Study to Evaluate Adverse Events and Change in Disease Activity With Oral Capsules of Galicaftor/Navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 Combination Therapies in Adult Participants With Cystic Fibrosis

Study Overview
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Brief Summary
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Cystic Fibrosis (CF) is a rare, life-threatening, genetic disease that affects the lungs and digestive system, significantly impairing the quality of life, with those affected having a median age of death at 40. The main objective of this study is to assess how safe and effective is the combination therapy of galicaftor/navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 in adult participants with CF who are homozygous or heterozygous for the F508del mutation in each arm. Galicaftor/Navocaftor/ABBV-119 combination therapy and Galicaftor/Navocaftor/ABBV-576 is being developed as an investigational drug for the treatment of CF. Study doctors place participants in 1 of the 4 groups, called treatment arms. Each group receives a different treatment. Around 90 adult participants with a diagnosis of CF will be enrolled in the study around approximately 35 sites worldwide. Participants in arm 1 will receive oral capsules of galicaftor/navocaftor dual combination for 28 days followed by galicaftor/navocaftor/ABBV-119 triple combination for 28 days. Participants in arms 2 and 3 will receive the galicaftor/navocaftor/ABBV-119 triple combination or placebo for 28 days. Participants in arm 4 will receive galicaftor/navocaftor/ABBV-576 triple combination therapy for 28 days. For all study arms, ABBV-576, galicaftor, navocaftor, will be given once daily and ABBV-119 twice a day. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

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

Conditions
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Cystic Fibrosis (CF)

Intervention / Treatment
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* Drug: ABBV-576
* Drug: Galicaftor
* Drug: Placebo
* Drug: Navocaftor
* Drug: ABBV-119


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed clinical diagnosis of cystic fibrosis (CF). Arm 1 participants with genotype homozygous for the F508del CF transmembrane conductance regulator (CFTR) mutation and not receiving elexacaftor/tezacaftor/ivacaftor (ETI) treatment . Arm 2 and 3 participants with genotype heterozygous for the F508del CFTR mutation and a minimal function and not receiving ETI treatment. Arm 4 participants with genotype either homozygous or heterozygous for the F508del mutation. Participants must be receiving stable (ETI) treatment. Percent predicted forced expiratory volume in 1 second (ppFEV1) >= 40% and <=90% of predicted normal for age, gender and height at screening. For arms 1 and 2: sweat chloride (SwCl) >= 60 mmol/L at screening. For participants who participated in Study M19-530, it is acceptable to use a SwCl value that the central lab provided in Study M19-530 to establish eligibility. Weight >= 35 kg at screening and Day -28 for arm 1 or day 1 for arms 2 to 4. Exclusion Criteria: - Clinically significant laboratory values at screening that would pose undue risk for the participant or interfere with safety assessments (per the investigator).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: F508del Homozygous Cystic Fibrosis (CF) Participants<br>F508del homozygous cystic fibrosis (CF) participants receive galicaftor/navocaftor dual combination (28 days) followed by galicaftor/navocaftor/ABBV-119 triple combination therapy (28 days). | Drug: Galicaftor<br>* Oral capsules<br>Drug: Navocaftor<br>* Oral capsules<br>Drug: ABBV-119<br>* Oral capsules<br>|
| Experimental: F508del Heterozygous CF Participants (Active Drug Group)<br>F508del heterozygous CF participants receive galicaftor/navocaftor/ABBV-119 combination therapy (28 days). | Drug: Galicaftor<br>* Oral capsules<br>Drug: Navocaftor<br>* Oral capsules<br>Drug: ABBV-119<br>* Oral capsules<br>|
| Placebo Comparator: F508del Heterozygous CF Participants (Placebo Group)<br>F508del heterozygous CF participants receive placebo (28 days). | Drug: Placebo<br>* Oral capsules<br>|
| Experimental: F508del Homozygous and Heterozygous CF Participants<br>F508del homozygous and heterozygous CF participants receive galicaftor/navocaftor/ABBV-576 triple combination therapy for 28 days. | Drug: ABBV-576<br>* Oral capsules<br>Drug: Galicaftor<br>* Oral capsules<br>Drug: Navocaftor<br>* Oral capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohorts 1 and 2: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | Percent predicted forced expiratory volume in 1 second (ppFEV1). | Up to 29 days | 
| Cohort 3: Absolute change in Sweat Chloride (SwCl). | Sweat chloride (SwCl) concentration is a biomarker of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel function. | Up to 29 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohorts 1 and 2: Absolute Change From Baseline in Sweat Chloride (SwCl) | SwCl concentration is a biomarker of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel function. | Up to 29 days | 
| Absolute Change From Baseline in Forced Vital Capacity [FVC] | Forced vital capacity (FVC). | Up to 29 days | 
| Absolute Change From Baseline in Forced Expiratory Flow at Mid-Lung Capacity [FEF25-75] | Forced expiratory flow between 25% and 75% of exhaled volume (FEF25-75). | Up to 29 days | 
| Relative Changes From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | Percent predicted forced expiratory volume in 1 second (ppFEV1). | Up to 29 days | 
| Relative Changes From Baseline in Forced Vital Capacity [FVC] | Forced vital capacity (FVC). | Up to 29 days | 
| Relative Changes From Baseline in Forced Expiratory Flow Between 25% and 75% of Exhaled Volume (FEF25-75) | Forced expiratory flow between 25% and 75% of exhaled volume (FEF25-75). | Up to 29 days | 
| Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline | The CFQ-R is designed for use in participants with a diagnosis of cystic fibrosis and is designed to measure impact on overall health, daily life, perceived well-being, and symptoms. Participants will complete the CFQ-R electronically via a tablet device. | Up to 29 days | 
| Cohort 3: Absolute Changes From Baseline in ppFEV1 | Percent predicted forced expiratory volume in 1 second (ppFEV1). | Up to 29 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis (CF), Galicaftor, Navocaftor, ABBV-119, ABBV-576