post-baseline data 
during triple combination treatment period with respect to the corresponding endpoint will be 
excluded from the analysis.

A valid post-baseline data refers to data collected at a post-baseline visit for a subject who 
has not started another CFTR modulator treatment.
7.4 Statistical Analyses for Efficacy
Analysis of the Primary Endpoints
Analysis of the primary endpoint will be conducted on the PP population for each cohort and by CFTR 
genotypes (homozygote, heterozygote) based on treatment as received.  If a subject takes more than 
one treatment, the subject will be grouped in the treatment group for which they received the most 
doses.  The null hypothesis for the primary endpoint is that the within-group absolute change from 
Baseline (Day 1) through Day 29 in ppFEV1 (Cohorts 1 and 2) or SwCI (Cohort 3) is zero.  This null 
hypothesis will be tested for each cohort separately at 1-sided alpha level of 0.05.
For each cohort, the primary analysis will be performed using a mixed-effect model with repeated 
measures (MMRM) with change from Baseline in ppFEV1 (Cohorts 1 and 2) or SwCI (Cohort 3) as the 
dependent variable, treatment (Cohort 2 only), visit, and treatment-by-visit interaction (Cohort 2 only) 
as fixed effects, subject as a random effect, and baseline ppFEV1 (Cohorts 1 and 2) or baseline SwCI 
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(Cohort 3) as a covariate.  The estimate for the within-group least squares (LS) mean change along with
the 90% confidence intervals and the corresponding P values will be calculated as the primary analysis. 
Additionally, 95% CIs will also be provided for informational purpose. For Cohort 2, the between group 
comparison (treatment effect compared to placebo) will be estimated using the same model.
Analysis of Secondary Endpoints
The secondary endpoints of SwCL (Cohorts 1 and 2), ppFEV1 (Cohort 3), FVC, and FEF25-75 will be analyzed 
based on an MMRM model similarly as the primary endpoint.  Details on the secondary efficacy analyses 
will be provided in the SAP.
7.5 Statistical Analyses for Safety
All safety analyses will be performed on the safety analysis set for each cohort based on the treatment 
subjects actually receive.  Safety will be assessed by AEs, AESIs, weight, vital signs, clinical laboratory 
data, 12-lead ECGs, pulse oximetry and spirometry, as well as mental health outcome measures.  Details 
on the safety analyses will be provided in the SAP.
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA).  A treatment-emergent 
adverse event (TEAE) is defined as an AE with an onset date on or after the first dose of study drug and 
within 30 days after the last dose of study drug.  The number and percentage of subjects experiencing 
TEAEs will be tabulated using MedDRA system organ class (SOC) and preferred term as well as by 
severity and by relationship to the study drug as assessed by the investigator.  Summaries (i.e., number 
and percentages) of TEAEs, SAEs, deaths, AEs leading to discontinuation, and AESIs will be provided.
For laboratory test and vital signs variables, mean change from Baseline before the first dose of study 
drugs and percentage of subjects with evaluations meeting criteria for predefined potentially clinically 
significant (PCS) values will be summarized.
7.6 Pharmacokinetic and Exposure-Response Analyses
Individual galicaftor, navocaftor, and ABBV-119 or ABBV-576 plasma concentrations at each study visit 
will be tabulated and summarized with appropriate statistical methods.  For subjects receiving 
ivacaftor/tezacaftor at study entry, individual ivacaftor and tezacaftor plasma concentrations from the 
screening visit will be tabulated and summarized with appropriate statistical methods.
Data from this study may be combined with data from other studies for the population PK and 
exposure-response analyses.  Population PK and exposure-response analyses of data only from this 
study may not be conducted.  The following general methodology will be used for the population PK and 
exposure-response analyses.
The relationships between galicaftor, navocaftor, and ABBV-119 or ABBV-576 exposure and clinical 
observations (primary efficacy variable) will be explored.  Exposure-response relationships for secondary 
efficacy variables or safety responses may be explored.  The relationship between exposure (e.g., 
population PK model predicted average concentrations, area under the curve, trough concentrations, 
the individual model-predicted PK profiles, or some other appropriate measure of exposure) and drug 
effect will be explored.  Several classes of models (e.g., linear, log-linear, exponential, Emax, sigmoid Emax, 
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etc.) will be evaluated to characterize the exposure-response relationship based on observed data.  
Ivacaftor and tezacaftor plasma concentrations may be evaluated as a covariate.  Results of the PK and 
exposure response analyses may be summarized in a separate report before regulatory filing, rather 
than in the clinical study report.
Additional analyses will be performed if useful and appropriate.
7.7 Interim Analysis
One interim analysis for Cohort 1 was conducted for this study, which took place after 15 subjects in 
Cohort 1 completed the triple combination treatment period or prematurely discontinued study drug 
treatment.  The scope of the interim analysis included the efficacy and safety assessment of the dual 
treatment and triple treatment of subjects in Cohort 1 at the time of the interim analysis.  The primary 
purpose of this interim analysis was to inform AbbVie internal decision making.
Since Cohort 1 was open label, unblinding was not applicable for this interim analysis.  The interim 
analysis was performed and reviewed by the sponsor.
Based on the efficacy results of this interim analysis, Cohort 1 and Cohort 2 have been terminated (see 
Section 2.2).  Cohort 3 is modified to replace ABBV-119 with ABBV-576, a structurally differentiated 
modulator with improved safety and pharmacokinetic profiles.  Interim analyses for Cohort 3 may be 
performed when approximately 10 and/or 15 homozygous subjects in Cohort 3 have either completed 
the triple combination treatment period or prematurely discontinued study drug treatment to inform 
AbbVie internal program development decision.
Since Cohort 3 is open label, unblinding is not applicable for the interim analyses.  The interim analyses 
will be performed and reviewed by the sponsor. The details of the interim analyses will be specified in 
the Statistical Analysis Plan.
7.8 Overall Type I Error Control
Multiplicity adjustment for Type I error rate is not planned for this proof-of-concept study.  The primary 
endpoint will be analyzed and tested independently for each Cohort at 1-sided alpha level of 0.05.
7.9 Sample Size Determination
Sample size and power calculations are based on the primary efficacy endpoint of the within-group 
absolute change from Baseline (Day 1) in ppFEV1 (Cohorts 1 and 2) or in SwCI (Cohort 3) through Study 
Day 29.
For Cohort 1 (homozygote cohort, not receiving ETI at screening), a sample size of 18 subjects in 
galicaftor/navocaftor/ABBV-119 triple combination treatment will provide > 99% power to detect an 
estimated 8 to 12 percentage points absolute increase from galicaftor/navocaftor dual combination 
baseline (i.e., measured at the end of the galicaftor/navocaftor dual combination treatment run-in 
period) in ppFEV1 at one-sided type I error of 0.05, assuming a standard deviation of 7.5%.
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For Cohort 2 (heterozygote cohort, not receiving ETI at screening), a sample size of 18 subjects in 
galicaftor/navocaftor/ABBV-119 triple combination treatment will provide > 99% power to detect an 
estimated 14 to 18 percentage points absolute increase from treatment naïve baseline in ppFEV1 at 
1-sided type I error of 0.05, assuming a standard deviation of 7.5%.  
For Cohort 3 (ETI treated subjects at screening), a sample size of 18 subjects in each genotype subgroup 
(homozygotes, heterozygotes) will provide >85% power to detect an estimated 10 mmol/L absolute 
decrease from ETI baseline in SwCI with standard deviation of 15 mmol/L at 1-sided type I error of 0.05. 
With this sample size, it provides > 90% power to detect an estimated 4 percentage points absolute 
increase from ETI baseline (Day 1) in ppFEV1 at 1-sided type I error of 0.05, assuming a standard 
deviation of 5%.
The final sample size for all cohorts will be adjusted considering a 10% dropout rate.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, ICF, recruitment materials, and all subject materials will be submitted to the IEC/IRB for 
review and approval.  Approval of both the protocol and the ICF must be obtained before any subject is 
enrolled.  Any amendment to the protocol will require review and approval by the IEC/IRB before the 
changes are implemented to the study.  In addition, all changes to the consent form(s) will be IEC/IRB 
approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, 
applicable laws and regulations, and guidelines governing clinical study conduct and the ethical 
principles that have their origin in the Declaration of Helsinki.  Responsibilities of the investigator are 
specified in Appendix B.
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, conflict/combat) 
occurs leading to difficulties in performing protocol-specified procedures, AbbVie may engage with 
study site personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity of care.  This 
may include alternative methods for assessments (e.g., phone contacts or virtual site visits), alternative 
locations for data collection (e.g., use of a local lab instead of a central lab), and shipping investigational 
product and/or supplies direct to subjects to ensure continuity of treatment where allowed.  In all cases, 
these alternative measures must be allowed by local laws and regulations and permitted by IRB/IEC.  
Investigators should notify AbbVie if any urgent safety measures are taken to protect the subjects 
against any immediate hazard.
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8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).  During the COVID-19 pandemic, remote source data review and verification may be 
employed if allowed by the local regulatory authority, IRB/IEC, and the study site.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
START AND COMPLETION OF THE STUDY
The start-of-study is defined as the date of the first site activated.
The end-of-study is defined as the date of end of study participation by the last subject in the last 
country where the study was conducted.
12
REFERENCES
1.
Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor 
plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del 
mutation: a double-blind, randomised, phase 3 trial. Lancet. 2019;394(10212):1940-8.
2.
AbbVie. ABBV-576 Investigator's Brochure Edition 1. 2021.
3.
AbbVie. Galicaftor Investigator's Brochure Edition 4. 2022.
4.
AbbVie. Navocaftor Investigator's Brochure Edition 5. 2022.
5.
AbbVie. ABBV-119 Investigator's Brochure Edition 4. 2022.
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6.
Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a 
Single Phe508del Allele. N Engl J Med. 2019;381(19):1809-19.
7.
Nichols DP, Morgan SJ, Singh SB, et al. Elexacaftor/tezacaftor/ivacaftor markedly reduces sputum 
pathogen density in people with CF; a PROMISE study [abstract].  North American Cystic Fibrosis 
Conference, abstract 465. Pediatr Pulmonol. 2020;55(S2):S220.  Available from:  
https://onlinelibrary.wiley.com/doi/epdf/10.1002/ppul.25089.
8.
SYMDEKO® (tezacaftor/ivacaftor; ivacaftor) tablets [prescribing information]. Boston, MA; Vertex 
Pharmaceuticals Inc., 2020.
9.
Trimble AT, Donaldson SH. Ivacaftor withdrawal syndrome in cystic fibrosis patients with the G551D 
mutation. J Cyst Fibros. 2018;17(2):e13-e6.
10. Moss RB, Flume PA, Elborn JS, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis 
who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir 
Med. 2015;3(7):524-33.
11. US Department of Health and Human Services NIoH, National Cancer Institute. Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 2017 [cited 10 Feb 2020]. Available 
from: 
https://ctep.cancer.gov/protocoldevelopment/electronic applications/docs/CTCAE v5 Quick Refer
ence 8.5x11.pdf.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ABPA
allergic bronchopulmonary aspergillosis
AE
adverse event
AESI
adverse events of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATS
American Thoracic Society
AUC
area under the plasma concentration curve
AUC24,ss
area under the plasma concentration-time curve from time 0 to 24 hours at steady-state
AUC0-τ
area under the concentration vs. time curve from 0 to τ
BID
twice daily
BP
blood pressure
cAMP
cyclic adenosine monophosphate
CBC
complete blood count
CF
cystic fibrosis
CFQ-R
CF Questionnaire-Revised
CFTR
CF transmembrane conductance regulator
CL/F
oral clearance
ClinRo
Clinician-Reported Outcome
Cmax
maximum observed concentration
COVID-19
Coronavirus Disease – 2019
CRF
case report form
CRO
clinical research organization
CTCAE
Common Terminology Criteria for Adverse Events
CYP2C9
cytochrome P450 2C9 isoform subfamily
DMC
data monitoring committee
DTP
direct-to-patient
EC50
effective concentration providing 50% of the maximal response
EC90
effective concentration providing 90% of the maximal response
ECG
electrocardiogram
eCRF
electronic case report form
ERS
European Respiratory Society
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ETI
Elexacaftor /tezacaftor/ivacaftor
EU
European Union
EudraCT
European Clinical Trials Database
FAS
full analysis set
FEF25-75
forced expiratory flow at mid-lung capacity
FEV
forced expiratory volume
FEV1
forced expiratory volume in the first second of expiration
FIH
first-in-human
FSH
follicle-stimulating hormone
FVC
forced vital capacity
GAD-7
7-item Generalized Anxiety Disorder scale
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GLI
Global Lung Function Initiative
HBE
human bronchial epithelial/epithelium
HBsAg
hepatitis B virus surface antigen
HCV
hepatitis C virus
HDRS
Hamilton Depression Rating Scale
HIV
human immunodeficiency virus
HR
heart rate
hsCRP
high-sensitivity C-reactive protein
IB
Investigator's Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
independent ethics committee
IEC/IRB
Independent Ethics Committee/Institutional Review Board
IMP
investigational medicinal product
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
IU
International Unit
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
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LFT
liver function test
LS
least squares
MAD
multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effect model with repeated measures
N/A
not applicable
NCI
National Cancer Institute
NOEL
no-observed effect level
NRI
Non-Responder Imputation
PCR
polymerase chain reaction
PCS
potentially clinically significant
PD visit
Premature Discontinuation visit
PK
pharmacokinetics
PP
Per-Protocol
ppFEV1
percent predicted forced expiratory volume in 1 second
PT
prothrombin time
QA
quality assurance
QD
once daily
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia's formula
RNA
ribonucleic acid
RR
respiration rate
SAD
single ascending dose
SAE
serious adverse event
SAP
Statistical analysis plan
SAR
serious adverse reaction
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SDAC
statistical data analysis center
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
SwCl
sweat chloride
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
V/F
volume of distribution
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vs.
versus
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M19-771:  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
Protocol Date:  26 August 2022
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and local laws, 
regulations and guidelines governing the study at the site location.  In signing the Investigator Agreement, the 
investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, current 
protocol and operations manual, and making changes to a protocol only after notifying AbbVie and the 
appropriate IRB/IEC, except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for investigational 
purposes and complying with the requirements relating to informed consent and ethics committees (e.g., 
IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about their 
obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records available 
for inspection by representatives of AbbVie and/or the appropriate regulatory agency, and retaining all 
study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial clinical 
protocol and all of its amendments.
9.
Reporting promptly (within 1 calendar day to AbbVie, the ethics committees/institutional review boards 
(as required) and other appropriate individuals (e.g., coordinating investigator, institution director):

All changes in the research activity and all unanticipated problems involving risks to human subjects 
or others.

Any departure from relevant clinical trial law or regulation, GCP, or the trial protocol that has the 
potential to affect the following:

Rights, safety, physical or mental integrity of the subjects in the clinical trial

Scientific value of the clinical trial, reliability or robustness of data generated
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Study Project Manager II
Clinical Study Leadership
Director
Medical Writing
Executive Medical Director
Specialty Development
Senior Scientific Director
Specialty Development
Associate Director, Statistics
Data and Statistical Sciences
Senior Director and Statistics Therapeutic 
Area Head
Data and Statistical Sciences
Senior Clinical Pharmacologist
Clinical Pharmacology and 
Pharmacometrics
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APPENDIX E. EXAMPLES OF PROHIBITED MEDICATIONS AND 
THERAPY
Strong CYP3A4 inhibitors, such as
Clarithromycin
Cobicistat
Conivaptan
Itraconazole
Ketoconazole
Nefazodone
Ritonavir
Posaconazole
Telaprevir
Telithromycin
Voriconazole
Grapefruit or grapefruit juice
Seville oranges (commonly used in marmalade)
Strong CYP3A4 inducers, such as
Carbamazepine
Enzalutamide
Fosphenytoine
Lumacaftor
Mitotane
Phenobarbital
Phenytoin
Primidone
Rifabutin
Rifampin
Rifapentine
St. John's Wort
Strong CYP2C9 inducers, such as
Enzalutamide
Rifampin
Carbamazepine
Dabrafenib
Substrates of CYP2C8, such as
Paclitaxel
Torasemide
Amiodiaqine
Cerivastatin
Repaglinide
Montelukast
CYP = cytochrome P450
Note:
This should not be considered an exhaustive list.
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APPENDIX F. CFTR MINIMAL FUNCTION MUTATIONS 
ELIGIBLE FOR COHORT 2 AND COHORT 3
1078delT
1119delA
1138insG
1154insTC
1161delC
1213delT
1248+1G→A
1249-1G→A
124del23bp
1259insA
1288insTA
1341+1G→A
1343delG
1461ins4
1471delA
1497delGG
1525-1G→A
1525-2A→G
1548delG
1609del CA
1677delTA
1717-1G→A
1717-8G→A
1782delA
1811+1.6kbA→G
1811+1643G→T
1811+1G→C
1812-1G→A
1824delA
182delT
1833delT
185+1G→T
1898+1G→A
1898+1G→C
1924del7
2043delG
2055del9→A
2721del11
2732insA
2790-1G→C
2869insG
2896insAG
2942insT
2957delT
296+1G→A
296+1G→T
2991del32
3007delG
3028delA
3040G→C (G970R)
306delTAGA
306insA
3120+1G→A
3120G→A
3121-1G→A
3121-2A→G
3121-977_3499+248del2515
3171delC
3171insC
3271delGG
3349insT
3500-2A→G
3600+2insT
365-366insT
3659delC
3667ins4
3737delA
3791delC
3821delT
3850-1G→A
3876delA
3878delG
3905insT
394delTT
4374+1G→T
442delA
444delA
457TAT→G
541delC
574delA
602del14
621+1G→T
663delT
711+1G→T
711+5G→A
712-1G→T
849delG
852del22
935delA
991del5
A46D
A559T
A561E
C276X
C524X
CFTR50kbdel
CFTRdele1
CFTRdele11
CFTRdele13,14a
CFTRdele14b-17b
CFTRdele16-17b
CFTRdele17a,17b
CFTRdele17a-18
CFTRdele19
CFTRdele19-21
CFTRdele2
CFTRdele2,3
CFTRdele21
CFTRdele22,23
CFTRdele22-24
CFTRdele2-4
G542X
G550X
G673X
G85E
I507del
K710X
L1065P
L1077P
L1254X
L218X
L467P
L732X
L88X
M1101K
N1303K
Q1042X
Q1313X
Q1330X
Q1382X
Q1411X
Q220X
Q290X
Q2X
Q39X
Q414X
Q493X
Q525X
Q552X
Q685X
Q715X
Q890X
Q98X
R1066C
R1102X
R1158X
R1162X
R347P
S489X
S4X
S912X
V520F
W1089X
W1098X
W1145X
W1204X
W1282X
W19X
W216X
W401X
W496X
W57X
W846X
W882X
Y1092X
Y122X
Y275X
Y569D
Y849X
Y913X
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
2105-
2117del13insAGAAA
2143delT
2183AA→Ga
2184delA
2184insA
2307insA
2347delG
2372del8
2585delT
2594delGT
2622+1G→A
2711delT
4005+1G→A
4010del4
4016insT
4021dupT
4022insT
4040delA
405+1G→A
405+3A→C
406-1G→A
4209TGTT→AA
4279insA
4326delTC
CFTRdele3-10,14b-16
CFTRdele4-7
CFTRdele4-11
CFTRdup6b-10
E1104X
E1371X
E193X
E585X
E60X
E822X
E92X
G27X
G330X
R553X
R560S
R560T
R709X
R75X
R764X
R785X
R792X
R851X
S1196X
S1255X
S434X
S466X
CFTR = CF transmembrane conductance regulator; SwCl = sweat chloride
Note:
The minimal function mutation is defined as a mutation that is predicted to result in CFTR protein with minimal 
function.  This list is based on the mutation class (e.g., nonsense mutations that do not produce the full length CFTR 
protein) and the evidence of clinical severity on a population basis (average SwCl > 86 mmol/L and %pancreatic 
insufficiency > 50%) that is reported in CFTR2 patient registry (https://cftr2.org/) as of 29 April 2022.  This should not 
be considered an exhaustive list, and the investigator should contact the medical monitor regarding other mutations 
that may also meet study eligibility criteria.
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STUDY M19-771  |  Version 7.0  |  EudraCT 2020-005805-25
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX G. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
14 January 2021
Admin Change 1
22 February 2021
Version 2.0 
24 March 2021
Version 3.0
04 June 2021
Version 4.0
22 October 2021
Version 4.1 (Belgium only)
22 October 2021
Version 4.1.1 (Belgium only)
09 December 2021
Version 4.2 (UK only)
16 February 2022
Version 5.0
02 March 2022
Version 5.1 (Belgium only)
21 March 2022
Version 5.2 (UK only)
21 March 2022
Version 6.0 
30 June 2022
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol in 
addition to making the following changes: 
Added that Cohorts 1 and 2 were terminated based on efficacy results of an interim analysis to 
Section 1, Section 4.1, and Section 7.7 of the protocol.  Rationale:  To provide further details on the 
reason for changing the study regimen.
Added 'with and without other CFTR modulators (such as ABBV-119)' to Section 2.2 and Section 6.1 of 
the protocol.  Rationale:  To provide further information to clarify the safety profile of the study 
regimen.
Added further information on hepatobiliary events to Section 2.2 and Section 6.1 of the protocol.  
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 in Section 3.6 of the protocol.  
Further details regarding the assessment have been included in Section 3.5 and Section 3.6 of the 
Operations Manual, respectively (see Appendix H).  The scheduled assessments are described in
Appendix D of the protocol and in Section 2.1 of the Operations Manual(see Appendix H).  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' to Section 4.1 of the protocol.  Rationale:  To improve clarity regarding the timing 
of study activities at Day 29.
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STUDY M19-771  |  Version 7.0  |  EudraCT 2020-005805-25
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Added clarification on the type of cirrhosis that must be absent for subjects to participate in the study 
under each cohort, to eligibility criterion number 10a (Section 5.1 of the protocol).  Rationale:  To 
provide further guidance to guide sites in interpreting eligibility criterion 10.
Removed withdrawal criteria related to the use of triazole antimicrobial from Section 5.5 of the 
protocol.  Rationale:  Criteira removed due to redundancy with the prohibited medications listed in 
Appendix E of the protocol. 
Added 'as well as mental health outcome measures' to Section 7.5 of the protocol.  Rationale:  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 Appendix D of the 
protocol and in Section 2.1 of the Operations Manual (see Appendix H).  Rationale:  To update schedule 
of activity based on the updated Cohort 3 design.
Added definition for minimal function mutations in Appendix F.  Rationale:  Updated criteria definition 
based on regulatory agency feedback.
Added amylase and lipase laboratory tests to Table 1 of the Operations Manual (Appendix H).  
Rationale:  To incorporate additional safety monitoring parameters.
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SAP_001.pdf: 
Galicaftor/Navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576
M19-771 – Statistical Analysis Plan
Version 3.0 – 31 May 2023
1 
Statistical Analysis Plan for Study M19-771
A Phase 2 Study of Galicaftor/Navocaftor/ABBV-119 
or Galicaftor/Navocaftor/ABBV-576 in Subjects with 
Cystic Fibrosis Who Are Homozygous or 
Heterozygous for the F508del Mutation
Date: 31 May 2023 
Version 3.0
NCT04853368


Galicaftor/Navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576
M19-771 – Statistical Analysis Plan
Version 3.0 – 31 May 2023
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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives, Hypotheses and Estimands ..................................................... 5
2.2
Study Design Overview ............................................................................. 6
2.3
Treatment Assignment and Blinding ......................................................... 8
2.4
Sample Size Determination ...................................................................... 10
3.0
Endpoints................................................................................11
3.1
Primary Endpoint(s) ................................................................................. 11
3.2
Secondary Endpoint(s) ............................................................................. 11
3.3
Exploratory Efficacy Endpoints ............................................................... 12
3.4
Safety Endpoint(s) ................................................................................... 12
3.5
Exploratory Safety Endpoints .................................................................. 12
3.6
Additional Endpoint(s) ............................................................................. 12
4.0
Analysis Populations .............................................................12
5.0
Subject Disposition................................................................13
6.0
Study Drug Duration and Compliance................................14
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................15
7.1
Demographics and Baseline Characteristics ............................................ 16
7.2
Medical History ....................................................................................... 17
7.3
Prior and Concomitant Medications ........................................................ 17
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints..............................18
9.0
Efficacy Analyses...................................................................19
9.1
General Considerations ............................................................................ 19
9.2
Handling of Missing Data ........................................................................ 21
9.3
Primary Efficacy Endpoint(s) and Analyses ............................................ 21
9.3.1
Primary Efficacy Endpoint(s) .................................................................. 21
9.3.2
Main Analysis of Primary Efficacy Endpoint(s) ..................................... 21
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint(s) ............................................................................................... 24


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9.4
Secondary Efficacy Endpoints and Analyses .......................................... 24
9.4.1
Key Secondary Efficacy Endpoints ......................................................... 24
9.4.2
Main Analyses of Key Secondary Efficacy Endpoints ............................ 25
9.5
Additional Efficacy Analyses .................................................................. 29
9.6
Efficacy Subgroup Analyses .................................................................... 30
10.0
Safety Analyses ......................................................................30
10.1
General Considerations ............................................................................ 30
10.2
Adverse Events ........................................................................................ 31
10.2.1
Treatment-Emergent Adverse Events ...................................................... 31
10.2.2
Adverse Event Overview ......................................................................... 32
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT ....................... 32
10.2.4
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ............................................................................... 33
10.2.5
Adverse Events of Special Interest .......................................................... 33
10.2.6
Other Adverse Events of Interest ............................................................. 34
10.3
Analysis of Laboratory Data .................................................................... 34
10.4
Analysis of Vital Signs ............................................................................ 37
10.5
Other Safety Analyses .............................................................................. 37
11.0
Interim Analyses....................................................................38
11.1
Data Monitoring Committee .................................................................... 39
12.0
Overall Type-I Error Control ..............................................40
13.0
Version History......................................................................41
14.0
References...............................................................................42
List of Tables
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint(s) ............................................................................................... 23
Table 2.
Summary of the Estimand Attributes of the Key Secondary 
Efficacy Endpoints ................................................................................... 26
Table 3.
SAP Version History Summary ............................................................... 41


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List of Figures
Figure 1.
Study Schematic ......................................................................................... 8
List of Appendices
Appendix A.
Protocol Deviations .................................................................................. 43
Appendix B.
Potentially Clinically Important Criteria for Safety Endpoints ............... 44


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Study M19-771 
titled "A Phase 2 Study of Galicaftor/Navocaftor/ABBV-119 or 
Galicaftor/Navocaftor/ABBV-576 in Subjects with Cystic Fibrosis Who Are Homozygous 
or Heterozygous for the F508del Mutation." 
Study M19-771 examines the safety, tolerability, and efficacy of 
Galicaftor/Navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 combination 
therapy in adult subjects with Cystic Fibrosis (CF) who are homozygous or heterozygous 
for the F508del mutation. 
The analyses of pharmacokinetic endpoints, biomarker samples will not be covered in this 
SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis. 
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC 27513) or later under the UNIX operating system. 
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The primary objective is to evaluate the safety, tolerability, and efficacy for 
Galicaftor/Navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 combination 
therapy in adult subjects with CF who are homozygous or heterozygous for the F508del 
mutation.
The statistical hypothesis for the primary efficacy objective is that the absolute change 
from Baseline through Day 29 in percent predicted forced expiratory volume in 1 second 
(ppFEV1) (Cohorts 1 and 2) or sweat chloride (SwCl) (Cohort 3) is statistically 
significantly greater than zero in subjects treated with Galicaftor/Navocaftor/ABBV-119 


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(Cohorts 1 and 2) or Galicaftor/Navocaftor/ABBV-576 (Cohorts 3) combination 
therapies. This hypothesis will be tested for Cohort 1 and Cohort 2, separately, at 1-sided 
type I error of 5%. For Cohort 3, no hypothesis testing will be performed due to early 
termination of the trial before the anticipated number of subjects to be enrolled for 
planned interim analysis. 
For Cohorts 1 and 2, the estimand corresponding to the primary efficacy objective is the 
mean estimate of the absolute change from Baseline through Day 29 in ppFEV1 for 
subjects with CF who are homozygous (Cohort 1) or heterozygous (Cohort 2) for the 
F508del mutation and received at least one dose of Galicaftor/Navocaftor/ABBV-119 
combination treatment in the per-protocol population (see definition in Section 4.0).
Subjects who do not have baseline and at least one post-baseline ppFEV1 value from the 
triple combination treatment period will be excluded. Additionally, subject's post-baseline
ppFEV1 data that are collected with inconsistent bronchodilator or airway clearance status 
at Baseline or after a subject starts another CFTR modulator therapy will be excluded 
from the analysis. 
For Cohort 3, the estimand corresponding to the primary efficacy objective is the mean 
estimate of the absolute change from Baseline through Day 29 in SwCl for subjects with 
CF who are homozygous or heterozygous for the F508del mutation and received at least 
one dose of Galicaftor/Navocaftor/ABBV-576 (Cohort 3) combination treatment in the 
per-protocol population (see definition in Section 4.0). Subjects who do not have baseline 
and at least one post-baseline SwCl value from the triple combination treatment period 
will be excluded. Subject's post-baseline SwCl data collected after a subject starts another 
CFTR modulator therapy will be excluded from the analysis. 
2.2
Study Design Overview
This Phase 2, proof-of-concept study will enroll subjects with a confirmed clinical 
diagnosis of CF who carry at least one copy of the F508del mutation. Subjects will be 
enrolled to one of three cohorts according to their genotype and prior use of CFTR 
modulator therapy. 


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Cohort 1 will include adult CF subjects who are homozygous for the F508del mutation 
and are not receiving elexacaftor/tezacaftor/ivacaftor (ETI) treatment, with a single arm, 
open-label design. Subjects will receive the Galicaftor/Navocaftor Dual Therapy for 
28 days as the run-in period, followed by Galicaftor/Navocaftor/ABBV-119 Triple 
Therapy for 28 days. For subjects on stable treatment of ivacaftor/tezacaftor (Symkevi), a 
washout period of five days will occur before the start of the Dual Therapy run-in period. 
After the Triple Therapy ends, the subjects may resume Symkevi after a washout period 
of 5 days. Approximately 20 subjects will be enrolled in this cohort. 
Cohort 2 will include adult CF subjects who are heterozygous for the F508del mutation 
and a minimal function mutation and are not receiving ETI treatment, with a double-blind, 
placebo-controlled, parallel-arm design. Subjects will receive 
Galicaftor/Navocaftor/ABBV-119 Triple Therapy, or placebo treatment for 28 days. For 
Cohort 2, study sites and subjects will remain blinded for the duration of the study. 
Approximately 30 subjects will be enrolled in this cohort and will be randomized at a 2:1 
treatment to placebo ratio.
Cohort 3 will include adult CF subjects who are homozygous or heterozygous for the 
F508del mutation and are receiving stable treatment with ETI at the time of screening, 
with a single-arm, open-label design. Subjects will receive 
Galicaftor/Navocaftor/ABBV-576 Triple Therapy for 28 days. No washout period is 
planned before the start of the Triple Therapy to minimize the risk of withdrawal 
syndromes. Approximately 20 homozygous and up to 20 heterozygous subjects (a total of 
up to 40 subjects) will be enrolled in this cohort. 
For all cohorts, the follow-up period after the last dose of the study drug will be 30 days. 
The schematic of the study is shown in Figure 1. 


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Figure 1. 
Study Schematic
2.3
Treatment Assignment and Blinding
The treatment assignment is defined as below:
Cohort 1: 28 days of galicaftor 300 mg QD + navocaftor 50 mg QD + ABBV-119 210 mg 
BID preceded by 28 days of galicaftor 300 mg QD + navocaftor 50 mg QD 


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Cohort 2 (active): 28 days of galicaftor 300 mg QD + navocaftor 50 mg QD + ABBV-119 
210 mg BID 
Cohort 2 (placebo): 28 days of matching placebo for galicaftor 300 mg QD + navocaftor 
50 mg QD + ABBV-119 210 mg BID 
Cohort 3: 28 days of galicaftor 300 mg QD + navocaftor 50 mg QD + ABBV-576 5 mg 
QD  
Throughout this document, Galicaftor/Navocaftor combination treatment will be referred 
to as the Dual Therapy, and Galicaftor/Navocaftor/ABBV-119 or 
Galicaftor/Navocaftor/ABBV-576 combination treatment as the Triple Therapy.
All subjects will be assigned a unique identification number by the interactive response 
technology (IRT) vendor at the Screening visit. For subjects who rescreen, the screening 
number assigned by the IRT at the initial Screening visit should be used. Cohort 1 and 
Cohort 3 are open-label, single arm design. In Cohort 2, which is a double-blind, placebo-
controlled design, the IRT will assign a randomization number to each subject. This 
randomization number will encode the subject's treatment assignment according to the 
randomization schedule generated by the statistics department at AbbVie. The 
randomization in Cohort 2 will also be stratified by ppFEV1 at screening (< 70% vs 
≥70%).
For Cohort 2, all AbbVie personnel with direct oversight of the conduct and management 
of the trial (with the exception of AbbVie Drug Supply Management Team), as well as the 
investigator, study site personnel, and the subjects themselves, will remain blinded to each 
subject's treatment assignment throughout the study. 
Also, to minimize the potential for unblinding and/or bias, the AbbVie study team will not 
have access to the post-first-dose spirometry or SwCl results of Cohort 2 subjects until 
after the study database is locked for analysis. For all cohorts, site personnel and subjects 
will not be informed of the subjects' study-related post-first-dose SwCl results until the 


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end of the cohort. Subjects will not be informed of their study-related spirometry results 
until the end of the study. 
2.4
Sample Size Determination
Sample size and power calculations are based on the primary efficacy endpoint of the 
within-group absolute change from baseline (Day 1) in ppFEV1 (Cohorts 1 and 2) or in 
SwCl (Cohort 3) through Study Day 29. 
For Cohort 1 (homozygote cohort, not receiving ETI at screening), a sample size of 18 
subjects in Galicaftor/Navocaftor/ABBV-119 triple combination treatment will provide > 
99% power to detect an estimated 8 to 12% percentage points absolute increase from 
Galicaftor/Navocaftor dual combination baseline (i.e., measured at the end of the 
Galicaftor/Navocaftor dual combination treatment run-in period) in ppFEV1 at 1-sided 
type I error of 0.05, assuming a standard deviation of 7.5%. 
For Cohort 2 (heterozygote cohort, not receiving ETI at screening), a sample size of 
18 subjects in Galicaftor/Navocaftor/ABBV-119 triple combination treatment will provide 
> 99% power to detect an estimated 14 to 18% absolute increase from treatment naïve 
baseline in ppFEV1 at 1-sided type I error of 0.05, assuming a standard deviation of 7.5%. 
For Cohort 3 (ETI treated subjects at screening), a sample size of 18 subjects in each 
genotype subgroup (homozygous, heterozygous) will provide > 85% power to detect an 
estimated 10 mmol/L absolute decrease from ETI baseline in SwCl with standard 
deviation of 15 mmol/L at 1-sided type I error of 0.05. With this sample size, it provides 
> 90% power to detect an estimated 4 percentage points absolute increase from ETI 
baseline (Day 1) in ppFEV1 at 1-sided type I error of 0.05, assuming a standard deviation 
of 5%.
The final sample size in all cohorts has been adjusted for a 10% dropout rate. The placebo 
group in Cohort 2 (n = 10) is mainly for safety assessment, not for formal efficacy 
comparisons. 


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3.0
Endpoints
3.1
Primary Endpoint(s)
The primary endpoint is the absolute change from baseline through Day 29 in ppFEV1 for 
Cohorts 1 and 2, and in SwCl for Cohort 3. 
3.2
Secondary Endpoint(s)
The secondary endpoints for Cohorts 1 and 2: 
●
Absolute change from baseline through Day 29 in SwCl 
●
Absolute change from baseline through Day 29 in forced vital capacity (FVC) 
●
Absolute change from baseline through Day 29 in forced expiratory flow at 
mid-lung capacity (FEF25-75) 
●
Relative changes from baseline through Day 29 in ppFEV1
●
Relative changes from baseline through Day 29 in FVC 
●
Relative changes from baseline through Day 29 in FEF25-75
●
Absolute change in CF Questionnaire-Revised (CFQ-R) respiratory domain 
score from baseline.
The secondary endpoints for Cohort 3: 
●
Absolute change from baseline through Day 29 in ppFEV1
●
Absolute change from baseline through Day 29 in FVC 
●
Absolute change from baseline through Day 29 in FEF25-75
●
Relative changes from baseline through Day 29 in ppFEV1
●
Relative changes from baseline through Day 29 in FVC 
●
Relative changes from baseline through Day 29 in FEF25-75
●
Absolute change in CFQ-R respiratory domain score from baseline through 
Day 29. 


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3.3
Exploratory Efficacy Endpoints
The additional exploratory endpoint is ppFEV1 change over time monitored via home 
spirometer.
3.4
Safety Endpoint(s)
The following endpoints will be included in the safety analyses: 
●
Treatment emergent adverse events
●
Serious adverse events
●
Adverse events of special interest
●
Clinical laboratory tests, 12-lead electrocardiogram, vital signs, weight, 
physical examinations (including neurologic examination), pulse oximetry and 
spirometry parameters.
3.5
Exploratory Safety Endpoints
Cohort 3 will include mental health outcome measures as exploratory safety endpoints 
that are monitored via the Hamilton Depression Rating Scale (HDRS) and the 7-item 
Generalized Anxiety Disorder scale (GAD-7).
3.6
Additional Endpoint(s)
The pharmacokinetic endpoints and biomarker research endpoints will be analyzed 
separately and not be covered in this SAP. 
4.0
Analysis Populations
Since the database lock and formal analysis may be performed separately for each cohort 
(Section 9.1), the analysis populations defined below apply to each cohort. 
The Full Analysis Set (FAS) includes all enrolled subjects (randomized subjects for 
Cohort 2) who received at least one dose of the study drug as Dual or Triple Therapy (or 


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corresponding placebo). The FAS will be used for the analyses of subject disposition, 
demographics, and baseline characteristics. Subjects will be grouped according to 
treatment as enrolled (randomized for Cohort 2). 
The Per-Protocol (PP) Population includes all enrolled subjects (randomized subjects for 
Cohort 2) who carry the intended CFTR mutation based on central lab report and received 
at least one dose of the Triple Therapy or placebo. The primary efficacy endpoint will be 
analyzed in the PP Population. For Cohorts 1 and 2, subjects who did not have the 
intended genotype as confirmed by results from central lab will be excluded from the PP 
Population. For Cohort 3, subjects will be grouped into the intended genotype group 
based on the central lab test results (or screening visit genotype if central lab test results 
are not available). If a subject did not receive the intended treatment regimen, the subject 
will be grouped in the treatment group for which they received on Day 1. 
The Safety Analysis Set consists of all enrolled subjects (randomized subjects for 
Cohort 2) who received at least one dose of study drug (Dual Therapy, Triple Therapy, or 
placebo). The Safety Analysis Set will be used for safety analyses. Subjects will be 
included in the analysis according to the study drug that they actually received. If a 
subject takes more than one treatment, the actual treatment group will be determined by 
the kits dispensed on Day 1. 
For analyses and summaries of the Cohort 1 Triple Therapy throughout this document, a 
subject will be excluded if the subject discontinued during or after the Dual Therapy and 
never took a dose of the triple therapy. 
5.0
Subject Disposition
The number of subjects in each of the following categories will be summarized by 
investigator and overall, for the following group (according to assignment at 
randomization/enrollment): Cohort 1 total, Cohort 2 Triple Therapy, Cohort 2 placebo, 
Cohort 2 total, Cohort 3 homozygous, Cohort 3 heterozygous, Cohort 3 total. 
●
Subjects who were screened.


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●
Subjects who were randomized/enrolled. 
●
Subjects who took at least one dose of the Triple Therapy. 
●
Subjects who completed the Triple Therapy. 
●
Subjects who prematurely discontinued the Triple Therapy. 
●
Subjects who took at least one dose of the Dual Therapy (Cohort 1 only). 
●
Subjects who completed the Dual Therapy (Cohort 1 only). 
●
Subjects who prematurely discontinued the Dual Therapy (Cohort 1 only). 
●
Subjects who completed study. 
●
Subjects who prematurely discontinued study. 
●
Subjects in the FAS, PP Population, and Safety Analysis Set. 
●
Subjects who received treatment other than the randomized treatment. 
The number and percentage of subjects, overall and by treatment arm, who prematurely 
discontinued the Dual Therapy or Triple Therapy will be summarized by each primary 
reason. Similar summaries will be provided for the premature discontinuation of study 
participation. The number and percentage of subjects, overall and by treatment arm, who 
had interruption of the Triple Therapy before discontinuation of study treatment will also 
be summarized. The denominator of these summaries will be FAS.
The number and percentage of subjects who were not included in the FAS, including 
subjects who were not randomized/enrolled and/or were screen failures will be 
summarized for each reason. The denominator of this summary will be all subjects who 
were not included in the FAS. 
The number and percentage of subjects who were not included in the PP Population out of 
all subjects who received at least one dose of the study drug will be summarized by 
cohort. 
6.0
Study Drug Duration and Compliance
Study drug duration, treatment compliance and temporary interruptions of study drug will 
be summarized for the Safety Analysis Set by the following group: Cohort 1 Dual 


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Therapy, Cohort 1 Triple Therapy, Cohort 2 Triple Therapy, and Cohort 2 placebo. For 
Cohort 3, treatment compliance will not be summarized due to the early termination of the 
study requested by the sponsor and resulting treatment discontinuation. 
Duration of treatment is defined for each subject as last dose date minus first dose 
date + 1, and temporary interruptions of study drug will not be subtracted from the 
duration. It will be summarized using the number of subjects treated, mean, standard 
deviation, median, minimum and maximum. In addition, the number and percentage of 
subjects in each treatment duration interval (1 to 7, 8 to 14, 15 to 21, 22 to 28, and 
> 28 days) will be summarized.
Treatment compliance is defined as the number of capsules actually taken divided by the 
number of tablets or capsules that should have been taken. It will be summarized using the 
number of subjects with available treatment compliance, mean, standard deviation, 
median, minimum and maximum. A listing of the treatment compliance for each subject 
will also be provided for Cohorts 1 and 2. 
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline characteristics, medical history, and prior and concomitant 
medications will be summarized for the FAS Population by the following group: Cohort 1 
Dual Therapy, Cohort 1 Triple Therapy, Cohort 2 Triple Therapy, Cohort 2 placebo, 
Cohort 2 total, Cohort 3 homozygous, Cohort 3 heterozygous, and Cohort 3 total. 
Demographics and baseline characteristics will also be summarized for the PP Population 
by the same group. 
Categorical variables will be summarized using the number and percentage of subjects; 
percentages will be calculated based on the number of non-missing observations. 
Continuous variables will be summarized using number of non-missing observations, 
mean and standard deviation, median, minimum and maximum. 


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7.1
Demographics and Baseline Characteristics
The following demographic and baseline characteristics parameters will be summarized.
Subject Demographics
●
Sex (male, female)
●
Age (years)
●
Race (White, Black, American Indian/Alaska Native, Native Hawaiian or 
Other Pacific Islander, Asian, Multi, Other) 
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
●
Country 
●
Region (Europe, Rest of World) 
●
Body weight (kg) at baseline 
●
Height (cm) at baseline
●
BMI (kg/m2) baseline
Disease Characteristics
●
Alcohol status (Never, Current, Former) 
●
F508del CFTR mutation as reported at screening (Homozygous, 
Heterozygous) 
●
F508del CFTR mutation as determined by central lab genotyping 
(Homozygous, Heterozygous with eligible minimal function mutations, 
Heterozygous without eligible minimal function mutations) 
●
Continuous value of ppFEV1 at screening visit (%)
●
Continuous value of ppFEV1 at baseline (%)
●
Stratification factor of screening ppFEV1 (< 70%, ≥ 70%)
●
Screening ppFEV1 category (< 40%, ≥ 40% to < 70%, ≥ 70% to < 90%, or 
≥90%; < 70%, or ≥ 70%)
●
Baseline ppFEV1 category (< 40%, ≥ 40% to < 70%, ≥ 70% to < 90%, ≥ 90%)
●
Continuous value of sweat chloride at baseline (mmol/L) 


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●
Continuous value of FEV1 at baseline (L)
●
Continuous value of FVC at baseline (L) 
●
Continuous value of FEF25-75 at baseline (L/sec)
●
CFQ-R respiratory domain score at baseline 
●
Prior use of CFTR modulators (Yes, No) 
●
For subjects with prior use of CFTR modulators only: 
○
prior CFTR modulator medication 
○
reason for discontinuation of prior CFTR modulators (Lack of efficacy, 
Tolerability, Other)
●
Number of exacerbations requiring hospitalization and/or intravenous 
antibiotics in last 12 months
●
Supplemental oxygen use while awake (Yes, No) 
●
Supplemental oxygen use while sleeping (> 2 L/minute, ≤ 2 L/minute, No)
●
Microbiology history in the past year as captured on the Microbiology History 
eCRF
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report. The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized. The system organ class (SOC) will be presented in alphabetical order, and 
the preferred terms (PTs) will be presented in alphabetical order within each SOC. 
Subjects reporting more than one condition/diagnosis will be counted only once in each 
row (SOC or PT).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name. A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug. A concomitant medication is defined as any medication that started prior to the date 


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of the first dose of study drug and continued to be taken after the first dose of study drug 
or any medication that started on or after the date of the first dose of study drug, but not 
after the date of the last dose of study drug. The number and percentage of subjects taking 
medications will be summarized by generic drug name based on the World Health 
Organization (WHO) Drug Dictionary for both prior and concomitant medications. 
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints
Cohorts 1 and 2: 
The primary efficacy endpoint of ppFEV1 (defined in Section 3.1) will be analyzed using 
the PP Population and the following methods will be used to address the potential 
intercurrent events:
●
If a subject starts another CFTR modulator therapy, ppFEV1 data for this 
subject on or after the start date of the new CFTR modulator therapy will be 
excluded from analyses. 
●
Post-baseline ppFEV1 data used for efficacy analyses should be consistent with 
baseline in terms of the timing of the last use of bronchodilator and airway 
clearance regimen. Otherwise, the data will be excluded from analyses.
The secondary efficacy endpoints related to spirometry evaluation (e.g., relative change in 
ppFEV1, absolute and relative change in FVC, FEV25-75, defined in Section 3.2) will be 
analyzed in the PP and the following methods will be used to address the potential 
intercurrent events:
●
If a subject starts another CFTR modulator therapy, efficacy data related to 
spirometry for this subject on or after the start date of the new CFTR 
modulator therapy will be excluded from analyses. 
●
Post-baseline spirometry data used for efficacy analyses should be consistent 
with baseline in terms of the timing of the last use of bronchodilator and 
airway clearance regimen. Otherwise, the data will be excluded from analyses.


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The secondary efficacy endpoints related to SwCl and CFQ-R (defined in Section 3.2) 
will be analyzed in the PP and the following methods will be used to address the potential 
intercurrent events:
●
If a subject starts another CFTR modulator therapy, SwCl and CFQ-R for this 
subject on or after the start date of the new CFTR modulator therapy will be 
excluded from analyses. 
Cohort 3: 
The primary efficacy endpoint of SwCl (defined in Section 3.1) will be analyzed in the PP 
and the following methods will be used to address the potential intercurrent events: 
●
If a subject starts another CFTR modulator therapy, SwCl data for this subject 
on or after the start date of the new CFTR modulator therapy will be excluded 
from analyses.
The secondary efficacy endpoints related to spirometry evaluation (e.g., absolute and 
relative change in ppFEV1, FVC, FEV25-75, defined in Section 3.2) and CFQ-R will be 
analyzed in the PP and the following methods will be used to address the potential 
intercurrent events:
●
If a subject starts another CFTR modulator therapy, efficacy data related to 
spirometry for this subject on or after the start date of the new CFTR 
modulator therapy will be excluded from analyses. 
9.0
Efficacy Analyses
9.1
General Considerations
All efficacy analyses will be conducted in the PP Population separately for all Cohort 1 
subjects, all Cohort 2 subjects, and Cohort 3 subjects (homozygous, heterozygous, 
overall). The Primary Analysis for each cohort will be conducted after all subjects in that 
cohort have completed the study or prematurely discontinued from the study. If the timing 


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of the completion of each cohort differs significantly, the database lock and formal 
analysis may be performed separately for each cohort.
For Cohorts 1 and 2, unless otherwise specified, continuous efficacy variables (SwCl, 
spirometry data, CFQ-R) will be analyzed using Mixed-Effect Model Repeat 
Measurement (MMRM) method. Point estimates, 90% confidence intervals (CIs) and 
95% CIs of mean change from baseline within each applicable treatment group, as well as 
applicable comparison of the mean change from baseline between treatment groups will 
be provided. The observed baseline and visit means will also be summarized for each 
applicable treatment group among subjects who have both the baseline value and one 
post-baseline value. All tests for Cohorts 1 and 2 will be 1-sided at an alpha level of 0.05. 
Additionally, for Cohorts 1 and 2, post-baseline spirometry values that are inconsistent 
with the baseline value will be excluded from the efficacy analysis. For example, if the 
baseline spirometry value was pre-bronchodilator, post-baseline spirometry values must 
also be pre-bronchodilator. 
For Cohort 3, given the early termination of study trial and small number of subjects 
completed Day 15 and/ or Day 29 treatment, all spirometry data regardless the consistent 
or inconsistent use of bronchodilator and/or airway clearance regimen will be included in 
the efficacy summary of visit means and mean change from Day 1/Baseline (pre-dose). In 
addition, efficacy data (SwCl, spirometry data, CFQ-R) at each visit and change from Day 
1/baseline (pre-dose) will only be summarized descriptively (N, mean, median, SD, 
minimum, maximum). Statistical analyses that were performed for Cohorts 1 and 2 
(e.g., MMRM, sensitivity analysis excluding spirometry data with inconsistent use of 
bronchodilator and/or airway clearance regimen) will not be conducted for Cohort 3 data.
For all cohorts, "Baseline" refers to the last non-missing observation before the first 
administration of the Triple Therapy. If a subject starts another CFTR modulator 
treatment during the study period, all efficacy measures for this subject on or after the 
start date of the new CFTR modulator treatment will be excluded from analyses. Mean 
plots, spaghetti plots, and/or waterfall plots of ppFEV1 and SwCl will be created for each 


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treatment group for Cohorts 1 and 2, for each genotype (homozygous, heterozygous) and 
both genotypes combined for Cohort 3. 
9.2
Handling of Missing Data
For Cohorts 1 and 2, the primary endpoint and key secondary endpoints will use the same 
analysis method: Mixed-Effect Model Repeat Measurement (MMRM). This modeling 
approach handles partially missing dependent variables based on the assumption of data 
being missing at random. No other imputation will be used in these cohorts. For Cohort 3, 
the change in the primary and key secondary endpoints from baseline to Day 29 will be 
summarized descriptively. No missing data handling technique will be employed in this 
cohort.  
9.3
Primary Efficacy Endpoint(s) and Analyses
9.3.1
Primary Efficacy Endpoint(s)
For Cohorts 1 and 2, the primary endpoint is the absolute change from baseline through 
Day 29 in ppFEV1. The predicted values of FEV1 (L) at all study visits will be calculated 
for age, gender, and height using the 2012 Global Lungs Initiative equation.1 ppFEV1 is 
the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a percentage. The null 
hypothesis for the primary endpoint is that the within-group absolute change from 
baseline through Day 29 in ppFEV1 is zero.
For Cohort 3, the primary endpoint is the absolute change from baseline through Day 29 
in SwCl. 
9.3.2
Main Analysis of Primary Efficacy Endpoint(s)
Cohorts 1 and 2 
The primary endpoint of ppFEV1 will be analyzed using a MMRM model with each 
subject's change in ppFEV1 from baseline through Day 29 as the dependent variable. For 
all cohorts, the model will include baseline ppFEV1 and visit (Day 15, Day 29) as fixed 


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effect covariates. For Cohort 2, the model will also include treatment (Triple Therapy or 
placebo) and the interaction term between treatment and visit. Subject will be treated as 
the random effect in all models.
For both cohorts, the least squares (LS) estimates for within-group mean change in 
ppFEV1 from baseline through Day 29 (with point estimate for Day 29) will be presented 
along with the 90% CIs, 95% CIs and the corresponding p-values for testing the null 
hypothesis. For Cohort 2, the estimate for the treatment effect (comparison between the 
Triple Therapy and placebo) will also be presented along with the 95% confidence 
intervals and the corresponding p-values for testing whether the treatment effect in 
Cohort 2 is the same between the Triple Therapy and placebo group. For all cohorts, the 
LS estimate for Day 15 will also be presented. 
Cohort 3 
The primary endpoint of SwCl at each visit and change from Day 1/baseline will be 
summarized descriptively (N, mean, median, SD, minimum, maximum) given that this 
cohort is early terminated, and the treatment discontinued. 
The attributes of the estimands corresponding to the primary efficacy endpoint are 
summarized in Table 1. 


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Table 1. 
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint(s)
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Primary
(Cohorts 1 
and 2)
Cohort 1: Galicaftor 
/ Navocaftor / 
ABBV-119 (Triple 
Therapy) 28 days 
with prior run-in of 
Galicaftor / 
Navocaftor 28 days 
in homozygous 
subjects
Cohort 2 (active):
Triple Therapy 
28 days in 
heterozygous 
subjects
Cohort 2 (placebo):
Matching Placebo 
for the Triple 
Therapy 28 days in 
heterozygous 
subjects
Absolute 
change 
from 
baseline 
through 
Day 29 in 
ppFEV1
PP Population 
of subjects 
with CF who 
are 
homozygous or
heterozygous 
for the F508del 
mutation and 
received at 
least one dose 
of the Triple 
Therapy or 
placebo.
IE1: A subject's 
post-baseline 
corresponding 
spirometry data 
collected after the 
subject starts another 
CFTR modulator 
therapy will be 
excluded from the 
analyses.
IE2: A subject's 
post-baseline 
corresponding 
spirometry data used 
for efficacy analyses 
should be consistent 
with baseline in terms 
of the timing of the 
last use of 
bronchodilator and 
airway clearance 
regimen. Otherwise, 
the data will be 
excluded from 
analyses.
Least squares 
mean estimate 
of change 
from baseline 
through 
Day 29 in 
ppFEV1 based 
on MMRM 
model
Primary
(Cohort 3)
Galicaftor / 
Navocaftor / 
ABBV-576 (Triple 
Therapy) 28 days in 
homozygous or 
heterozygous 
subjects
Absolute 
change 
from 
baseline 
through 
Day 29 in 
SwCl
PP Population 
of subjects 
with CF who 
are 
homozygous or
heterozygous 
for the F508del 
mutation and 
received at 
least one dose 
of the Triple 
Therapy
A subject's 
post-baseline SwCl
data collected after 
the subject starts 
another CFTR 
modulator therapy 
will be excluded from 
the analyses.
Mean change 
from baseline 
through 
Day 29 in
SwCl


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9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint(s)
Cohorts 1 and 2 
Supplementary analysis for the primary endpoint of ppFEV1 will be conducted for each 
cohort using all spirometry values as collected, even if the timing of bronchodilator or 
airway clearance regimen of certain post-baseline values were inconsistent with baseline 
values or if the spirometry values were after the start of other CFTR modulator therapy. 
Cohort 3 
No additional sensitivity analysis for the primary endpoint of SwCl will be conducted for 
this cohort. 
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints are outlined below. 
Cohorts 1 and 2 
●
Absolute change from baseline through Day 29 in SwCl 
●
Absolute change from baseline through Day 29 in FVC, FEF25-75
●
Relative change, calculated as percent change, from baseline through Day 29 
in ppFEV1, FVC, and FEF25-75
●
Absolute change in CFQ-R respiratory domain score from baseline through 
Day 29. 
Cohort 3 
●
Absolute change from baseline through Day 29 in ppFEV1
●
Absolute change from baseline through Day 29 in FVC, FEF25-75
●
Relative change, calculated as percent change, from baseline through Day 29 
in ppFEV1, FVC, and FEF25-75


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●
Absolute change in CFQ-R respiratory domain score from baseline through 
Day 29. 
9.4.2
Main Analyses of Key Secondary Efficacy Endpoints
Cohorts 1 and 2 
For all the key secondary efficacy endpoints, analyses will be performed similarly to the 
primary endpoint using MMRM models (Section 9.3.2), except that the baseline covariate 
needs to match the endpoint (baseline FVC, baseline FEF25-75, baseline SwCl, baseline 
CFQ-R). The summary of results and testing will also be performed similarly.
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, will be 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 will be set as missing. Since CFQ-R will not be collected at Day 15 and 
only change from baseline to Day 29 score will be used for the dependent variable, no 
subject-level random effect will be included in the model. 
Cohort 3 
All the key secondary efficacy endpoints will be summarized descriptively (N, mean, 
median, SD, minimum, maximum) given that this cohort is early terminated, and the 
treatment is discontinued.
The attributes of the estimands corresponding to the key secondary efficacy endpoints are 
summarized in Table 2. 


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Table 2. 
Summary of the Estimand Attributes of the Key Secondary Efficacy 
Endpoints
Estimand Label
Attributes of the Estimand
Treatmenta
Endpoint
Population
Handling of 
Intercurrent 
Events
Statistical 
Summary
Cohorts 1 and 2
SwCl absolute 
change  
Same as in 
Table 1  
Absolute 
change from 
baseline 
through 
Day 29 in 
SwCl. 
Same as in 
Table 1
A subject's 
post-baseline 
SwCl data 
collected after 
the subject starts 
another CFTR 
modulator 
therapy will be 
excluded from 
the analyses.
Least squares 
mean estimate of 
change from 
baseline through 
Day 29 in SwCl
based on MMRM 
model. 
FVC absolute 
change
Same as in 
Table 1
Absolute 
change from 
baseline 
through 
Day 29 in 
FVC. 
Same as in 
Table 1
Same as in 
Table 1 (IE1 and 
IE2).
Least squares 
mean estimate of 
change from 
baseline through 
Day 29 in FVC
based on MMRM 
model.
FEF25-75 absolute 
change
Same as in 
Table 1
Absolute 
change from 
baseline 
through 
Day 29 in 
FEF25-75
Same as in 
Table 1
Same as in 
Table 1 (IE1 and 
IE2).
Least squares 
mean estimates of 
change from 
baseline through 
Day 29 in FEF25-75
based on MMRM 
model.
ppFEV1 relative 
change  
Same as in 
Table 1
Relative 
change from 
baseline 
through 
Day 29 in 
ppFEV1
Same as in 
Table 1
Same as in 
Table 1 (IE1 and 
IE2).
Least squares 
mean estimate of 
percentage change 
from baseline 
through Day 29 in 
ppFEV1 based on 
MMRM model.


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Table 2. 
Summary of the Estimand Attributes of the Key Secondary Efficacy 
Endpoints (Continued)
Estimand Label
Attributes of the Estimand
Treatmenta
Endpoint
Population
Handling of 
Intercurrent 
Events
Statistical 
Summary
Cohorts 1 and 2 (continued)
FVC relative 
change
Same as in 
Table 1
Relative 
change from 
baseline 
through 
Day 29 in 
FVC
Same as in 
Table 1
Same as in 
Table 1 (IE1 and 
IE2).
Least squares 
mean estimate of 
percentage change 
from baseline 
through Day 29 in 
FVC based on 
MMRM model.
FEF25-75 relative 
change
Same as in 
Table 1
Relative 
change from 
baseline 
through 
Day 29 in 
FEF25-75
Same as in 
Table 1
Same as in 
Table 1 (IE1 and 
IE2).
Least squares 
mean estimate of 
percentage change 
from baseline 
through Day 29 in 
FEF25-75 based on 
MMRM model.
CFQ-R absolute 
change
Same as in 
Table 1
Absolute 
change from 
baseline in 
CFQ-R 
respiratory 
domain score
Same as in 
Table 1
A subject's 
post-baseline 
CFQ-R data 
collected after 
the subject starts 
another CFTR 
modulator 
therapy will be 
excluded from 
the summary. 
Least squares 
mean estimate of
change from 
baseline through 
Day 29 in CFQ-R 
based on MMRM 
model.
Cohort 3
ppFEV1 absolute 
change
Same as in 
Table 1
Absolute 
change from 
baseline 
through 
Day 29 in 
ppFEV1
Same as in 
Table 1
Same as in 
Table 1 (IE1).
Mean change 
from baseline 
through Day 29 in 
ppFEV1. 


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Table 2. 
Summary of the Estimand Attributes of the Key Secondary Efficacy 
Endpoints (Continued)
Estimand Label
Attributes of the Estimand
Treatmenta
Endpoint
Population
Handling of 
Intercurrent 
Events
Statistical 
Summary
Cohort 3 (continued)
FVC absolute 
change
Same as in 
Table 1
Absolute 
change from 
baseline 
through 
Day 29 in 
FVC
Same as in 
Table 1
Same as in 
Table 1 (IE1).
Mean change 
from baseline 
through Day 29 in 
FVC.
FEF25-75 absolute 
change
Same as in 
Table 1
Absolute 
change from 
baseline 
through 
Day 29 in 
FEF25-75
Same as in 
Table 1
Same as in 
Table 1 (IE1)
Mean change 
from baseline 
through Day 29 in 
FEF25-75. 
ppFEV1 relative 
change  
Same as in 
Table 1
Relative 
change from 
baseline 
through 
Day 29 in 
ppFEV1
Same as in 
Table 1
Same as in 
Table 1 (IE1)
Mean percentage 
change from 
baseline through 
Day 29 in ppFEV1
FVC relative 
change
Same as in 
Table 1
Relative 
change from 
baseline 
through 
Day 29 in 
FVC
Same as in 
Table 1
Same as in 
Table 1 (IE1)
Mean percentage 
change from 
baseline through 
Day 29 in FVC
FEF25-75 relative 
change
Same as in 
Table 1
Relative 
change from 
baseline 
through 
Day 29 in 
FEF25-75
Same as in 
Table 1
Same as in 
Table 1 (IE1)
Mean percentage 
change from 
baseline through 
Day 29 in FEF25-75


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Table 2. 
Summary of the Estimand Attributes of the Key Secondary Efficacy 
Endpoints (Continued)
Estimand Label
Attributes of the Estimand
Treatmenta
Endpoint
Population
Handling of 
Intercurrent 
Events
Statistical 
Summary
Cohort 3 (continued)
CFQ-R absolute 
change
Same as in 
Table 1
Absolute 
change from 
baseline in 
CFQ-R 
respiratory 
domain score
Same as in 
Table 1
A subject's 
post-baseline 
CFQ-R data 
collected after 
the subject starts 
another CFTR 
modulator 
therapy will be 
excluded from 
the summary. 
Mean change
from baseline 
through Day 29 in 
CFQ-R 
a.
Treatments: 
Cohort 1: Galicaftor / Navocaftor / ABBV-119 28 days with prior run-in of Galicaftor / Navocaftor 28 days in 
homozygous subjects
Cohort 2 (active): Galicaftor / Navocaftor / ABBV-119 28 days in heterozygous subjects
Cohort 2 (placebo): Matching Placebo for the Triple Therapy 28 days in heterozygous subjects
Cohort 3: Galicaftor / Navocaftor / ABBV-576 28 days in homozygous or heterozygous subjects
9.5
Additional Efficacy Analyses
The efficacy of the Dual Therapy in Cohort 1 subjects will also be analyzed using a 
MMRM model. Each subject's change in ppFEV1 from the last data point before the first 
dose of the Dual Therapy through Day 1 of the Triple Therapy will be the dependent 
variable in the MMRM model. The fixed effect covariates in the model are the last 
ppFEV1 before the first dose of the Dual Therapy and visit (Day -15, Day 1). Subject will 
be treated as the random effect. Point estimates for Day -15 and Day 1 will be presented, 
along with 90% CIs and 95% CIs. 
Home spirometry is a different part of spirometry data than the spirometry data used for 
efficacy analyses. Due to discontinuation of further development of ABBV-119 and early 


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termination of Cohort 3 that replaced ABBV-119 with ABBV-576, the analyses on home 
spirometry will not be performed. 
9.6
Efficacy Subgroup Analyses
Descriptive statistics (number of non-missing observations, mean and standard deviation, 
median, minimum and maximum) of the primary endpoint will be provided for the 
following subgroups to evaluate the consistency of the efficacy across subgroup levels. 
●
Geographic region (Europe, Rest of World) 
●
Screening ppFEV1 as observed (< 70%, ≥ 70%)
95% CIs of the mean using the normal distribution will be provided for each subgroup 
level if there are at least 10 subjects in that subgroup. No p-value will be provided for 
subgroup analysis. 
Subgroup analysis will not be conducted for Cohort 3 due to early termination of this 
cohort. 
10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for the Safety Analysis Set by the following group: 
Cohort 1 Dual Therapy, Cohort 1 Triple Therapy, Cohort 2 Triple Therapy, Cohort 2 
placebo, Cohort 3 homozygous, Cohort 3 heterozygous, Cohort 3 total. 
For the safety analysis, subjects are assigned to a treatment group based on the treatment 
actually received, regardless of the treatment randomized. If a subject received more than 
one treatment, the subject will be grouped in the treatment group for which they received 
the most doses. All safety analyses will be based on observed data. Missing safety data 
will not be imputed.


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For Cohort 1, any safety data collected after the first dose of Triple Therapy will be 
summarized in the group of Cohort 1 Triple Therapy. Data collected after the first dose of 
Dual Therapy and before the first dose of Triple Therapy will be summarized in the group 
of Cohort 1 Dual Therapy. 
10.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock. The actual version of the 
MedDRA coding dictionary used will be noted in the AE tables and in the clinical study 
report. Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise. In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported. 
10.2.1
Treatment-Emergent Adverse Events
Treatment-emergent (TE) AEs are defined as any AE with an onset date that is after the 
first dose of study drug and no more than 30 days after the last dose of study drug. Events 
where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent. For Cohort 1 Dual Therapy, the study drug refers to Dual Therapy 
during the run-in period, and the definition of TEAE is further modified to exclude any 
AE with an onset date that is after the first dose of Triple Therapy. For Cohort 1 Triple 
Therapy, the study drug refers to Triple Therapy after the run-in period. 
The number and percentage of subjects experiencing TEAEs will be summarized. All 
TEAEs will be summarized overall, as well as by primary MedDRA SOC and PT. The 
SOCs will be presented in alphabetical order, and the PTs will be presented in 
alphabetical order within each SOC.
Pre-treatment AEs will be summarized separately in listing format. The number and 
percentage subjects experiencing AEs within 5 days before the first dose of the Dual 


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Therapy for subjects who were on Symkevi in Cohort 1 or within 7 days after the first 
dose of the Triple Therapy for subjects in Cohort 3 will be summarized by PT. AEs 
starting more than 30 days following the last dose of study drug will be summarized 
separately in listing format.
10.2.2
Adverse Event Overview
An overview of TEAEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any TEAE
●
Any TEAE related to study drug according to the investigator 
●
Any TEAEs of Grade 3 or higher 
●
Any serious TEAE 
●
Any serious TEAE related to study drug according to the investigator 
●
Any TEAE leading to discontinuation of study drug 
●
TEAEs leading to interruption of study drug 
●
Any fatal TEAE
●
AEs of special interest (AESI) (defined in Section 10.2.5) 
●
All deaths
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent AEs will be summarized by SOC and PT; by maximum relationship 
to study drug as assessed by the investigator (e.g., reasonable possibility or no reasonable 
possibility) and SOC and PT; by maximum grade and SOC and PT; and by subject 
number and SOC and PT. Specific adverse events will be counted once for each subject 
for calculating percentages, unless stated otherwise. In addition, if the same adverse event 
occurs multiple times within a subject, the highest grade and level of relationship to 
investigational product will be reported. 


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If a subject has an AE with unknown severity or relationship to study drug, then the 
subject will be counted in the grade/relationship level category of "unknown" even if the 
subject has another occurrence of the same event with a known grade/relationship. The 
only exception is if the subject has another occurrence of the same AE with the highest 
level of grade or a relationship assessment of "Reasonable possibility." In this case, the 
subject will be counted under the most extreme grade/relationship category.
10.2.4
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
Treatment-emergent SAEs (including deaths) and AEs leading to study drug 
discontinuation will be summarized by SOC and PT and in listing format. 
A listing of all deaths will be generated.
10.2.5
Adverse Events of Special Interest
The rash related AESIs will be identified per a Customized MedDRA Query (CMQ) of 
"Drug Induced rash (Cystic Fibrosis Transmembrane Regulator [CFTR] Modulators 
Product Specific)" and be summarized by SOC and PT. The following categories will also 
be summarized:
●
Any rash related AESIs (by gender, hormonal contraceptive use in female, 
maximum grade, and overall) 
●
Any rash related AESIs related to study drug according to the investigator 
●
Any rash related AESIs leading to discontinuation of study drug 
●
Any rash related AESIs leading to interruption of study drug 
●
Any serious rash related AESIs 
●
Any serious rash related AESIs related to study drug according to the 
investigator 


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The hepatobiliary AESIs will be identified per a Standard MedDRA Query (SMQ) of 
"Drug-related hepatic disorders – comprehensive search SMQ (narrow)" and be 
summarized by SOC and PT. The following categories will also be summarized: 
●
Any hepatobiliary AESIs 
●
Any hepatobiliary AESIs related to study drug according to the investigator 
●
Any hepatobiliary AESIs leading to discontinuation of study drug 
●
Any hepatobiliary AESIs leading to interruption of study drug 
●
Any serious hepatobiliary AESIs 
●
Any serious hepatobiliary AESIs related to study drug according to the 
investigator 
Tabular listings of AESIs will also be provided. 
10.2.6
Other Adverse Events of Interest
Treatment-emergent AEs related to creatine kinase increase will be identified per a 
Standard MedDRA Query (SMQ) of "rhabdomyolysis/myopathy SMQ (narrow)" as well 
as the following PTs: myalgia, myositis, blood creatine phosphokinase increased, 
musculoskeletal pain. The identified AEs will be summarized by SOC and PT and will 
also be presented in a tabular listing. 
For all subject with relative (percent) ppFEV1 decline ≥ 10% from the pre-dosing value 
(see Section 10.5), treatment-emergent respiratory AEs of interest will be identified using 
the following PTs: chest discomfort, dyspnoea, respiration abnormal, asthma, bronchial 
hyperreactivity, bronchospasm, wheezing. The identified AEs will be presented in a 
tabular listing.
10.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded. For 


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Cohort 1 Dual Therapy, the study drug refers to Dual Therapy during the run-in period. 
For Cohort 1 Triple Therapy, the study drug refers to Triple Therapy after the run-in 
period. Baseline will be defined relative to the first dose of study drug accordingly. The 
clinical laboratory tests defined in the protocol operations manual (e.g., hematology and 
clinical chemistry) will be summarized.
Each laboratory variable will be summarized for all visits (starting with baseline) with the 
number of non-missing observations, mean and standard deviation, median, minimum and 
maximum. Mean change from baseline to each applicable post-baseline visit will be 
summarized for laboratory variables with the number of observations, baseline mean, and 
visit mean. The change from baseline mean, standard error, and 95% confidence interval 
will be presented for the mean change from baseline.
Changes in selected laboratory parameters will be tabulated using shift tables for 
categories of low, normal, or high based on the normal ranges. A shift table from baseline 
values of high or normal to post-baseline low, or from baseline values of low or normal to 
post-baseline high will be created based on the worst post-baseline value during treatment. 
Shifts from baseline grade to the worst post-baseline grade (CTCAE 4.03 or later version) 
during treatment will be summarized in a cross-tabulation of grades. Similar shift tables 
by normal range and grade will be provided for shifts from baseline to the final post-
baseline value.
Laboratory abnormalities for selected parameters will be evaluated based on Potentially 
Clinically Significant (PCS) criteria (Appendix B). For each laboratory PCS criterion, the 
number and percentage of subjects with a laboratory value meeting the criteria during 
treatment will be summarized. Listings will be provided for summarizing subject-level 
laboratory data for subjects meeting PCS criteria.
The number and percentage of subjects with laboratory values meeting the following 
criteria during treatment will be summarized to support the assessment of potential 
hepatotoxicity. 


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●
ALT > 3 × ULN, > 5 × ULN, > 10 × ULN, > 20 × ULN 
●
AST > 3 × ULN, > 5 × ULN, > 10 × ULN, > 20 × ULN 
●
ALT and/or AST > 3 × ULN, > 5 × ULN, > 8 × ULN 
●
Total bilirubin (TBL) > ULN and ≤ 1.5 × ULN, > 1.5 × ULN and ≤ 2 × ULN, 
> 2 × ULN
●
Direct bilirubin > ULN and ≤ 1.5 × ULN, > 1.5 × ULN
●
Indirect bilirubin > ULN and ≤ 1.5 × ULN, > 1.5 × ULN and ≤ 2 × ULN, 
> 2 × ULN and ≤ 3 × ULN, > 3 × ULN
●
ALT and/or AST > 3 × ULN and TBL > 1.5 × ULN 
●
ALT and/or AST > 3 × ULN and TBL > 2 × ULN 
●
ALT > 3 × ULN and TBL > 1.5 × ULN
●
ALT > 3 × ULN and TBL > 2 × ULN
●
Alkaline phosphatase > 1.5 × ULN 
Listing of ALT, AST, TBL, and alkaline phosphatase values will be provided for each 
subject who met one or more of the criteria defined above. 
For Cohorts 1 and 2, additional plots of Drug Induced Serious Hepatotoxicity, descriptive 
statistics for the time to ALT/AST elevation, and listings for subjects with increased 
creatine kinase outlined below will be provided. 
An Evaluation of Drug Induced Serious Hepatotoxicity (eDISH) plot displaying the 
maximum on-treatment values of TBL (as multiple of ULN) versus ALT (as multiple of 
ULN), not necessarily concurrent, will be created. A similar eDISH plot and subject 
listing will be presented for TBL vs. AST. 
Descriptive statistics for the time to ALT/AST elevation (> 5 × ULN) as well as the 
duration of ALT/AST elevation will be summarized.
Listing of creatine kinase and creatinine values for subjects with increased creatine kinase 
or related treatment-emergent adverse events (Section 10.2.6) will be provided. 


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10.4
Analysis of Vital Signs
Vital sign measurements include systolic blood pressure [mmHg], diastolic blood pressure 
[mmHg], pulse [beats per minute], body temperature [°C], oxygen saturation [%], 
respiratory rate [breaths/minute] and weight [kg]. 
Each vital sign variable will be summarized for all visits (starting with baseline) with the 
number of non-missing observations, mean and standard deviation, median, minimum and 
maximum. Mean change from baseline to each applicable post-baseline visit will be 
summarized for each vital sign variable, with the number of observations, baseline mean, 
and visit mean. 
Vital sign variables will be evaluated based on potentially clinically important (PCS) 
criteria (Appendix B). For each vital sign PCS criterion, the number and percentage of 
subjects with a vital sign value meeting the criteria during treatment will be summarized. 
A post-baseline value must be more extreme than the baseline value to be considered a 
PCS finding. Listings will be provided to summarize subject-level vital sign data for 
subjects meeting PCS criteria.
10.5
Other Safety Analyses
Pulse Oximetry
For oxygen saturation values by pulse oximetry, the number and percentage of subjects 
with shift changes from baseline (categorized as < 95% or ≥ 95%) to the minimum value 
of oxygen saturation during treatment (categorized as < 90%, 90 – < 95%, or ≥ 95%) will 
be tabulated.
Post-dose Spirometry
The absolute change and relative (percent) change from the pre-dosing value to the 
post-dosing value of ppFEV1 on the same visit day will be provided for Day -28, Day -15, 
Day 1 and Day 15 (Day -28 and Day -15 only apply to Cohort 1 Dual Therapy). The 


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descriptive statistics include the number of observations, mean, median, standard 
deviation, median, minimum and maximum. 
In addition, the number and percentage of subjects with relative (percent) ppFEV1 decline 
≥ 10% from the pre-dosing value for all applicable visits will be summarized.
ECG
ECG findings will be summarized for Screening, Day -15, Day 1, Day 15 and Day 29 
(Day -15 and Day 1 only apply to Cohort 1 Dual Therapy). Summaries will include n (%) 
of patients in following categories: 
●
Normal
●
Abnormal - Not Clinically Significant
●
Abnormal - Clinically Significant
●
Not evaluable 
●
Missing
11.0
Interim Analyses
Cohort 1: One interim analysis is planned for Cohort 1, which will take place when 
10 subjects in Cohort 1 have completed or prematurely discontinued the open-label Triple 
Therapy. The scope of the interim analysis will include the efficacy and safety assessment 
of the Dual Therapy and Triple Therapy of the first 10 subjects in Cohort 1. No statistical 
testing will be made for the interim analysis, and no type I error adjustment will be made 
for the final analysis. The primary purpose of this interim analysis is to support AbbVie 
internal decision making for the development program. 
Cohort 2: No planned interim analysis. 
Cohort 3: Cohort 3 is modified to replace ABBV-119 with ABBV-576, a structurally 
differentiated modulator with improved safety and pharmacokinetic profiles. Interim 
analyses for Cohort 3 may be performed when approximately 10 and/or 15 homozygous 


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subjects in Cohort 3 have either completed the triple combination treatment period or 
prematurely discontinued study drug treatment to inform AbbVie internal program 
development decision. No statistical testing will be made for the interim analysis, and no 
type I error adjustment will be made for the final analysis.
Since both Cohorts 1 and 3 are open-label, unblinding is not applicable for these interim 
analyses. Cohort 1 interim analysis was performed by the internal study team and 
reviewed by the sponsor, which led to the discontinuation of Cohort 1 and Cohort 2. For 
Cohort 3, the interim monitoring of the efficacy and safety data of enrolled subjects led to 
the decision of early termination. Therefore, the planned interim analyses for Cohort 3 
will not be performed. Instead, summary information on subjects' disposition, study safety 
and efficacy, will be provided when all enrolled subjects completed/discontinued study 
treatment.
11.1
Data Monitoring Committee
An external data monitoring committee (DMC) composed of persons independent of 
AbbVie and with relevant expertise in the Cystic Fibrosis field will review unblinded 
study results from the Phase 1 studies for ABBV-119 (e.g., single and multiple ascending 
dose portions of Study M19-775, drug-drug interaction Study M20-065) before the start 
of Study M19-771 and will provide a recommendation on the start of Study M19-771. 
DMC recommendation, including the DMC approved final dose and dosing regimen for 
ABBV-119 will be documented in DMC meeting minutes as described in a separate DMC 
charter.
The DMC will also review the safety and PK data from co-administered galicaftor, 
navocaftor, and ABBV-576 Phase 1 studies (M21-054 and Study M20-974) before the 
start of Cohort 3 and provide a recommendation on the start of Cohort 3. DMC 
recommendation, including the DMC final approval of the start of Cohort 3 will be 
documented in DMC meeting minutes as described in a separate DMC charter. The DMC 
will also periodically review the accumulating unblinded safety data for the study, as well 
as monitor the integrity and interpretability of the study. The DMC will provide 


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recommendations to the sponsor regarding ongoing study conduct or modifications to the 
study as described in the DMC Charter. 
The DMC charter will describe the roles and responsibilities of the DMC members, 
frequency and scope of the data reviews, and expectations for blinded communications. In 
addition, the detailed data analysis and specifications for the DMC reviews are included in 
a separate DMC TFL specifications document.
In order to maintain sponsor blinding, an independent statistical data analysis center 
(SDAC) is responsible for performing the analyses described in the DMC charter as well 
as additional analyses requested by the DMC and facilitating interpretation and answering 
questions that arise before, during or after DMC review. 
12.0
Overall Type-I Error Control
Multiplicity adjustment for Type I error rate is not planned for this proof-of-concept 
study. The primary endpoint will be analyzed and tested independently for each cohort at 
1-sided alpha level of 0.05 for Cohorts 1 and 2. No statistical testing will be performed for 
Cohort 3 due to cohort early termination and the fact that only a very few subjects 
completed the planned primary efficacy evaluation visit. Since there are no efficacy 
analyses for early stopping planned for the DMC review, no alpha spending is needed due 
to the DMC review.


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13.0
Version History
Table 3. 
SAP Version History Summary
Version
Date
Summary
1.0
08 Sep 2021
Original version
2.0
10 Nov 2021
1.
Added waterfall plots to Section 9.1
2.
Added additional summaries for rash AESI to Section 10.2.5
3.
Added Section 10.2.6 Other Adverse Events of Interest
4.
Added additional summaries for ALT/AST, total bilirubin, direct 
bilirubin, indirect bilirubin, and listing for creatine kinase and 
creatinine to Section 10.3
5.
Added the interim analysis to Section 11.0
6.
Added additional thresholds for creatine kinase (CPK) to 
Appendix B
3.0
31 May 2023
Changes were made mainly due to the update of protocol amendment 
V6.0 and V7.0, which modified Cohort 3 by replacing ABBV-119 
with ABBV-576 in the triple therapy, and the resulted relevant 
changes.
1.
Cohort 3 was modified, replacing the triple therapy 
Galicaftor/Navocaftor/ABBV-119 with 
Galicaftor/Navocaftor/ABBV-576
2.
Figure 1 (study schematic) was updated to reflect the changes 
made to Cohort 3.
3.
Section 2.4 (sample size determination) was updated to 
incorporate the modifications made to Cohort 3.
4.
Section 3.0 (Endpoints) included the revisions for Cohort 3:
o
The primary endpoint was changed from ppFEV1 to SwCl.
o
The secondary endpoint was changed from SwCl to ppFEV1
o
HDRS and GAD-7 exploratory safety endpoints related to 
mental health (depression, anxiety) were added.
5.
Section 8.0 (handling of potential intercurrent events for the 
primary and secondary efficacy endpoints) was updated for 
Cohort 3.
6.
Section 9.3 (primary efficacy endpoints and analyses) was 
updated for Cohort 3. Estimands summary of the efficacy 
endpoints in Table 1 and Table 2 relevant to Cohort 3 were 
updated.
7.
An interim analysis for Cohort 3 was added in Section 11.0. 
8.
Section 11.1 (Data Monitoring Committee) included a mention 
of the DMC's review of ABBV-576 Phase 1 safety data and 
provided a recommendation on the start of Cohort 3 before 
initiating Cohort 3 enrollment.


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14.0
References
1.
Quanjer PH, Stanojevic S, Cole TJ. Multi-ethnic reference values for spirometry 
for the 3 - 95 year age range: the global lung function 2012 equations. Eur Respir J. 
2012;40(6):1324-43. 


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Appendix A.
Protocol Deviations 
The number and percentage of subjects for each category in the collected protocol 
deviation data will be summarized.


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Appendix B.
Potentially Clinically Important Criteria for Safety Endpoints 
The criteria for Potentially Clinically Significant (PCS) laboratory findings are described 
in Table B-1 and Table B-2, and the PCS criteria for vital sign findings are described in 
Table B-3. 
Table B-1. 
Criteria for Potentially Clinically Important Hematology Values 
Hematology Variables
Units
Definition of Potentially Clinically Significant
Very Low
Very High
Hemoglobin
g/dL
< 8.0
Platelets count
109/L
< 75.0
WBC count
109/L
< 2.0
Neutrophils
109/L
< 1.0
Lymphocytes decrease
109/L
< 0.5
Reticulocyte/Erythrocytes
% 
< LLN and < baseline
> ULN and > baseline
INR
N/A
> 1.5
Note:
A post-baseline value must be more extreme than the baseline value to be considered a potentially clinically 
significant finding.


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Table B-2. 
Criteria for Potentially Clinically Important Chemistry Values
Chemistry Variables
Units
Definition of Potentially Clinically Significant
Very Low
Very High
Total Bilirubin
mcmol/L
> 1.5 × ULN if baseline was normal; 
> 1.5 × baseline if baseline was abnormal 
SGOT/AST
U/L
> 5.0 × ULN if baseline was normal; 
> 5.0 × baseline if baseline was abnormal
SGPT/ALT
U/L
> 5.0 × ULN if baseline was normal; 
> 5.0 × baseline if baseline was abnormal
Albumin
g/L
< 20
Glucose
mmol/L
< 2.2
> 13.9
Creatinine
mcmol/L
> 1.5 × ULN or 1.5 × baseline
Sodium
mmol/L
< 130
> 155
Potassium
mmol/L
< 3.0
> 6.0
Calcium
mmol/L
< 1.75
> 3.1
CPK
U/L
> ULN and ≤ 2.5 × ULN
> 2.5 × ULN and ≤ 5 × ULN
> 5.0 × ULN
Total Cholesterol
mmol/L
> 10.34
GGT
U/L
> 5.0 × ULN if baseline was normal; 
> 5.0 × baseline if baseline was abnormal
Alkaline phosphatase
U/L
> 5.0 × ULN if baseline was normal; 
> 5.0 × baseline if baseline was abnormal
Note:
A post-baseline value must be more extreme than the baseline value to be considered a potentially clinically 
significant finding.


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Table B-3. 
Criteria for Potentially Clinically Important Vital Sign Values
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood 
pressure
Low
Value ≤ 90 mmHg and decrease ≥20 mmHg from baseline
High
Value ≥ 160 mmHg and increase ≥20 mmHg from baseline
Diastolic blood 
pressure
Low
Value ≤ 50 mmHg and decrease ≥10 mmHg from baseline
High
Value ≥ 100 mmHg and increase ≥10 mmHg from baseline
Pulse
Low
Value < 50 bpm and decrease ≥15 bpm from baseline
High
Value ≥ 116 bpm and increase ≥15 bpm from baseline
Weight
Low
≥ 5% decrease from baseline
High
≥ 10% increase from baseline
Temperature
High
> 39.0
Oxygen saturation
Low
< 90%
ESC = European Society or Cardiology; ESH = European Society of Hypertension
Note:
A post-baseline value must be more extreme than the baseline value to be considered a potentially clinically 
significant finding.