Clinical trial NCT03969888
Conditions: Cystic Fibrosis
Keywords: Cystic Fibrosis ABBV-3067 ABBV-2222, F508del Mutation
Sponsor: AbbVie
Start date: 2019-12-11; Completion date: 2022-06-09
Enrollment: 78 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, tolerability, and efficacy of ABBV-3067 given alone and in combination with various doses of ABBV-2222 in adults with Cystic Fibrosis who are homozygous for the F508del mutation.

Detailed description:

Arms: arm 1: Participants received ABBV-3067 50 mg tablet orally once daily (QD) plus placebo matching ABBV-2222 capsule, orally QD for 28 days. arm 2: Participants received ABBV-3067 150 mg tablet orally QD plus placebo matching ABBV-2222 capsule, orally QD for 28 days. arm 3: Participants received ABBV-3067 150 mg tablet orally QD plus ABBV-2222 10 mg capsule orally QD for 28 days. arm 4: Participants received ABBV-3067 150 mg tablet orally QD plus ABBV-2222 30 mg capsule orally QD for 28 days. arm 5: Participants received ABBV-3067 150 mg tablet orally QD plus ABBV-2222 100 mg capsule orally QD for 28 days. arm 6: Participants received ABBV-3067 150 mg tablet orally QD plus ABBV-2222 200 mg capsule, orally QD for 28 days. arm 7: Participants received ABBV-3067 150 mg tablet orally QD plus ABBV-2222 300 mg capsule, orally QD for 28 days. arm 8: Participants received placebo matching ABBV-3067 tablet orally QD plus placebo matching ABBV-2222 capsule, orally QD for 28 days.
Interventions: intervention 1: ABBV-3067 intervention 2: Placebo ABBV-3067 intervention 3: ABBV-2222 intervention 4: Placebo ABBV-2222
Intervention descriptions: intervention 1: Tablet taken orally. intervention 2: Tablet taken orally. intervention 3: Capsule taken orally. intervention 4: Capsule taken orally.

Protocol documents:
Prot_000.pdf: 


  
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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
7
2.1
BACKGROUND AND RATIONALE
7
2.2
BENEFITS AND RISKS TO SUBJECTS
7
3
STUDY OBJECTIVES AND ENDPOINTS
8
3.1
OBJECTIVES
8
3.2
EFFICACY ENDPOINTS
9
3.3
SAFETY ENDPOINTS
9
3.4
PHARMACOKINETIC ENDPOINTS
9
3.5
BIOMARKER RESEARCH
9
4
INVESTIGATIONAL PLAN
10
4.1
OVERALL STUDY DESIGN AND PLAN
10
4.2
DISCUSSION OF STUDY DESIGN
14
5
STUDY ACTIVITIES
16
5.1
ELIGIBILITY CRITERIA
16
5.2
CONTRACEPTION RECOMMENDATIONS
18
5.3
PROHIBITED MEDICATIONS AND THERAPY
21
5.4
PRIOR AND CONCOMITANT THERAPY
22
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
23
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
24
5.7
STUDY DRUG
25
5.8
RANDOMIZATION/DRUG ASSIGNMENT
26
5.9
PROTOCOL DEVIATIONS
27
6
SAFETY CONSIDERATIONS
27
6.1
COMPLAINTS AND ADVERSE EVENTS
27
6.2
TOXICITY MANAGEMENT
31
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
31
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7.1
STATISTICAL AND ANALYTICAL PLANS
31
7.2
DEFINITION FOR ANALYSIS POPULATIONS
32
7.3
STATISTICAL ANALYSES FOR EFFICACY
32
7.4
STATISTICAL ANALYSES FOR SAFETY
32
7.5
PHARMACOKINETIC AND EXPOSURE-RESPONSE ANALYSES
33
7.6
INTERIM ANALYSIS
33
8
ETHICS
34
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
34
8.2
ETHICAL CONDUCT OF THE STUDY
34
8.3
SUBJECT CONFIDENTIALITY
34
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
34
10 DATA QUALITY ASSURANCE
34
11 COMPLETION OF THE STUDY
35
12 REFERENCES
35
LIST OF TABLES
TABLE 1.
IDENTITY OF INVESTIGATIONAL PRODUCTS IN PART 1
26
TABLE 2.
IDENTITY OF INVESTIGATIONAL PRODUCTS IN PART 2
26
LIST OF FIGURES
FIGURE 1.
PART 1 SCHEMATIC
12
FIGURE 2.
PART 2 SCHEMATIC
13
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
36
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
38
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APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
39
APPENDIX D.
ACTIVITY SCHEDULE
40
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
42
APPENDIX F.
OPERATIONS MANUAL
43
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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 regulatory (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, with approximately half of the CF patients in the 
United States and Europe having the mutation present on both alleles, meaning that they are 
homozygous for this mutation.  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 in this study are compounds designed to increase the cell surface expression and 
restore the function of F508del CFTR.  ABBV-2222 (also known as galicaftor, or referred to as GLPG2222 
or G957389) is a CFTR corrector that improves F508del CFTR expression and ABBV-3067 (also known as 
navocaftor, or referred to as GLPG3067 or G914167) is a CFTR potentiator that restores F508del CFTR 
function.  Results from in vitro studies using cultivated human bronchial epithelial (HBE) cells 
demonstrated that the combination of ABBV-2222 and ABBV-3067 significantly restored F508del CFTR 
expression and function to a greater degree than observed for either individual component.  ABBV-3067 
and ABBV-2222 are under development as an oral treatment for CF.
Clinical Hypothesis
ABBV-3067 alone and in combination with ABBV-2222 given for 28 days is safe and well tolerated in 
adults with CF.
The combination of ABBV-3067 and ABBV-2222 administered together for 28 days will result in 
significant improvements from baseline in pharmacodynamic (PD) markers of CFTR function (lung 
function and sweat chloride [SwCl]) in individuals with CF who are homozygous for the F508del 
mutation.
The decrease in SwCl and improvement of lung function as assessed by percent predicted forced 
expiratory volume in 1 second (ppFEV1) will be greater for the ABBV-3067/ABBV-2222 combination than 
for ABBV-3067 monotherapy.
2.2 Benefits and Risks to Subjects
The safety results from Phase 1 studies demonstrated that ABBV-2222 and ABBV-3067 were generally 
well tolerated in healthy volunteers, either as single agent or combination regimen.
ABBV-2222 treatment in vitro improved CFTR channel expression and function in HBE cells.  The 
completed Phase 2 study (Study GLPG2222-CL-202) showed that 4-week treatment of ABBV-2222 
significantly reduced SwCl in CF subjects homozygous for F508del mutation.  Preliminary results from 
the ongoing Phase 1 study (Study GLPG2737-CL-105) also showed that the dual combination of 
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ABBV-2222 and GLPG2451 (another potentiator under development with a similar mechanism of action 
as ABBV-3067) reduced SwCl and increased ppFEV1 in patients with CF who are homozygous for the 
F508del mutation.  Therefore, it is anticipated that the combination of ABBV-2222 and ABBV-3067 has 
the potential to improve F508del CFTR function in patients with CF, as well as their lung function 
measured by ppFEV1.
The following paragraphs describe the main risks that are potentially associated with repeated doses of 
ABBV-2222, in combination with potentiator/corrector compounds (GLPG2451, ABBV-3067, and 
).
Rash
Nonserious adverse events (AEs) of rash of mild to moderate severity have been observed following 
multiple-dose treatment with ABBV-2222 in combination with ABBV-3067 or GLPG2451, 
 
.  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 ABBV-2222 alone, 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 F).  Rash is considered an adverse event of 
special interest (AESI) (see Section 6.1).
Taken together, the safety and efficacy data from the Phase 1 and Phase 2 programs support further 
development of ABBV-3067 and ABBV-2222 in Phase 2 studies in subjects with CF.
For further details, please see findings from completed studies, including safety data in the ABBV-3067 
and ABBV-2222 Investigator's Brochures.1-2
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
Part 1
1.
Evaluate the safety, tolerability, and efficacy of ABBV-3067 given alone and in combination with 
varied dose levels of ABBV-2222 in adult subjects with CF who are homozygous for the F508del 
mutation.
2.
Select a dose of ABBV-2222 to use in Part 2 based on safety, tolerability, efficacy, and 
pharmacokinetic data.
Part 2
1.
Evaluate the safety, tolerability, and efficacy of ABBV-2222 (fixed dose from Part 1) combined 
with varied dose levels of ABBV-3067 in CF subjects who are homozygous for the F508del 
mutation.
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2.
Select a dose of ABBV-3067 to carry forward to future combination studies.
3.2 Efficacy Endpoints
Primary Endpoint
Absolute change from Baseline through Day 29 in percent predicted forced expiratory volume in 
1 second (ppFEV1, a measure of lung function) 
Secondary Endpoints
1.
Absolute change from Baseline through Day 29 in SwCl (a biomarker of CFTR activity)
2.
Absolute change from Baseline through Day 29 in other spirometric measures (forced vital 
capacity [FVC], forced expiratory flow at mid-lung capacity [FEF25-75])
3.
Relative changes from Baseline through Day 29 in ppFEV1, FVC, and FEF25-75
3.3 Safety Endpoints
Safety endpoints will be AEs, AESIs, weight, vital signs, physical exams, clinical laboratory data, 12-lead 
electrocardiogram (ECG), pulse oximetry, and spirometry throughout the study.
3.4 Pharmacokinetic Endpoints
Blood samples for determination of ABBV-2222 and ABBV-3067 plasma concentrations will be collected 
from subjects 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 ABBV-3067 and ABBV-2222 oral clearance (CL/F) and volume of distribution (V/F).  Additional 
parameters may be estimated if useful in the interpretation of the data.  Data from this study may be 
combined with data from other studies for the population pharmacokinetic or exposure-response 
analyses.
3.5 Biomarker Research
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 ABBV-2222 and/or ABBV-3067.  Genes of interest may include those 
associated with pharmacokinetics (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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The samples may be retained for no longer than 20 years after study completion or per local 
requirements.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a multicenter, multi-country, Phase 2, double-blind, placebo-controlled, parallel-arm, 2-part study 
of ABBV-3067 given alone and in combination with ABBV-2222 for 28 days in adult subjects with CF who 
are homozygous for F508del CFTR mutation.  This study is designed to evaluate the safety and efficacy 
of ABBV-3067 alone and in combination with ABBV-2222, and in a sequential manner that will also allow 
dose selection for these compounds.
This study will enroll subjects with a confirmed clinical diagnosis of CF who are homozygous for the 
F508del CFTR mutation.  In both Part 1 and Part 2, randomization will be stratified by ppFEV1 at 
Screening (< 70% vs ≥ 70%).  See Section 5 for detailed information regarding eligibility criteria.
Study drug will be administered in the morning from Day 1 to the day before the Day 29 visit.  In Part 1 
of the study, a fixed 150 mg once daily (QD) dose of ABBV-3067 will be administered with ABBV-2222 in 
a dose range-finding manner to enable a dose selection for ABBV-2222 for Part 2 and future 
combination studies.  In addition, ABBV-3067 will be given alone (i.e., with placebo for ABBV-2222) to 
evaluate the safety and efficacy of ABBV-3067 at 2 dose levels.  Differences in endpoint values between 
the dual therapy arms and monotherapy arms, from this study and a previous Phase 2 study 
(Study GLPG2222-CL-202), will demonstrate the respective contributions of ABBV-3067 and ABBV-2222 
to the combination.
In Part 2 of the study, the dose of ABBV-2222 selected from Part 1 will be administered with ABBV-3067 
in a dose-ranging manner to enable selection of the ABBV-3067 dose for future combination studies.
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Part 1
ABBV-3067 will be given alone or in combination with different dose levels of ABBV-2222 for 28 days.  
CF subjects (approximately n = 117) will be randomized to 8 parallel treatment arms with regimens 
defined below.  The randomization ratio will be 1:1:1:2:2:2:2:2 for Regimens A through H in Part 1.
Regimen
ABBV-3067
ABBV-2222
Number of Subjects
A
50 mg
Placebo
9
B
150 mg
Placebo
9
C
150 mg
10 mg
9
D
150 mg
30 mg
18
E
150 mg
100 mg
18
F
150 mg
200 mg
18
G
150 mg
300 mg
18
H
Placebo
Placebo
18
Part 2
Different dose levels of ABBV-3067 will be given in combination with ABBV-2222 for 28 days.  
Approximately 72 subjects with CF will be randomized to 5 parallel treatment arms with regimens 
defined below.  The randomization ratio will be 1:2:2:2:1 for Regimens I through M in Part 2.
Regimen
ABBV-3067
ABBV-2222
Number of Subjects
I
5 mg
TBD
9
J
15 mg
TBD
18
K
50 mg
TBD
18
L
150 mg
TBD
18
M
Placebo
Placebo
9
TBD = to be determined
Part 2 of the study will initiate after all subjects enrolled in Part 1 complete the 30-day safety follow-up
period.  The dose of ABBV-2222 in each regimen will be selected based on pharmacokinetics, safety, and 
efficacy data from Part 1 of the study.  The sponsor may also adjust the dose of ABBV-3067 or decide 
not to conduct a dose regimen if it is determined to be unnecessary.
Study sites and subjects will remain blinded for the duration of the study.  Interim analyses will be 
performed as described in Section 7.6.
To enhance the safety and integrity of the study data, a data monitoring committee (DMC) consisting of 
independent experts will convene periodically to review the accumulating unblinded safety data for the 
study and provide a recommendation on study continuation or early termination.  The DMC charter will 
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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.
Schematics of the 2 parts of the study are shown in Figure 1 and Figure 2.  Further details regarding 
study procedures are located in the Operations Manual (Appendix F).
Figure 1.
Part 1 Schematic
2222 = ABBV-2222; 3067 = ABBV-3067; PBO = placebo
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Figure 2.
Part 2 Schematic
2222 = ABBV-2222; 3067 = ABBV-3067
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 30-day screening period.

If the initial sweat collection has insufficient volume for chloride analysis, then the sweat 
collection may be repeated once.

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 
baseline ppFEV1 within 40% to 90% of predicted but have a first screening spirometry result just 
outside the eligibility range.
Otherwise, subjects not meeting one or more of eligibility criteria will be considered screen failures.  
Subjects may be rescreened 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 
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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
The control group consists of subjects randomly assigned to receive placebo.
The ABBV-3067 single-agent treatment groups (i.e., Regimens A and B) also serve as control groups for 
the dual combination treatment groups, in order to demonstrate the contribution of ABBV-2222.
Although there are dual combination products that have been approved to treat CF subjects who are 
homozygous for the F508del mutation, these products are not yet considered standard of care in all 
countries where this study will be conducted.  In countries where dual combination products are 
accessible as standard of care, this design will also allow the participation of CF subjects who are not on 
dual combination products due to concerns about safety or tolerability, lack of efficacy, or other 
concerns (see Eligibility Criteria #21).
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with CF.  All clinical 
and laboratory procedures in this study are standard and generally accepted.
Suitability of Subject Population
This study was designed to enroll subjects with a confirmed clinical diagnosis of CF who are also 
homozygous for the F508del CFTR mutation because ABBV-2222 and ABBV-3067 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 sweat chloride and ppFEV1 when given a combination of ABBV-2222 
and ABBV-3067.
Selection of Doses in the Study
Part 1
ABBV-2222 has been evaluated following multiple doses in healthy volunteers (Study GLPG2222-CL-101) 
and patients with CF who are homozygous for F508del mutation in a Phase 2 study 
(Study GLPG2222-CL-202), at dosages ranging from 50 mg QD to 600 mg QD.  ABBV-2222 was safe and 
well tolerated at all dosages tested.  In Study GLPG2222-CL-202, patients with CF who were dosed with 
ABBV-2222 for 29 days, there was a trend of dose-dependent decrease in SwCl was observed between 
50 mg and 200 mg doses on Day 15 and Day 29, with maximum decrease in SwCl observed in the 200 mg 
dose group. 
 
 
. 
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Considering the totality of the data from the in vitro HBE studies and Phase 1 and Phase 2 studies, a 
dose range of 10 mg to 300 mg would provide an opportunity to study and explore the dose range 
finding for ABBV-2222 in CF subjects homozygous of F508del mutation in Part 1 of the study.
 
 
 
.
Part 2
ABBV-2222 dose will be determined based on the analysis of Part 1 data and will be kept constant across 
all treatment groups in Part 2.
 
 
 
For both Part 1 and Part 2, treatment duration of 4 weeks was selected based on efficacy endpoint 
responses observed in the Phase 1 and Phase 2 studies.  In Phase 1 Study GLPG2737-CL-105, the 
reduction in SwCl and increase in ppFEV1 were observed following 1 week of treatment with the dual 
combination of GLPG2451 and ABBV-2222, with the effects sustained following 2 weeks of treatment.  
In Phase 2 Study GLPG2222-CL-202, reduction in SwCl was similar following 2 weeks and 4 weeks of 
treatment with ABBV-2222.  Therefore, it is expected that the 4-week treatment duration of ABBV-2222 
and ABBV-3067 dual combination will be sufficient to assess the responses in efficacy endpoints in this 
study.
The maximum dose of the ABBV-2222 administrated in this study will not exceed 
.  The 
maximum dose of ABBV-3067 administered in this study will not exceed 
.
Overall, ABBV-2222 exposure (maximum observed concentration [Cmax] and area under the 
concentration versus time curve from 0 to τ [AUC0-τ]) following multiple 
 
 the highest tolerated 
dose in the multiple ascending dose 
; and ABBV-3067 exposure following 
multiple doses up to
 
 the highest tolerated dose in the multiple ascending dose 
.
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5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the criteria below will result in exclusion from study participation.
Consent
1. Subjects must be able and willing to voluntarily sign and date each informed consent form 
(ICF), approved by an institutional review board (IRB), prior to the initiation of any Screening or 
study-specific procedures.
2. Subjects must be able to understand and adhere to protocol requirements, restrictions, and 
instructions (per investigator's judgment).
Demographic and Laboratory Assessments
3. Males and females 18 years of age or older on the day the ICF is signed.
4. Subjects must weigh ≥35 kg at Screening and Day 1
5. Subjects must have 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:

Hepatic function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], 
alkaline phosphatase) < 3 × the upper limit of normal (ULN) and total bilirubin < 1.5 × ULN.

Estimated creatinine clearance ≥ 50 mL/minute using the Cockroft-Gault equation

Hemoglobin ≥ 10 g/dL

Negative serology for human immunodeficiency virus (HIV) infection (HIV-1 and/or HIV-2 
antibodies), hepatitis B virus infection (hepatitis B virus surface antigen [HBsAg]), and 
hepatitis C virus infection (anti-HCV antibody)
7. Absence of clinically significant abnormality detected on electrocardiogram (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. A confirmed clinical diagnosis of CF and homozygous for the F508del CFTR mutation 
(documented in the subject's medical record or CF patient registry).  Subjects may be 
randomized based on prior documentation of F508del/F508del mutation, 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 M19-771, 
it is acceptable to use the CFTR genotype that the central lab provided in Study M19-771 to 
establish eligibility.
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9. ppFEV1 ≥40% and ≤ 90% of predicted normal for age, gender, and height (Global Lung 
Function Initiative [GLI] equations) at Screening
10. SwCl at the Screening visit must be ≥ 60 mmol/L.  For subjects who participated in Study 
M19-771, it is acceptable to use the SwCl value that the central lab provided from the screening 
visit in Study M19-771 to establish eligibility.
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 
baseline within 4 weeks prior to Day 1 (first dose of study drug).
12. Absence of comorbidities and medical history items listed below, or others that, in the 
opinion of the investigator, may pose additional risk by participating in the study, or may 
confound the results of the study.
a.
Cirrhosis with portal hypertension (e.g., splenomegaly, esophageal varices)
b.
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 (e.g., clarithromycin, 
rifampin, itraconazole, see table in Section 5.3).  To assure clinical stability, treatment for 
these organisms should start at least 8 weeks prior to screening, and the subjects will be 
expected to continue the treatment through the final study visit.
c.
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)
d.
Abuse of alcohol, medications, or illicit drugs within 1 year prior to Screening, per the 
investigator.
e.
Smoking or vaping tobacco or cannabis products within 1 year prior to Screening.
f.
History of solid organ or hematopoietic transplantation.
g.
History of known sensitivity to any component of the study drug.
h.
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 (for non-CFTR modulator studies) 
or a washout period of at least 5 terminal half-lives of the investigational drug (whichever is 
longer) have elapsed prior to Screening.  For prior participation in trials with CFTR modulators, 
at least 60 days must elapse between the last study dose and Screening.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Subjects who participated in Study M19-771 are allowed to participate Study M19-530 only if 
the subject was not withdrawn from Study M19-771 due to safety reasons.
15. Part 2 only:  Subjects who receive treatment in Part 1 may not participate in Part 2 of the 
study.
Contraception
16. Males who are sexually active with a female partner of childbearing potential and female 
subjects of childbearing potential must agree to use protocol-specified effective contraceptive 
measures (refer to Section 5.2, Contraception Recommendations).
17. Negative serum pregnancy test at Screening and negative urine pregnancy test on Day 1 visit 
prior to the first dose of study drug (females of childbearing potential only).
18. Females must not be pregnant, breastfeeding, or planning to become pregnant during or 
within 30 days of the end of study drug treatment.
19. Males must not be planning to father a child or donate sperm during the study or for 
approximately 90 days after the last dose of study drug.
Concomitant Medications
20. Stable concomitant medication and airway clearance regimen (including dose and 
frequency) for at least 4 weeks prior to Day 1 and willing to continue the same regimen for the 
duration of the study.
21. No use of approved or investigational CFTR modulator therapy (e.g., ivacaftor, lumacaftor, 
tezacaftor, elexacaftor, galicaftor, navocaftor, ABBV-119) for at least 60 days prior to Screening.  
Individuals who take CFTR modulators as part of their therapeutic regimen should not be 
encouraged to stop using them in order to participate in this trial; rather, the CFTR modulators 
may have been discontinued due to intolerance, side effects, lack of efficacy, nonadherence, 
personal choice, or other reasons.
22. No use of any strong inhibitor(s) or inducer(s) of cytochrome P-450 (CYP) 3A4 within 4 weeks 
prior to the first study drug administration and during the study period (see Section 5.3).
23. No use of drugs that are CYP2C8 substrates within 4 weeks prior to the first study drug 
administration or during the study period (e.g., paclitaxel, torasemide, amodiaquine, 
cerivastatin, repaglinide).
24. No use of oral cannabis products within 4 weeks prior to the first study drug administration 
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).
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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:

Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause.

Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause and a FSH level > 40 IU/L.

Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).

Females, of Childbearing Potential

Females of childbearing potential must avoid pregnancy during study participation and for 
at least 30 days after the last dose of study drug.

Females must commit to one of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral, 
intravaginal, transdermal, and injectable) associated with inhibition of ovulation plus a 
barrier method* initiated at least 30 days prior to study Baseline Day 1.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation plus a barrier method* initiated at least 30 days prior to study 
Baseline Day 1.

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS) plus a barrier method.*

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).

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.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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 and for approximately 90 days (1 sperm cycle) 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 Day 1 through approximately 90 days after last dose of study drug, unless the subject 
meets one of the criteria described below.
Contraception requirement for the male subject is not required for the following:

Vasectomized male subjects (vasectomy performed 6 months or more previously) or male 
subjects with complete bilateral absence of vas deferens are not required to use an additional 
form of contraception providing documented azoospermia by semen analysis or demonstration 
of the absence of vas deferens by ultrasound. 

Male subjects who have undergone bilateral orchiectomy
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5.3 Prohibited Medications and Therapy
Throughout the study, strong inhibitors and inducers of CYP3A4 or substrates of CYP2C8 and other 
investigational drugs are prohibited.  Examples of such compounds are shown below.
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
Substrates of CYP2C8, such as
Paclitaxel
Torasemide
Amiodiaqine
Cerivastatin
Repaglinide
Montelukast
Note:
This should not be considered an exhaustive list.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The use of topical treatments of CYP3A4 inhibitors/inducers would not be expected to impact study 
drug.  Consult with the AbbVie medical contact with questions regarding administration of an excluded
concomitant therapy prior to 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 prior to the first study drug administration (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 prior to the first study drug administration and remain on that regimen for the study 
duration.
Examples of therapeutic regimens for pulmonary health include 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.  Since ppFEV1 is the primary endpoint for this study, it is very important that the timing of 
these therapies is kept as consistent as possible relative to spirometry measurements at each 
research visit, starting with Baseline (Day 1).  In order to minimize disruptions in therapeutic 
regimens, it is recommended that subjects who routinely use bronchodilators be counseled to 
use them consistently according to their usual schedule throughout the study.  Further, study 
visits should be planned so that the timing of spirometry following bronchodilator use (if 
applicable) will be similar at each visit (e.g., within 2 hours of each other).  Subjects should also 
be allowed adequate time to complete their inhaled medication/airway clearance regimen (if 
applicable) before coming to the study visits to maintain consistency throughout the study.
If subjects miss their routine bronchodilator dose the morning of the Baseline (Day 1) visit, they 
should also withhold bronchodilators until after spirometry at subsequent visits to maintain 
consistency.  Subjects who use bronchodilators only on an as-needed basis will be asked to 
refrain from using them prior to spirometry on study visit days.  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, 
umaclidium, 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.  On study visit Days 1 and 15, 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
spirometry will be performed twice, before and after taking study medication.  Bronchodilators 
should not be given between the 2 spirometry measurements.
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 medical contact.  
Information regarding potential drug interactions with ABBV-3067 and/or ABBV-2222 can be located in 
the ABBV-3067 and ABBV-2222 Investigator's Brochures.
Subjects must be able to safely discontinue any prohibited medications after at least 5 half-lives or 
4 weeks prior to initial study drug administration, whichever is longer.  Subjects must be consented for 
the study prior to discontinuing any prohibited medications for the purpose of meeting study eligibility.
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 or 
the treatment period.
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.
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
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:

life-threatening AE or a serious adverse event (SAE) that places the subject at immediate risk; or 
maculopapular rash or other clinical manifestation of allergic drug reaction, for which the 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
severity is categorized as Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) 
Grade 3 or higher 

worsening pulmonary status that, in the opinion of the investigator, 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)

fungal infection requiring treatment with a triazole antimicrobial (e.g., fluconazole, itraconazole, 
voriconazole)

confirmed pregnancy

arrhythmia or conduction abnormality, including but not limited to prolonged QTcF, where the 
severity is categorized as CTCAE (version 5.0) Grade 3 or higher (QTc ≥501 msec 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 is 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 > 8 × ULN

AST and/or ALT elevations > 5 × ULN for more than 2 weeks

AST and/or ALT elevations > 3 × ULN, with total bilirubin > 2 x ULN

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 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 of the initial 
finding if possible, and then monitored closely until levels normalize or return to Baseline.
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 halt 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.
5.6 Follow-Up for Subject Withdrawal 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 and 30-day 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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 the 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 Premature 
Discontinuation 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.  A subject may withdraw consent for 
optional biomarker research at any time and remain in the clinical study.  Data generated from optional 
biomarker research, before subject withdrawal of consent, will remain part of the study results.
5.7 Study Drug
ABBV-3067 and ABBV-2222 and their matching placebos manufactured by AbbVie will be taken orally 
once daily beginning on Day 1 (Baseline) and should be taken at approximately the same time in the 
morning each day.  The study drug is to be taken within 1 hour after a meal.  If subjects should forget to 
take their assigned study drug at their regularly scheduled dosing time, they should take the forgotten 
dose as soon as they remember as long as it is at least 8 hours before their 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.
AbbVie will provide study drug for ABBV-3067 and ABBV-2222 and their matching placebos.  Study drug 
provided by AbbVie should not be substituted or alternately sourced unless otherwise directed by
AbbVie.
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.
Information about the drug formulations to be used in this study is presented in Table 1 for Part 1 and in 
Table 2 for Part 2.  Additional IMPD information regarding drug formulations for Part 2 will be provided 
prior to the start of Part 2.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Table 1.
Identity of Investigational Products in Part 1
Investigational Product Active
Investigational Product Placebo
Investigational product 
name
ABBV-3067
ABBV-2222
ABBV-3067 
placebo
ABBV-2222 
placebo
Active Ingredient
ABBV-3067
ABBV-2222
N/A
N/A
Mode/Route of 
administration 
Oral
Oral
Oral
Oral
Dosage form
Film-coated tablets
Capsules
Film-coated tablets
Capsules
Strength
50 mg
10, 30, and 
100 mg
0 mg
0 mg
Masking
Blinded
Blinded
Blinded
Blinded
Frequency of 
administration
QD
QD
QD
QD
Storage conditions
15° to 25°C
15° to 25°C
15° to 25°C
15° to 25°C
Drug packaging
Blister card
Blister card
Blister card
Blister card
N/A = not applicable; QD = once a day
Table 2.
Identity of Investigational Products in Part 2
Investigational Product Active
Investigational Product Placebo
Investigational product 
name
ABBV-3067
ABBV-2222
ABBV-3067 
placebo
ABBV-2222 
placebo
Active Ingredient
ABBV-3067
ABBV-2222
N/A
N/A
Mode/Route of 
administration 
Oral
Oral
Oral
Oral
Dosage form
Capsules
Capsules
Capsules
Capsules
Strength
TBD
TBD
0 mg
0 mg
Masking
Blinded
Blinded
Blinded
Blinded
Frequency of 
administration
QD
QD
QD
QD
Storage conditions
15° to 25°C
15° to 25°C
15° to 25°C
15° to 25°C
Drug packaging
Blister card
Blister card
Blister card
Blister card
N/A = not applicable; QD = once a day; TBD = to be determined
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 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
used.  The 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.
In both Part 1 and Part 2, randomization will be stratified by the Screening visit ppFEV1 (< 70% versus 
≥70% of predicted value).
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 will remain blinded to each subject's treatment throughout the study.  To maintain the blind, the 
active treatment and placebo formulations (Table 1 and Table 2) 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.
In addition, to minimize the potential of unblinding, the AbbVie study team will not have access to the 
post-first-dose spirometry or sweat chloride results until after the study is unblinded for Part 1 or Part 2 
analysis.  Site personnel and subjects will not be informed of the subjects' study-related post-first-dose 
sweat chloride results until the end of the corresponding study part (Part 1 or Part 2).  Subjects will not 
be informed of their study-related spirometry results until the end of the corresponding study Part 
(Part 1 or Part 2).
A limited number of AbbVie personnel who are not directly involved in the conduct of the study may 
receive unblinded data prior to full enrollment of Part 1 and Part 2 to help expedite dose selection of 
ABBV-2222 and ABBV-3067 for further combination studies.
5.9 Protocol Deviations
The investigator is responsible for complying with all protocol requirements, written instructions, and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  If a protocol deviation occurs (or is 
identified), the investigator is responsible for notifying independent ethics committee (IEC)/IRB, 
regulatory authorities (as applicable), and AbbVie.
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).
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been 
pre planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
A supplemental case report form should be completed for the following:

Discontinuation or interruption of study drug due to a hepatic-related AE, including laboratory 
criteria defined in Section 5.5:

A hepatic-related SAE 
Clinically Significant Assessments
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
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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.
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.
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 clinical research organization (CRO) (as appropriate) as 
an SAE within 24 hours after the site became made aware of the SAE (refer to Section 4.3 of the 
Operations Manual for reporting details and contact information):
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.
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.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
All AEs reported from the time of study drug administration until 30 days or 5 half-lives after 
discontinuation of study drug administration will be collected, whether solicited or spontaneously 
reported by the subject.  In addition, SAEs and protocol-related nonserious AEs will be collected from 
the time the subject signs the study-specific informed consent.
AbbVie will be responsible for suspected unexpected serious adverse reactions (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
Rash is an AE of special interest (AESI) and will be monitored during the study.
In prior Phase 1 studies, there were isolated instances of nonserious generalized, maculopapular rash 
that occurred when ABBV-3067 and ABBV-2222 were administered together.  The rashes resolved after 
study drug discontinuation.  Maculopapular rash is a disorder characterized by the presence of macules 
(flat) and papules (elevated).  Also known as morbilliform rash, maculopapular rash is one of the most 
common cutaneous AEs, frequently affecting the upper trunk, spreading centripetally, and associated 
with pruritus.
Rash is to be graded according to the CTCAE (adapted) version 5.0.3  All rash cases have to be reported 
within 24 hours from the time of knowledge of the event.  Refer to the Operations Manual (Appendix F) 
for details about management of these events.
Adverse Event Severity and Relationship to Study Drug
The investigators will rate the severity of each AE according to the CTCAE version 5.0.3
Grading System for Adverse Events (a semicolon indicated "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
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.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 1 working day after 
the site becomes aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (Section 5.5).  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 prior to collection of any such information.  AbbVie will provide a 
separate consent form for this purpose.  Pregnancy in a subject's partners 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 a 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 AE of special interest of rash) and laboratory parameters is 
described in the Operations Manual.  Specific management for elevated hepatic function tests is 
described in this protocol in Section 5.5.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the interim database lock.  The statistical 
analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
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STUDY M19-530  |  Version 3.0 / EudraCT 2019-000750-63
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.2 Definition for Analysis Populations
The full analysis set (FAS) includes all randomized subjects who received at least 1 dose of study drug.  
The FAS will be used for all efficacy and baseline analyses.  Subjects will be grouped according to 
treatment as randomized.
The safety analysis set consists of all subjects who received at least 1 dose of study drug.  For the safety 
analysis set, subjects are assigned to a treatment group based on the treatment actually received, 
regardless of the treatment randomized.
7.3 Statistical Analyses for Efficacy
All efficacy analyses will be conducted on the FAS based on treatment as randomized.
For the primary efficacy endpoint in both Part 1 and Part 2, the null hypothesis that the within-group 
absolute change from baseline in ppFEV1 through Day 29 is zero will be tested for each treated group at 
2-sided alpha of 0.05.  The primary analysis will be performed using a mixed-effect model with repeated 
measures (MMRM) with change from Baseline in ppFEV1 as the dependent variable; treatment group, 
visit, and treatment-by-visit interaction as fixed effects; subject as a random effect; and baseline ppFEV1
as a covariate.  The estimate for the within-group mean change along with the 95% confidence intervals 
and the corresponding P values will be calculated as the primary analysis.  The treatment effect 
compared to placebo will be estimated using the same model. 
The secondary endpoints of sweat chloride, ppFEV1, FVC, and FEF25-75 will be analyzed based on an 
MMRM model similarly as the primary endpoint.
Details on the efficacy analyses are provided in the SAP.
Sample Size Estimation
The power calculations are provided for the most potentially efficacious groups with the combination 
treatment for both Part 1 and Part 2 for the primary efficacy endpoint.  Placebo groups from both Part 1 
and Part 2 will be combined in the Part 2 efficacy analysis.  A sample size of 18 subjects in a group will 
provide 80% power to detect a 5.3% absolute increase from baseline in ppFEV1 for that group assuming 
a standard deviation of 7.5%.  When comparing to the placebo group, a sample size of 18 subjects in 
both treated group and placebo group will provide 80% power (Part 1), or a sample size of 18 subjects in 
treated group and 27 subjects in placebo group will provide approximately 87% power (Part 2), to detect 
a 7.3% effect size in ppFEV1 change from Baseline assuming the standard deviation of 7.5% for change in 
ppFEV1 for both groups.
7.4 Statistical Analyses for Safety
All safety analyses will be performed on the safety analysis set for both Part 1 and Part 2 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.  Details on the safety analyses are 
provided in the SAP.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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 (PT), 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 and percentage of subjects with 
evaluations meeting criteria for predefined potentially clinically significant (PCS) values will be 
summarized.
7.5 Pharmacokinetic and Exposure-Response Analyses
Individual ABBV-2222 and ABBV-3067 plasma concentrations at each study 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 pharmacokinetic 
and exposure-response analyses.  Population pharmacokinetic and exposure-response analyses of data 
only from this study may not be conducted.  The following general methodology will be used for the 
population pharmacokinetic and exposure-response analyses.
 
 
 
 
 
 
 
 
Additional analyses will be performed if useful and appropriate.
7.6 Interim Analysis
 
  
 
 
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) 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 (ICH) guidelines, applicable 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.
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 federal, state, provincial, 
country-specific, and local laws and regulatory requirement(s).
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 
federal, state, provincial, country-specific, and local laws and regulatory requirements.
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STUDY M19-530  |  Version 3.0 / EudraCT 2019-000750-63
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
11 COMPLETION OF THE STUDY
The end of study is defined as the date of the last subject's last visit.
12 REFERENCES
1.
ABBV-2222 Investigator's Brochure, Edition 1.  April 2019.
2.
ABBV-3067 Investigator's Brochure, Edition 1.  April 2019.
3.
Common Terminology Criteria for Adverse Events, Version 4.0, DCTD, NCI, NIH, DHHS.  June 14, 
2010.  Common Terminology Criteria for Adverse Events v4.03 (CTCAE) [cited 2019 January 11].  
Available from:  https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf.
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STUDY M19-530  |  Version 3.0 / EudraCT 2019-000750-63
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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
BID
Twice daily
cAMP
Cyclic adenosine monophosphate
CF
Cystic fibrosis
CFTR
CF transmembrane conductance regulator
CL/F
Oral clearance
Cmax
maximum observed concentration
CRO
Clinical research organization
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P-450
DMC
Data monitoring committee
EC50
Effective concentration providing 50% of the maximal response
EC90
Effective concentration providing 90% of the maximal response
ECG
Electrocardiogram
ERS
European Respiratory Society
EudraCT
European Clinical Trials Database
FAS
Full analysis set
FEF25-75
Forced expiratory flow at mid-lung capacity
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
GLI
Global Lung Function Initiative
HBE
Human bronchial epithelial/epithelium
HBsAg
Hepatitis B virus surface antigen
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus 
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STUDY M19-530  |  Version 3.0 / EudraCT 2019-000750-63
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent ethics committee
IMP
Investigational medicinal product
IMPD
Investigational Medicinal Product Dossier
IRB
Institutional review board
IRT
Interactive response technology
IU
International Unit
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effect model with repeated measures
N/A
Not applicable
PCS
Potentially clinically significant
PD
Pharmacodynamics
ppFEV1
Percent predicted forced expiratory volume in 1 second
PT
Preferred term
QD
Once daily
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia's formula
SAE
Serious adverse event
SAP
Statistical analysis plan
SOC
System organ class
SUSAR
Suspected unexpected serious adverse reactions
SwCl
Sweat chloride
TBD
To be determined
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
V/F
Volume of distribution
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STUDY M19-530  |  Version 3.0 / EudraCT 2019-000750-63
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M19-530:  A Phase 2 Study of ABBV-3067 Alone and in Combination with ABBV-2222
Protocol Date:  04 February 2022
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and federal, state, provincial, country-specific 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 federal, state, provincial, 
country-specific, and local laws and regulatory requirements, current protocol and Operations 
Manual, and making changes to a protocol only after notifying AbbVie and the appropriate 
institutional review board (IRB)/independent ethics committee (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, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
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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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Study Project Manager II
Clinical Study Leadership
Principal Medical Writer
Medical Writing 
Therapeutic Area Medical Director
General Medicine
Scientific Director
General Medicine
Director, Biostatistics
Data and Statistical Sciences 
Senior Director and TA Head
Data and Statistical Sciences
Senior Director
Clinical Pharmacology and Pharmacometrics
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STUDY M19-530  |  Version 3.0 / EudraCT 2019-000750-63
CONFIDENTIAL INFORMATION
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions 
Protocol 
Date
Version 1.0
02 May 2019
Version 2.0
28 August 2019
The purpose of this version is to make the following changes:
Modified rescreening language regarding SwCl test in Section 4.2. Rationale: SwCl test does not need 
to be repeated during rescreening as disease diagnosis biomarker.
Added eligibility criteria to specify the requirements for subjects from Study M19-771 in Section 5.1. 
Rationale: Subjects participated in Study M19-771 are allowed to participate in Study M19-530 as long 
as they meet the eligibility criteria.
Added Montelukast to prohibited medication list in Section 5.3. Rationale: Montelukast is a CYP2C8 
substrate, and is a commonly used medication in CF patients.
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APPENDIX F. OPERATIONS MANUAL
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p. 2 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/
Emergency 
Medical Contact
Sponsor Contact:
AbbVie Inc.
Dept. R440, 
1 North Waukegan Road
North Chicago, IL 60064
Medical Contact:
AbbVie Inc.
Dept. R440, 
1 North Waukegan Road 
North Chicago, IL 60064
EMERGENCY 24 hour Number:
+1 (973) 784-6402
Office:
Mobile:
Fax:
Email: 
 
Office:
Mobile:
Fax:
Email:
Safety Concerns
General Medicine Safety Team
Dept. R48S, Bldg. AP31-1
1 North Waukegan Road 
North Chicago, IL 60064
Phone:
+1 (847) 935-7577
Email:
GPRD_SafetyManagement_Hormones@abbvie.com
SAE Reporting 
outside of RAVE
Email:
PPDINDPharmacovigilance@abbvie.com
Fax:
+1 (847) 938-0660
Protocol 
Deviations
AbbVie Inc.
Dept. R477, 
1 North Waukegan Road 
North Chicago, IL 60064
Phone:
Fax:
Email:
Certified Clinical 
Lab
Labcorp CLS
8211 SciCor Drive
Indianapolis, IN 46214
Phone:
+1 (866) 762-6209
Pharmacokinetic 
Lab
Bioanalysis
AbbVie Inc.
1 North Waukegan Rd.
North Chicago, IL 60064
Phone:
+1 (847) 936-1382
Fax:
+1 (847) 938-9898
Email:
sample.receiving@abbvie.com
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
5
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
5
2.2
INDIVIDUAL POST-TREATMENT PERIOD VISIT ACTIVITIES
9
3
STUDY PROCEDURES
9
3.1
SUBJECT INFORMATION AND INFORMED CONSENT
9
3.2
MEDICAL HISTORY
10
3.3
DRUG AND ALCOHOL SCREEN
10
3.4
ADVERSE EVENT ASSESSMENT
10
3.5
PHARMACOKINETIC SAMPLING
10
3.6
BIOMARKER SAMPLING
11
3.7
12-LEAD ELECTROCARDIOGRAM
11
3.8
HEIGHT AND WEIGHT
12
3.9
VITAL SIGNS
12
3.10
PHYSICAL EXAMINATION
12
3.11
PULSE OXIMETRY
12
3.12
SWEAT COLLECTION
12
3.13
SPIROMETRY
13
3.14
DISPENSE STUDY DRUG
14
3.15
CLINICAL LABORATORY TESTS
14
3.16
SUBJECT WITHDRAWAL FROM STUDY
17
4
SAFETY MANUAL
17
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
17
4.2
RECORDING DATA AND ANALYSES OF SAFETY FINDINGS
18
4.3
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
19
5
COUNTRY-SPECIFIC REQUIREMENTS
20
5.1
SUSAR REPORTING
20
6
STUDY DRUG
20
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6.1
TREATMENTS ADMINISTERED
20
6.2
PACKAGING AND LABELING
21
6.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
21
6.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
21
7
REFERENCES
22
LIST OF TABLES
TABLE 1.
CLINICAL LABORATORY TESTS
15
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
24
APPENDIX B.
ADVERSE EVENT OF SPECIAL INTEREST RASH QUESTIONNAIRE
25
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Optional biomarker research samples will only be collected if the subject has voluntarily signed and 
dated a written consent form describing the research.  The written consent may be part of the main 
consent form.  If the subject does not consent to providing optional samples, the subject will still be 
allowed to participate in the study.
3.2 Medical History
A complete medical history including demographics, medical conditions, surgical history, genotype, 
medication use, and history of tobacco, cannabis, alcohol, and drug use will be taken at screening.  The 
number of hospitalizations and/or number of episodes of intravenous (IV) antibiotic use for 
sinopulmonary signs and symptoms (i.e., exacerbations) in the 12 months prior to Screening will be 
recorded.  The subject's medical history will be updated at the Day 1 visit.  This updated medical history 
will serve as the baseline for clinical assessment.
3.3 Drug and Alcohol Screen
Urine specimens will be tested at the screening visit for the presence of drugs of abuse.  The panel for 
drugs of abuse will minimally include the drugs listed below.  Any positive result must be assessed for 
clinical significance.  These analyses will be performed by the certified central laboratory chosen for the 
study.

Opiates

Barbiturates

Amphetamines

Cocaine

Benzodiazepines

Alcohol

Phencyclidine

Propoxyphene

Methadone
3.4 Adverse Event Assessment
Please refer to Section 4.2.
3.5 Pharmacokinetic Sampling
Collection of Samples for Analysis 
Blood samples for the analysis of ABBV-2222 and ABBV-3067 plasma concentrations will be collected 
from subjects on the study days and time points specified in Section 2.1. 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Subjects should be instructed to not to take study drug before coming to the site on the day of the 
Day 15 and Day 29 visits.
At the Day 15 visit, a trough (predose) pharmacokinetic sample should be collected prior to the 
administration of study drug.  Additional pharmacokinetic samples will be taken 2, 4, and 6 hours 
following the dose, as outlined in Section 2.1.  Subjects should take the dose of study drug within an 
hour after eating a meal at the study site.
For all pharmacokinetic samples, the date and accurate time of the pharmacokinetic sample collection 
will be recorded on the lab requisition form. 
At the Day 15 and Day 29 visits, the date and time of the previous 3 study drug doses before those visits 
will be recorded on the electronic case report form (eCRF).
Refer to the study specific laboratory manual for detailed instructions on sample collection, processing, 
and shipment.
Measurement Method
Plasma concentrations of ABBV-3067 and ABBV-2222 will be determined by the Bioanalysis Department 
at AbbVie using a validated method.
3.6 Biomarker Sampling
Optional whole blood samples will be collected for biomarker research as specified in Section 2.  All 
biomarker samples should be labeled and shipped as outlined in the study-specific laboratory manual.  
AbbVie (or people or companies working with AbbVie) will store the samples and data in a secure 
storage space with adequate measures to protect confidentiality.  The samples may be retained while 
research on ABBV-3067 and ABBV-2222 (or drugs of this class) or cystic fibrosis (CF) and related 
conditions continues, but for no longer than 20 years after study completion, or per local requirements.
3.7 12-Lead Electrocardiogram
A 12-lead ECG will be performed at the designated study visits as specified in Section 2.  The ECG should 
be performed prior to blood collection and after the subject has been resting supine for at least 
5 minutes.
The ECGs will be evaluated by an appropriately trained physician at the site ("local reader").  The local 
reader from the site will sign and date all ECG tracings and will provide his/her global interpretation as a 
written comment on the tracing using the following categories:

Normal ECG

Abnormal ECG – not clinically significant

Abnormal ECG – clinically significant
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Only the local reader's evaluation of the ECG will be collected and documented in the subject's source 
folder.  The automatic machine reading (i.e., machine-generated measurements and interpretation that 
are automatically printed on the ECG tracing) will not be collected.  If an ECG at the Day 29 visit is 
interpreted as abnormal – clinically significant, it should be repeated at the follow-up visit or earlier, per 
the investigator's discretion until satisfactory clinical resolution or stabilization of the finding.
3.8 Height and Weight
Height will be measured at Screening only, with shoes removed.  Body weight will be measured at 
scheduled visits as specified in Section 2.  It is recommended that the subject wear lightweight clothing 
and no shoes during weighing.
3.9
Vital Signs
Vital sign determinations of body temperature, respiration rate, pulse rate, and systolic and diastolic 
blood pressure will be obtained at visits as specified in Section 2.  Blood pressure, pulse rate and 
respiratory rate should be measured after the subject has been sitting for at least 5 minutes.
3.10 Physical Examination
A complete physical examination (excluding genitourinary) will be performed at the Screening visit as 
specified in Section 2.  Subsequent physical examinations will be limited to evaluations of throat, chest, 
and heart.  At any time, a symptom-directed physical examination can be performed as deemed 
necessary by the investigator.  The physical examination performed on Study Day 1 will serve as the 
baseline physical examination for the entire study.  Any significant physical examination findings after 
the first dose will be recorded as AEs.  All findings, whether related to an AE or part of each subject's 
medical history, will be captured on the appropriate eCRF page.
3.11 Pulse Oximetry
Pulse oximetry is an indirect measurement of oxygen saturation in blood.  It will be performed beginning 
at Screening and as specified in Section 2.  Pulse oximetry should be measured after the subject has 
been sitting for at least 5 minutes.
3.12 Sweat Collection
Sweat collection will be performed to evaluate sweat chloride (SwCl).  Sweat chloride concentration is a 
biomarker of CFTR ion channel function.  It is a sensitive, standardized and non-invasive measure to 
assess systemic CFTR modulator effects.  Chloride concentration will be measured in sweat collected by 
an approved collection device provided to sites by a central provider and according to the 2009 
guidelines issued by the Clinical and Laboratory Standards Institute.
To ensure consistency and reproducibility in this multicenter study, trained clinical study centers will 
collect sweat according to procedures as outlined in the lab manual.  Two sweat collections, one from 
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p. 13 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
each arm, will be obtained from each subject at the time points indicated in the protocol activity 
schedule.  Sweat samples will immediately be frozen and sent to the central laboratory for testing and 
interpretation of results.
The clinical study center should be encouraged to select subjects for the study for which it is known that 
adequate quantities of sweat can be collected.
The sites will be provided with sweat collection equipment and kits, and a central laboratory will act as 
central readers for SwCl.  Sweat collection will be measured beginning at Screening and as specified in 
Section 2.  
To prevent the potential unblinding, site personnel and subjects will not be informed of the subjects' 
study-related post-first-dose sweat chloride results until the end of the corresponding study part (Part 1 
or Part 2).  
3.13 Spirometry
Spirometry will be performed to assess pulmonary function beginning at Screening and as specified in 
Section 2.  At the Day 1 and Day 15 visits, spirometry must be performed pre-dose and between 3 and 
5 hours following dosing.
The spirometry test must meet the criteria for acceptability and repeatability as defined in the 2005 
American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines on standardization of lung 
function testing.1
Consistency is very important for subjects who take bronchodilators and perform airway clearance on a 
regular basis, since they may have short-term effects on FEV1, the primary endpoint for this study.  
Please refer to Section 5.4 of the protocol for detailed guidance on the timing of dosing for these 
therapies relative to spirometry.
The following parameters will be measured as part of the spirometry assessment:

FEV1 (L) and percent predicted FEV1 for age, gender, and height;

Forced vital capacity (FVC) (L) and percent predicted FVC for age, gender, and height;

FEV1/FVC ratio;

Forced expiratory flow between 25% and 75% of exhaled volume (FEF25-75).
Predicted values will be estimated using the 2012 Global Lungs Initiative equation.2
The vendor will provide the sites with spirometers and will act as the central reader for spirometry 
results.  
To prevent the potential unblinding, subjects will not be informed of their study-related spirometry 
results until the end of the corresponding study Part (Part 1 or Part 2). 
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p. 14 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.14 Dispense Study Drug
Study drug will be dispensed to subjects beginning at Baseline (Day 1) and as specified in Section 2.  The 
first dose of study drug will be administered after all other Baseline (Day 1) procedures are completed.  
At the visits specified in Section 2.1, the site personnel will review returned study drug kits, and empty 
study drug packaging to verify compliance.  
Study drug (i.e., ABBV-3067, ABBV-2222, and respective placebos) should be dosed together and taken 
within approximately 1 hour after a meal.  Study drugs will need to be taken at the investigative site at 
the Day 1 and Day 15 visits.  The site will provide meals at those visits.  Subjects should be instructed to 
take their study medications at the same time every day.
3.15 Clinical Laboratory Tests
The blood samples for serum chemistry tests will be collected prior to study drug dosing on Day 1 and 
Day 15.  Fasting or non-fasting status will be recorded in the source documents and on the laboratory 
requisition.  The baseline laboratory test results for clinical assessment for a particular test will be 
defined as the last measurement prior to the initial dose of study drug.
Samples will be obtained for the laboratory tests listed in Table 1 at the time points specified in 
Section 2.
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p. 15 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Table 1.
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Other Tests
Hematocrit
Hemoglobin
Mean Corpuscular volume
White blood cell count
Neutrophils
Lymphocytes
Monocytes
Eosinophils 
Reticulocyte count
Platelet count (estimate not 
acceptable)
Bands (if present)
hsCRP
Blood urea nitrogen
Creatinine
Total bilirubin
Direct and indirect bilirubin
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Total protein
Glucose
Albumin
Chloride
Bicarbonate
Creatinine clearance (Cockcroft-
Gault calculation)
Gamma-glutamyl transferase 
(GGT)
Uric acid
Lactate dehydrogenase
Creatine phosphokinase
Cholesterol
Triglycerides
Urine:b  drugs of abuse and alcohol
Urinef and serum
human chorionic gonadotropinb,c,d
follicle-stimulating hormoneb,c,e
Urinalysis:a
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Bilirubin
Leukoesterase
Nitrites
Microscopic examination, if indicated
Coagulationa
Serologyb
Prothrombin time (PT)/INR
Activated partial 
thromboplastin 
time (aPTT)
HBsAg
Anti-HCV antibody 
HIV-1 and HIV-2 antibodies
INR = international normalized ratio, HBsAG = Hepatitis B virus surface antigen, HCV = Hepatitis C virus, HIV = Human 
immunodeficiency virus, hsCRP = High-sensitivity C-reactive protein
a.
Chemistries, hematology, coagulation and urinalysis labs should be performed at all visits.
b.
Performed only at screening.
c.
Females only.
d.
Pregnancy testing is not required for females of non-childbearing potential.
e.
If needed to determine postmenopausal status.
f.
Local test.
A certified laboratory will be utilized to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.
Instructions regarding the collection, processing, and shipping of these samples will be provided by the 
central laboratory and sent to the following certified laboratory addresses:
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p. 16 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Covance CLS
8211 Scicor Drive
Indianapolis, IN  46214
USA
Covance Central Laboratory Services S.A. 
Rue Moïse-Marcinhes 7 
1217 Meyrin Geneva 
Switzerland
ERT 
1818 Market Street
Philadelphia, PA  19103
USA
ERT
Sieboldstraße 3
97230 Estenfeld
Germany
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will:

repeat the test to verify the out-of-range value using the appropriate Central lab kit;

follow the out-of-range value to a satisfactory clinical resolution; 

if deemed appropriate, discontinue the subject from the study or require the subject to receive 
treatment; in this case, the laboratory result will be recorded as an AE; 

document the result and appropriate follow-up in the subject's source records and applicable 
eCRFs.
Pregnancy Tests (Serum and Urine)
Pregnancy testing should be performed only for women of childbearing potential.
A qualitative serum pregnancy test will be performed at Screening for all female subjects of childbearing 
potential.  The serum pregnancy test will be sent to and performed by the central laboratory.  If the 
serum pregnancy test is positive, the subject is considered a screen failure.  If the serum pregnancy test 
is borderline, it should be repeated ≥ 3 days later to determine eligibility.
If the repeat serum pregnancy test is:

Positive, the subject is considered a screen failure;

Negative, the subject can be enrolled into the trial;
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p. 17 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Still borderline, ≥ 3 days later, this will be considered documentation of continued lack of a 
positive result and the subject can be enrolled into the study (unless prohibited per local 
requirements) in the absence of clinical suspicion of pregnancy and other pathological causes of 
borderline results.
Additional urine pregnancy tests will be performed at visits indicated in the Activity Schedule 
(Protocol Appendix D) and Section 2.  More frequent pregnancy tests can be performed throughout the 
study at the investigator's discretion or if required per local/country requirements.

If the baseline urine pregnancy test is negative, then dosing with study drug may begin.

If the baseline or post-baseline urine pregnancy test is positive, dosing with study drug must be 
withheld and a serum pregnancy test is required (as stated above).  If the serum pregnancy test 
is positive, the subject should be discontinued from the study.

Unless a woman is suspected to have become pregnant, additional pregnancy testing during the 
clinical trial is not necessary.
A serum pregnancy test will also be performed at the post-treatment Day 30 follow-up visit if the urine 
pregnancy test at this visit is positive.
Urinalysis
Dipstick urinalysis will be completed by the central laboratory at all required visits.  Specified abnormal 
macroscopic urinalyses defined as leukocytes, nitrite, protein, ketones, or blood greater than negative, 
or glucose greater than normal will be followed up with a microscopic analysis at the central laboratory.
3.16 Subject Withdrawal from Study
If subjects prematurely discontinue from the study, they should be asked to return for a Premature 
Discontinuation visit and participate in a 30-day follow-up visit if possible.
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.  Following discontinuation of study drug, the subject will be treated in accordance with the 
investigator's best clinical judgment, irrespective of whether or not the subject decides to continue 
participation in the study.  
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All serious adverse events (SAEs) as well as protocol-related nonserious AEs (e.g., bruising at 
phlebotomy site, done during Screening) will be collected from the time the subject signed the 
study-specific informed consent until study drug administration.  From the time of study drug 
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p. 21 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Section 2.1.  In Part 2, the study drugs ABBV-3067 or placebo and ABBV-2222 or placebo will be 
dispensed in the form of capsules at the visits listed in Section 2.1.  Subjects will be instructed to take 
study drugs once daily at the same time in the morning every day within approximately 1 hour after a 
meal.
Dosing times for the Day 1 and Day 15 visits and for the 3 doses before the Day 15 and Day 29 visits will 
be captured in the source records and eCRFs, as specified in Section 3.5.
Study drug must not be dispensed unless the IRT system is contacted.  Study drug may only be 
dispensed to subjects enrolled in the study through the IRT system.  At the end of the Treatment Period 
or at the Premature Discontinuation visit, the site will contact the IRT system to provide visit date 
information and study drug return information for each kit.
6.2 Packaging and Labeling
All study drugs will be supplied in blister cards.
Each blister card will be labeled as required per country requirements.
The labels must remain affixed to the blister cards.  All blank spaces should be completed by site staff 
prior to dispensing to subject.
Storage and Disposition of Study Drug
Study drugs must be stored at controlled room temperature (15° to 25°C/59° to 77°F).
The investigational products are for investigational use only and are to be used only within the context 
of this study.  The study drug supplied for this study must be maintained under adequate security and 
stored under the conditions specified on the label until dispensed for subject use or destroyed on site as 
appropriate.
6.3 Method of Assigning Subjects to Treatment Groups
This is a double-blind, placebo-controlled, dose-ranging study.  Once assigned to a regimen, all eligible 
subjects will receive that same assigned dosage for up to 28 days (± 2 days).
At the Screening visit, all subjects will be assigned a unique subject number through the use of the IRT.  
For subjects who do not meet the study selection criteria, the site personnel must contact the IRT 
system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number assigned at the screening visit throughout the 
study.  Upon receipt of study drug, the site will acknowledge receipt in the IRT system.
User guidelines for IRT use will be made available separately.
6.4 Selection and Timing of Dose for Each Subject
Subjects will be randomly assigned to one of 8 regimens in Part 1 and to one of 5 regimens in Part 2.
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p. 22 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Part 1
ABBV-3067 will be given alone or in combination with dose levels of ABBV-2222 for 28 days as Regimens 
A through H in Part 1.
Regimen
ABBV-3067
ABBV-2222
A
50 mg
Placebo
B
150 mg
Placebo
C
150 mg
10 mg
D
150 mg
30 mg
E
150 mg
100 mg
F
150 mg
200 mg
G
150 mg
300 mg
H
Placebo
Placebo
Part 2  
Different dose levels of ABBV-3067 will be given in combination with ABBV-2222 for 28 days as 
Regimens I through M in Part 2.
Regimen
ABBV-3067
ABBV-2222
I
5 mg
TBD
J
15 mg
TBD
K
50 mg
TBD
L
150 mg
TBD
M
Placebo
Placebo
TBD = to be determined
The tablets or capsules as assigned will be dosed together once daily.  All subjects should take all doses 
of study drug with food at approximately the same time in the morning each day.
The maximum dose of the ABBV-2222 administrated in this study will not exceed 300 mg per day.  The 
maximum dose of ABBV-3067 administered in this study will not exceed 250 mg per day.
7 REFERENCES
1.
Miller MR, Hankinson J, Brusasco V, et al.  Standardisation of spirometry.  Eur Respir J.  
2005;26(2):319-38.
2.
Quanjer PH, Stanojevic S, Cole TJ, et al.  Multi-ethnic reference values for spirometry for the 3-
95 year age range:  the global function 2012 equations:  Report of the Global Lung Function 
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p. 23 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Initiative (GLI), ERS Task Force to establish improved lung function reference values.  Eur Respir 
J.  2012;40(6):1324-43.
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p. 24 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
Adverse event
AESI
Adverse events of special interest
ATS/ERS
American Thoracic Society/European Respiratory Society
BSA
Body surface area
CBC
Complete blood count
CF
Cystic fibrosis
CFTR
CF transmembrane conductance regulator
CTCAE
Common Terminology Criteria for Adverse Events
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
FEF25-75
Forced expiratory flow at mid-lung capacity
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
HBsAg
Hepatitis B virus surface antigen
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus 
hsCRP
High-sensitivity C-reactive protein
IMP
Investigational medicinal product
IRT
Interactive response technology
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
RSI
Reference safety information
SAE
Serious adverse event
SOC
System organ class
SUSAR
Suspected unexpected serious adverse reactions
SwCl
Sweat chloride
TBD
To be determined
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p. 25 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. ADVERSE EVENT OF SPECIAL INTEREST
RASH QUESTIONNAIRE
Part 1
Adverse Event Serial Number:
Question
Response
Was the subject seen by a 
dermatologist or allergy 
specialist for this event?
No 
Yes 
Date ____/____/_____Findings 
                                 DD/MM/YYYY 
Was the event treated? 
☐Yes (If yes, treatment should be documented under "action taken" on AE 
CRF.) 
☐No
Was a skin biopsy 
performed?
☐Yes (If yes, please describe findings.)
☐No
Does the PI think there is an 
alternative etiology?
☐Yes (If yes, please specify.)
☐No
Continued on next page.
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p. 26 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Was the rash localized or 
generalized?
☐Localized
☐Generalized
Which body areas were involved?  (e.g., whole body, scalp, ear, face, oral 
cavity, neck, chest, abdomen, upper back, lower back, arm, forearm, hand, 
inguinal region, genitalia, buttock, perineum, thigh, leg, foot)
Did the rash progress?
☐Yes, How rash progressed: 
              Where rash progressed:
☐No
Specify type of rash below: 
Yes
No
Unknown
Wheal?
Nodule?
Vesicule/Bulla?
Scaling or exfoliating?
Macular?
Papular?
Raised?
Morbilliform?
Flat?
Confluent?
Mucous membrane involvement?
Ocular involvement?
Petechial or purpuric?
Urticarial (hives)?  
Pustule?
Atrophy?
Blisters?
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p. 27 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Part 2
Did the subject experience any of the following symptoms 
associated with the reported event? 
Yes
No
Unknown
Pruritus?
Fever (> 101.5 degrees F or 38.5 degrees C)?
Headache?
Joint pain/arthralgia?
Neck stiffness?
Lymphadenopathy?
Hypotension?
Angioedema?
Bronchospasm and/or laryngeal edema?
Rhinoconjunctivitis?
Nausea, vomiting and/or diarrhea?
Other
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p. 28 of 28
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-530 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Part 3
Were there any lab abnormalities 
associated with the event?
☐Yes, specify 
☐No
Did the subject experience any viral 
illness in the past month?
☐Yes (If yes, please update Medical History eCRF or Adverse Event 
eCRF as appropriate.)
☐No
Did the subject have any recent 
contact/exposure with an irritant 
(foods, chemicals, medications)?
☐Yes, specify 
☐No
Does the subject have a family history 
of allergies?
☐Yes, specify 
☐No
Does the subject have a history of 
atopy?
☐Yes, specify if anything made it worse or improved: 
              Describe: 
              Was there anything that made it better? 
      If yes, please describe: 
☐No
Does the subject have medical history 
of skin disorders?  (Please add to 
Medical History eCRF as applicable.)
☐Yes
☐No
Did the subject receive prior 
treatment for historical condition of 
skin disorder?  (Please add to Prior 
Procedure or Prior Concomitant 
Medication eCRF as applicable.)
☐Yes
☐No
Page 71 of 75
 

SAP_001.pdf: 
ABBV-3067/ABBV-2222
M19-530 – Statistical Analysis Plan
Version 2.0 – 27 July 2021
1
Statistical Analysis Plan for Study M19-530
A Phase 2 Study of ABBV-3067 Alone and in 
Combination with ABBV-2222 in Cystic Fibrosis 
Subjects Who Are Homozygous for the F508del 
Mutation
Date:  27 July 2021
Version 2.0
 
NCT03969888


ABBV-3067/ABBV-2222
M19-530 – Statistical Analysis Plan
Version 2.0 – 27 July 2021
2
Table of Contents
1.0
Introduction .............................................................................4
2.0
Study Design and Objectives..................................................4
2.1
Objectives and Hypotheses ........................................................................4
2.2
Study Design Overview .............................................................................5
2.3
Treatment Assignment and Blinding .........................................................8
2.4
Sample Size Determination........................................................................9
3.0
Endpoints..................................................................................9
3.1
Primary Endpoint(s)...................................................................................9
3.2
Secondary Endpoint(s)...............................................................................9
3.3
Other Efficacy Endpoint(s)......................................................................10
3.4
Safety Endpoint(s) ...................................................................................10
3.5
Additional Endpoint(s).............................................................................10
4.0
Analysis Populations .............................................................10
5.0
Subject Disposition................................................................11
6.0
Study Drug Duration and Compliance................................11
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................12
7.1
Demographics and Baseline Characteristics............................................12
7.2
Medical History .......................................................................................14
7.3
Prior and Concomitant Medications ........................................................14
8.0
Efficacy Analyses...................................................................15
8.1
General Considerations............................................................................15
8.2
Handling of Missing Data........................................................................16
8.3
Primary Efficacy Endpoint(s) and Analyses............................................16
8.3.1
Primary Efficacy Endpoint(s) ..................................................................16
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint(s)............17
8.3.3
Primary Efficacy Analysis .......................................................................17
8.3.4
Additional Analyses of the Primary Efficacy Endpoint(s) ......................17
8.4
Secondary Efficacy Analyses...................................................................17
8.5
Additional Efficacy Analyses ..................................................................18
8.6
Efficacy Subgroup Analyses....................................................................18
 


ABBV-3067/ABBV-2222
M19-530 – Statistical Analysis Plan
Version 2.0 – 27 July 2021
3
9.0
Safety Analyses ......................................................................18
9.1
General Considerations............................................................................18
9.2
Adverse Events ........................................................................................19
9.2.1
Treatment-Emergent Adverse Events ......................................................19
9.2.2
Adverse Event Overview .........................................................................20
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................20
9.2.4
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................21
9.2.5
Adverse Events of Special Interest ..........................................................21
9.3
Analysis of Laboratory Data....................................................................21
9.4
Analysis of Vital Signs ............................................................................23
9.5
Safety Subgroup Analyses .......................................................................24
9.6
Other Safety Analyses..............................................................................24
10.0
Other Analyses.......................................................................25
11.0
Interim Analyses....................................................................25
11.1
Data Monitoring Committee....................................................................25
12.0
Overall Type-I Error Control ..............................................25
13.0
Version History......................................................................26
14.0
References...............................................................................26
List of Tables
Table 1.
SAP Version History Summary...............................................................26
List of Figures
Figure 1.
Part 1 Study Schematic ..............................................................................7
Figure 2.
Part 2 Study Schematic ..............................................................................8
List of Appendices
Appendix A.
Protocol Deviations..................................................................................27
Appendix B.
Potentially Clinically Significant Criteria for Safety Endpoints..............28
 


ABBV-3067/ABBV-2222
M19-530 – Statistical Analysis Plan
Version 2.0 – 27 July 2021
4
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for 
ABBV-3067/ABBV-2222 Study M19-530 titled "A Phase 2 Study of ABBV-3067 Alone 
and in Combination with ABBV-2222 in Cystic Fibrosis Subjects Who Are Homozygous 
for the F508del Mutation."
Study M19-530 examines the safety, tolerability, and efficacy of ABBV-3067 given alone 
and in combination with ABBV-2222 in adult subjects with Cystic Fibrosis (CF) who are 
homozygous for the F508del mutation.
The analyses of pharmacokinetic endpoints, biomarker samples and exploratory research 
endpoints 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 and Hypotheses
The objectives of Part 1 in this study are to:
1.
Evaluate the safety, tolerability, and efficacy of ABBV-3067 given alone and in 
combination with varied dose levels of ABBV-2222 in adult subjects with CF who 
are homozygous for the F508del mutation.
2.
Select a dose of ABBV-2222 to use in Part 2 based on safety, tolerability, efficacy, 
and pharmacokinetic data.
The objectives of Part 2 in this study are to:
 


ABBV-3067/ABBV-2222
M19-530 – Statistical Analysis Plan
Version 2.0 – 27 July 2021
5
1.
Evaluate the safety, tolerability, and efficacy of ABBV-2222 (fixed dose from 
Part 1) combined with varied dose levels of ABBV-3067 in CF subjects who are 
homozygous for the F508del mutation.
2.
Select a dose of ABBV-3067 to carry forward to future combination studies.
2.2
Study Design Overview
This is a Phase 2, double-blind, placebo-controlled, parallel-arm, multicenter study to 
evaluate the safety, efficacy and pharmacokinetics of different dose levels of ABBV-3067 
given alone and in combination with different dose levels of ABBV-2222 for 28 days in 
subjects aged 18 years and older with CF who are homozygous for F508del CFTR 
mutation.
This study consists of 2 parts (Part 1 and Part 2) and will initially enroll CF subjects to 
Part 1.  Part 2 of the study will initiate after all subjects enrolled in Part 1 complete the 
30-day safety follow-up period or prematurely discontinue from the study.  Each part of 
the study is comprised of an approximately 30-day screening period, a 28-day double-
blind (DB) Treatment Period and a 30-day Follow-up Visit.
Part 1
In Part 1, approximately 117 eligible subjects with CF will be randomized in a 
1:1:1:2:2:2:2:2 ratio to 8 treatment arms in a dose range-finding manner to enable a dose 
selection for ABBV-2222 for Part 2:
A:
ABBV-3067 50 mg + Placebo for ABBV-2222
B:
ABBV-3067 150 mg + Placebo for ABBV-2222
C:
ABBV-3067 150 mg + ABBV-2222 10 mg
D:
ABBV-3067 150 mg + ABBV-2222 30 mg
 


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E:
ABBV-3067 150 mg + ABBV-2222 100 mg
F:
ABBV-3067 150 mg + ABBV-2222 200 mg
G:
ABBV-3067 150 mg + ABBV-2222 300 mg
H:
Placebo for ABBV-3067 + Placebo for ABBV-2222
Study drug will be administered from Baseline/Day 1 to Day 28.  The last visit in the DB 
Treatment Period is planned at Day 29, when all scheduled efficacy, safety and 
pharmacokinetics assessments will be performed.
Part 2
In Part 2, approximately 72 eligible subjects with CF will be randomized in a 
1:2:2:2:1 ratio to 5 treatment arms in a dose-ranging manner to enable selection of the 
ABBV-3067 dose for future combination studies:
I:
ABBV-3067 5 mg + ABBV-2222*
J:
ABBV-3067 15 mg + ABBV-2222*
K:
ABBV-3067 50 mg + ABBV-2222*
L:
ABBV-3067 150 mg + ABBV-2222*
M:
Placebo for ABBV-3067 + Placebo for ABBV-2222
*
A fixed dose for ABBV-2222 is to be determined based on Part 1 data.
Study drug will be administered from Baseline/Day 1 to Day 28.  The last visit in the DB 
Treatment Period is planned at Day 29, when all scheduled efficacy, safety and 
pharmacokinetics assessments will be performed.
 


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For both parts of the study, a follow-up visit will occur 30 days after the last dose of study 
drug to determine the status of any ongoing AEs/SAEs or the occurrence of any new 
AEs/SAEs and use of any concomitant medications.
Schematics of the 2 parts of the study are shown in Figure 1 and Figure 2.
Figure 1.
Part 1 Study Schematic
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 


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Figure 2.
Part 2 Study Schematic
2222 = ABBV-2222; 3067 = ABBV-3067; PBO = placebo
2.3
Treatment Assignment and Blinding
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.  The IRT will assign a randomization number that will 
encode the subject's treatment assignment according to the randomization schedule 
generated by the statistics department at AbbVie.
In Part 1, subjects meeting eligibility criteria will be randomized at the Baseline visit to 
Treatment A through H in a 1:1:1:2:2:2:2:2 ratio.  In Part 2, subjects meeting eligibility 
criteria will be randomized at the Baseline visit to Treatment I through M in a 
1:2:2:2:1 ratio.  Description of treatment arms are in Section 2.2.  In both Part 1 and 
Part 2, randomization will be stratified by the percent predicted forced expiratory volume 
in 1 second at Screening visit (ppFEV1 < 70% vs ppFEV1 ≥ 70%).  The calculation of 
percent predicted FEV1 is described in Section 8.3.1.
 
 
 
 
 
 
 
 
 
 
  
 
   
  
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
   
 
 
  
 
 
   
 
 
  
 
 
   
 
 
 
  
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  


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To minimize the potential of unblinding, the AbbVie study team will not have access to 
the post-first-dose spirometry or sweat chloride results until after the study is unblinded 
for Part 1 or Part 2 analysis.  During the blinding phases, the vendors for central reading 
of the spirometry data or sweat chloride data will only send the blinded files to the 
sponsor's database to be used for developing the statistical programs.
2.4
Sample Size Determination
The power calculations are provided for the most potentially efficacious groups with the 
combination treatment for both Part 1 and Part 2 for the primary efficacy endpoint.  
Placebo groups from both Part 1 and Part 2 will be combined in the Part 2 efficacy 
analysis.  A sample size of 18 subjects in a group will provide 80% power to detect a 
5.3% absolute increase from Baseline in ppFEV1 for that group assuming a standard 
deviation of 7.5%.  When comparing to the placebo group, a sample size of 18 subjects in 
both treated group and placebo group will provide 80% power (Part 1), or a sample size of 
18 subjects in treated group and 27 subjects in placebo group will provide approximately 
87% power (Part 2), to detect a 7.3% difference in ppFEV1 change from Baseline between 
a treated group and the placebo group assuming the standard deviation of 7.5% for change 
in ppFEV1 for both groups.
3.0
Endpoints
3.1
Primary Endpoint(s)
The primary endpoint is the absolute change from Baseline through Day 29 in percent 
predicted forced expiratory volume in 1 second (ppFEV1, a measure of lung function).
3.2
Secondary Endpoint(s)
The secondary endpoints are:
1.
Absolute change from Baseline through Day 29 in Sweat Chloride (a biomarker of 
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2.
Absolute change from Baseline through Day 29 in other spirometric measures 
(forced vital capacity [FVC], forced expiratory flow at mid-lung capacity 
[FEF25-75])
3.
Relative changes from Baseline through Day 29 in ppFEV1, FVC, and FEF25-75.
3.3
Other Efficacy Endpoint(s)
There are no additional efficacy endpoints for this study.
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 safety interest
●
Adverse events leading to study drug discontinuation
●
Clinical laboratory tests, 12-lead electrocardiogram, vital signs, weight, pulse 
oximetry and spirometry parameters.
3.5
Additional Endpoint(s)
The pharmacokinetic endpoints will be analyzed separately and not be covered in this 
SAP.
4.0
Analysis Populations
The following population sets will be used for analyses in each part of the study.
The Full Analysis Set (FAS) includes all randomized subjects who received at least 1 dose 
of study drug.  The FAS will be used for all efficacy and baseline analyses.  Subjects will 
be grouped according to treatment as randomized.
 


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The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.  
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 1 treatment, the subject will be grouped in the treatment group for which they 
received the most doses.
5.0
Subject Disposition
For each part of the study, the total number of subjects who were randomized and treated 
will be summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for each treatment group:
●
Subjects randomized in the study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed protocol-specified treatment;
●
Subjects who prematurely discontinued study drug;
●
Subjects who completed study;
●
Subjects in each analysis population, as applicable.
The number and percentage of subjects who discontinued study drug by reason (all 
reasons and primary reason) will be summarized overall and by treatment arm, as well as 
for the combined placebo arms from Part 1 and Part 2.  Similar summaries will be 
provided for discontinuations from the study.
6.0
Study Drug Duration and Compliance
Study drug duration, treatment compliance and study drug temporary interruptions will be 
summarized on the Safety Analysis Set for each treatment arm as well as for the combined 
placebo arms from Part 1 and Part 2.
 


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Duration of treatment is defined for each subject as last dose date minus first dose 
date + 1.  Study drug temporary interruptions will not be subtracted from the duration.  
Duration of treatment will be summarized including 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.
The number and percentage of subjects with reported study drug temporary interruptions 
will be summarized by reason as captured on the eCRF.
Treatment compliance is defined as the number of tablets or capsules actually taken 
divided by the number of tablets or capsules that should have been taken.  Percent 
compliance will be summarized by treatment arm, and a listing with percent compliance 
for each subject will be provided.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the FAS overall and by treatment arm, 
as well as for the combined placebo arms from Part 1 and Part 2.
Categorical variables will be summarized with the number and percentage of subjects; 
percentages will be calculated based on the number of non-missing observations.  
Continuous variables will be summarized with descriptive statistics including number of 
non-missing observations, mean and standard deviation, median, minimum and 
maximum.
7.1
Demographics and Baseline Characteristics
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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 (North America, 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 captured on the Cystic Fibrosis History eCRF 
(Homozygous, Heterozygous),
●
F508del CFTR mutation as determined by central lab genotyping 
(Homozygous, Heterozygous)
●
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%, ≥90%)
●
Baseline ppFEV1 category (< 40%, ≥ 40% to < 70%, ≥ 70% to < 90%, ≥ 90%)
●
Continuous value of sweat chloride at baseline (mmol/L)
●
Continuous value of FEV1 at baseline (L)
●
Continuous value of FVC at baseline (L)
●
Continuous value of FEF25-75 at baseline (L/sec)
●
Prior use of CFTR modulators (Yes, No)
●
For subjects with prior use of CFTR modulators only:
 


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○
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 overall and by treatment group.  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 
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.
 


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8.0
Efficacy Analyses
8.1
General Considerations
All efficacy analyses will be conducted for the FAS.  All tests will be 2-sided at an alpha 
level of 0.05.  For each part of the study, the efficacy analysis will be performed after all 
ongoing subjects have completed the study part and the database has been locked.
For the primary efficacy endpoint, the null hypothesis that the within-group absolute 
change from baseline in ppFEV1 through Day 29 is zero will be tested for each treated 
group at 2-sided alpha of 0.05.
Unless otherwise specified, any subject who is randomized based on a wrong stratum will 
be analyzed according to the actual stratum to which the subject belongs.
"Baseline" refers to the last non-missing observation before the first administration of 
study drug.
Unless otherwise specified, continuous variables will be analyzed using Mixed-Effect 
Model Repeat Measurement (MMRM) method with the model based mean and standard 
error being provided.  The Baseline and visit means will also be presented for each 
treatment group among subjects who have both Baseline and at least one post Baseline 
visit values.  Treatment groups will be compared using MMRM model as described in 
Section 8.2.  Point estimates and 95% CIs of mean change from Baseline within each 
treatment group, the difference between each active treatment group and placebo, and the 
difference between each combination therapy arm and the ABBV-3067 150 mg 
monotherapy arm (Part 1 only) will be provided.  Note that both placebo arms in Part 1 
and Part 2 will be combined into one placebo group for the Part 2 model comparison.
Plots of the primary endpoint and certain secondary endpoints by treatment group will be 
used to visualize the change of endpoint values over time and the difference between 
treatment groups.
 


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Use of bronchodilator medications and/or airway clearance techniques may affect lung 
function measurements in the short term.  Therefore, post-baseline spirometric 
measurement that are collected inconsistently with the conditions for the baseline 
spirometric measurement will be excluded from the efficacy analysis.  For example, if 
baseline spirometric measurement was collected prior to bronchodilator use, then any 
spirometric measurement collected post bronchodilator use at a subsequent visit will be 
excluded from analysis.
If a subject starts another CFTR modulator treatment during the study period, then all 
efficacy measures for this subject on or after the start date of the new CFTR modulator 
treatment will be excluded from analyses.
8.2
Handling of Missing Data
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 (change from Baseline to one of the visits is 
missing) based on the assumption of data being missing at random.  No other imputation 
will be used.
8.3
Primary Efficacy Endpoint(s) and Analyses
8.3.1
Primary Efficacy Endpoint(s)
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 estimated for age, gender, and 
height using the 2012 Global Lungs Initiative equation.2  Percent predicted FEV1 is the 
ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a percentage.  For the primary 
efficacy endpoint in both Part 1 and Part 2, the corresponding statistical null hypotheses 
are that there is no difference in the mean value of ppFEV1 from baseline through Day 29 
within each treatment group.
 


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8.3.2
Handling of Missing Data for the Primary Efficacy 
Endpoint(s)
Missing data will be handled using MMRM method as described in Section 8.2.
8.3.3
Primary Efficacy Analysis
The primary analysis will be performed using MMRM with change from Baseline in 
ppFEV1 as the dependent variable.  The mixed model includes the categorical fixed 
effects of treatment, visit and treatment-by-visit interaction, as well as the continuous 
fixed effect of baseline ppFEV1.  The random effects of the model will be subject ID. 
Parameter estimation will use the method of restrictive maximum likelihood (REML).1
The point estimate for the primary endpoint from the MMRM model along with the 
95% confidence interval and the corresponding p-value will be presented for the primary 
efficacy analysis.  The pairwise comparison of the primary endpoint of ppFEV1 between 
each active treatment group versus the placebo group will also be estimated using the 
same model.  The Least Squares Mean of the treatment difference between each active 
treatment group versus the placebo group will be presented along with the 
95% confidence interval and a 2-sided p-value.
8.3.4
Additional Analyses of the Primary Efficacy Endpoint(s)
Sensitivity analysis for the primary endpoint of ppFEV1 will be conducted using all 
spirometry data as collected if there are at least 5% of the total subjects in each study part 
who have at least one post-Baseline inconsistent use of bronchodilator medications and/or 
airway clearance.
8.4
Secondary Efficacy Analyses
Efficacy analyses will be performed by treatment group at each protocol-specified visit on 
each of the secondary efficacy endpoints including
●
absolute change from Baseline through Day 29 in Sweat Chloride (in mmol/L),
 


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absolute change from Baseline through Day 29 in FVC (in L), FEF25-75 (in L/s), 
and
●
relative change, calculated as percent change, from Baseline through Day 29 in 
ppFEV1, FVC, and FEF25-75
The point estimate for each of the secondary efficacy endpoints from the MMRM model 
along with the 95% confidence intervals and the corresponding p-values will be presented.  
In addition, pairwise comparison of each active treatment group versus placebo group will 
be analyzed using MMRM method as described in Section 8.3.3.
8.5
Additional Efficacy Analyses
There are no additional efficacy analyses planned for this study.
8.6
Efficacy Subgroup Analyses
Descriptive statistics of the primary endpoint will be provided for the following subgroups 
to evaluate the consistency of the efficacy across subgroup levels.
●
Geographic region (North America, Rest of World)
●
Stratification factor of screening ppFEV1 (< 70%, ≥ 70%)
●
Prior use of CFTR modulators (Yes, No)
The point estimates and 95% CIs will be provided within each subgroup level.  No 
p-value will be provided for subgroup analysis.
9.0
Safety Analyses
9.1
General Considerations
Safety data will be summarized for the Safety Analysis Set for each part of the study.  
Safety summaries will be presented by treatment arm, as well as for the combined placebo 
arms from Part 1 and Part 2.
 


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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.
9.2
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.
9.2.1
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.  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.
The number and percentage of subjects experiencing TEAEs will be summarized.
Pre-treatment AEs will be summarized separately in listing format.
AEs starting more than 30 days following the last dose of study drug will be summarized 
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9.2.2
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 9.2.5)
●
All deaths
9.2.3
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 severity 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 severity and level of relationship to 
investigational product will be reported.
If a subject has an AE with unknown severity or relationship to study drug, then the 
subject will be counted in the severity/relationship level category of "unknown" even if 
the subject has another occurrence of the same event with a severity present.  The only 
exception is if the subject has another occurrence of the same AE with the highest level of 
severity or a relationship assessment of "Reasonable possibility."  In this case, the subject 
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In addition, TEAEs will be summarized by PT and sorted by the overall descending 
frequency in the ABBV-3067 150 mg plus ABBV-2222 300 mg arm for Part 1 analysis 
and by the overall descending frequency in the ABBV-3067 150 mg plus ABBV-2222 
fixed dose arm for Part 2 analysis.
9.2.4
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.
9.2.5
Adverse Events of Special Interest
The rash AESIs will be identified per a Product MedDRA Query (PMQ) of "Drug 
Induced rash (Cystic Fibrosis Transmembrane Regulator [CFTR] Modulators Product 
Specific)" and be summarized by SOC and PT.  For rash related AESIs, the following 
categories will be summarized by treatment group:
●
Any rash AESIs
●
Any rash AESIs related to study drug according to the investigator
●
Any rash AESIs leading to discontinuation of study drug
●
Any rash AESIs leading to interruption of study drug
●
Any serious rash AESIs
●
Any serious rash AESIs related to study drug according to the investigator
Tabular listings of AESIs will also be provided.
9.3
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.  The 
 


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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 within each treatment group.
In the DB Treatment Period, 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) 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 who have a laboratory 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 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.
●
ALT > 3 × ULN, > 5 × ULN, > 10 × ULN, > 20 × ULN
●
AST > 3 × ULN, > 5 × ULN, > 10 × ULN, > 20 × ULN
 


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●
TBL > 1.5 × ULN, > 2 × 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, total bilirubin, and alkaline phosphatase values will be provided for 
each subject who met one or more of the criteria defined above.
An Evaluation of Drug Induced Serious Hepatotoxicity (eDISH) plot displaying the 
maximum on-treatment values of total bilirubin (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 AST vs. total bilirubin.
9.4
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 who have 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 
 


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considered a PCS finding.  Listings will be provided to summarize subject-level vital sign 
data for subjects meeting PCS criteria.
9.5
Safety Subgroup Analyses
There are no safety subgroup analyses planned for this study.
9.6
Other Safety Analyses
Pulse Oximetry
For oxygen saturation values by pulse oximetry, a summary of observed values and 
change from baseline values will be provided at each visit by treatment group.  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 by treatment group.
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 by treatment group for the 
Day 1 and Day 15 visit.  The 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 at the Day 1 and Day 15 visit will be summarized by 
treatment group.
ECG
ECG is collected at Screening, Day 15 and Day 29 visits.  ECG findings will be 
summarized by treatment group for each visit.  Summaries will include n (%) of patients 
in following categories:
●
Normal
 


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●
Abnormal - Not Clinically Significant
●
Abnormal - Clinically Significant
●
Unable to Evaluate
●
Missing
10.0
Other Analyses
There are no other safety analyses planned for this study.
11.0
Interim Analyses
One interim analysis is planned when all of the subjects participating in study Part 1 have 
completed the Follow Up Period (including those who discontinue prior to the Follow Up 
visit) and the database has been locked for analysis.  An additional interim analysis may 
be conducted when all of the subjects participating study Part 2 have completed or 
discontinued the Treatment Period and the database has been locked for analysis.
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 
safety data from the ongoing study.  The primary responsibility of the DMC will be to 
protect the safety of the subjects participating in this study.
A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.  In 
addition, the detailed data analysis and specifications for the DMC reviews are included in 
a separate DMC TFL specifications document.
12.0
Overall Type-I Error Control
There is no multiple testing procedure planned for this dose ranging study.
 


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Since Part 1 subjects and Part 2 subjects are two independent study populations and there 
is no plan to stop the study early for any efficacy claim after Part 1 is complete, no alpha 
spending is needed.
13.0
Version History
Table 1.
SAP Version History Summary
Version
Date
Summary
1.0
10 Feb 2020
Original version
2.0
27 Jul 2021

Added plots for the primary endpoint and certain 
secondary endpoints in Section 8.1

Clarified the missing data approach in Section 8.2

Changed "rash related AESIs" to "rash AESIs" in 
Section 9.2.5

For PCS labs in Section 9.3, changed "grade" to "value" in 
"post-baseline grade must be more extreme than baseline 
grade"

Specifically mentioned CTCAE v. 4.03 for grade shift 
tables in Section 9.4

Replaced specific categories of protocol deviations with a 
more general text in Appendix A
14.0
References
1.
SAS Institute Inc. SAS/STAT® 14.1 User's Guide, The MIXED Procedure.  Cary, 
NC; SAS Institute Inc., 2015.
2.
Quanjer PH, Stanojevic S, Cole TJ, et al.  Multi-ethnic reference values for 
spirometry for the 3 - 95-year age range:  the global function 2012 equations:  
Report of the Global Lung Function Initiative (GLI), ERS Task Force to establish 
improved lung function reference values.  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 Significant 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 Significant Chemistry Values
Chemistry Variables
Units
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
> 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-2.
Criteria for Potentially Clinically Significant Hematology and 
Coagulation Values
Hematology Variables
Units
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 count
109/L
> 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.
Table B-3.
Criteria for Potentially Clinically Important Vital Sign Values
Vital Sign
Category
Criteria for Potential Clinically 
Significant Vital Signs
Reference
Systolic blood 
pressure
Low
Value ≤ 90 mmHg and decrease 
≥20 mmHg from Baseline
Vaccine Trial Guidance, 
Grade 1 or above
High
Value ≥ 160 mmHg and increase 
≥20 mmHg from Baseline
CTCAE, Grade 3 or above, 
2018 ESC/ESH guidelines
Diastolic blood 
pressure
Low
Value ≤ 50 mmHg and decrease 
≥10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase 
≥10 mmHg from Baseline
CTCAE, Grade 3 or above, 
2018 ESC/ESH guidelines
Pulse
Low
Value < 50 bpm and decrease 
≥15 bpm from Baseline
Vaccine Trial Guidance, 
Grade 2 or above
High
Value ≥ 116 bpm and increase 
≥15 bpm from Baseline
Vaccine Trial Guidance, 
Grade 2 or above
Weight
Low
≥ 5% decrease from baseline
CTCAE, Grade 1 or above
High
≥ 10% increase from baseline
CTCAE, Grade 2 or above
Temperature
High
> 39.0
CTCAE, Grade 2 or above
Oxygen saturation
Low
< 90%
ESC = European Society of 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.