A Prospective Study to Evaluate Biological and Clinical Effects of Significantly Corrected CFTR Function

NCT ID: NCT04038047

Last Updated: 2025-01-28

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 490 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2019-10-22
• Study Completion Date: 2024-12-23

Brief Summary

This is a prospective, multi-center observational study. The study is designed to measure the clinical effectiveness of elexacaftor, tezacaftor and ivacaftor (ETI) triple combination therapy in people with one or more copies of the F508del mutation, study the effects of ETI across a number of CF disease manifestations, and collect specimens for future research. Subjects in the study will have one "before TCT" visit within 30 days before initiation of the therapy and five "after TCT" visits over a 30-month follow-up period. Participants who have participated in the original PROMISE cohort have the option of participating in a long-term extension with annual visits performed at the 42- and 54-month timepoints. The durability of the clinical and biological changes in PROMISE can be assessed with extended follow-up, which would enable the sub-studies to consider potential clinical consequences of the biological or physiological effects being studied. This work will help to inform long term prognosis and feasibility of certain clinical trials outcomes for interventional studies and may be useful when considering research priorities in drug development. Most participating sites have been divided into sub-study groups; each sub-study group has specific non-optional procedures conducted in addition to the "Core" procedures. Finally, there is one optional procedure (transient elastography) that will be offered to subjects at certain sites. The duration of participation for each subject is 30 months (with an additional 24 months if participants agree to the optional long-term extension). NOTE: FDA has reviewed the New Drug Application (NDA) for elexacaftor, tezacaftor and ivacaftor and has granted approval.

Detailed Description

Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In people with CF, this manifests as dysfunction in multiple organ systems including the lungs, pancreas, liver, intestines, skin and others.

While nearly 2000 mutations have been described, the most common disease-causing CFTR mutation is F508del, which is found in >85% of patients followed in the US CF Patient Registry. Two CFTR corrector drugs plus the potentiator ivacaftor have been developed as a triple combination therapy for CF patients with one or two copies of the F508del mutation. We predict that over 90% of CF patients (initially age 12 y/o and above) will be eligible for highly effective CFTR modulator therapy in the U.S.

The PROMISE study is designed to measure the direct and indirect CFTR-dependent anion secretion by collecting and analyzing clinical research outcomes and biomarkers on a large number of patients both before and after they begin treatment with elexacaftor, tezacaftor and ivacaftor triple combination therapy (TCT). This study will investigate the impact of TCT across a wide range of CF disease manifestations and organ systems. While specific biomarkers of special interest have been selected for detailed analysis in this study, an additional important goal is to collect blood, urine, stool, and airway epithelial cell specimens for long-term storage in a biorepository to enable future research. These samples can be made available for research beyond the current scope of work. The PROMISE study will provide a coordinated collection of clinical research outcomes data that can be linked with these specimens.

Conditions

Cystic Fibrosis

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Core

Cystic Fibrosis patients prescribed elexacaftor, tezacaftor and ivacaftor CFTR modulator therapy (TCT).

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

1. All genders within the age limit of the FDA approved indication for elexacaftor, tezacaftor and ivacaftor triple combination therapy (TCT) at Day 1.

2. Diagnosis of CF.

3. CFTR mutations consistent with the FDA approved indication for elexacaftor, tezacaftor and ivacaftor triple combination therapy (TCT).

4. Physician intent to prescribe elexacaftor, tezacaftor and ivacaftor triple combination therapy (TCT).

5. Willing to fast for 8 hours prior to all study visits (for subjects on overnight enteric tube feedings, willing to hold the feeding for at least 8 hours).

6. Able to perform the testing and procedures required for this study, as judged by the investigator.

7. Enrolled in the Cystic Fibrosis Foundation Patient Registry.

8. Clinically stable with no significant changes in health status within the 14 days prior to Visit 1.

Exclusion Criteria

1. Use of any TCT within the 180 days prior to Visit 1.

2. Any acute use of antibiotics (oral, inhaled or IV) or systemic corticosteroids within the 2 weeks prior to Visit 1 for lower respiratory tract symptoms.

3. Initiation of any new chronic therapy (e.g., ibuprofen, Pulmozyme®, hypertonic saline, azithromycin, inhaled tobramycin, Cayston®, Kalydeco, Orkambi®, Symdeko®) within the 4 weeks prior to Visit 1.

4. Use of an investigational agent within the 28 days prior to Visit 1.

5. Use of chronic oral corticosteroids (equivalent to 10 mg. or more per day of prednisone) within the 28 days prior to Visit 1.

6. Treatment for nontuberculous mycobacterial (NTM) infection, consisting of ≥ two antibiotics (oral, IV, and/or inhaled) within the 28 days prior to Visit 1.

7. History of lung or liver transplantation, or listing for organ transplantation.

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cystic Fibrosis Foundation

OTHER

Sponsor Role: collaborator

Nicole Hamblett

OTHER

Sponsor Role: lead

Responsible Party

Nicole Hamblett

Professor of Pediatrics, Division of Pulmonary and Sleep Medicine, University of Washington School of Medicine Adjunct Professor, Biostatistics, University of Washington School of Medicine Co-Executive Director, Cystic Fibrosis Therapeutics Development

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Steven Rowe, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

David Nichols, MD

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Providence Alaska Medical Center

Anchorage, Alaska, United States

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States

Stanford University Medical Center

Palo Alto, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

National Jewish Health

Denver, Colorado, United States

Yale University School of Medicine

New Haven, Connecticut, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

University of Florida

Gainesville, Florida, United States

Children's Healthcare of Atlanta and Emory University

Atlanta, Georgia, United States

Emory University

Atlanta, Georgia, United States

Augusta University

Augusta, Georgia, United States

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Saint Francis Medical Center

Peoria, Illinois, United States

Riley Hospital for Children

Indianapolis, Indiana, United States

University of Iowa

Iowa City, Iowa, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

University of Kentucky

Lexington, Kentucky, United States

John Hopkins Hospital

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Boston Children's Hospital, Brigham & Women's Hospital

Boston, Massachusetts, United States

University of Michigan Health System

Ann Arbor, Michigan, United States

Wayne State University Harper University Hospital

Detroit, Michigan, United States

Helen DeVos Children's Hospital

Grand Rapids, Michigan, United States

The Minnesota Cystic Fibrosis Center

Minneapolis, Minnesota, United States

Children's Mercy Kansas City

Kansas City, Missouri, United States

Washington University School of Medicine

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Rutgers Robert Wood Johnson Medical School

New Brunswick, New Jersey, United States

The Cystic Fibrosis Center of Western New York

Buffalo, New York, United States

Cohen Children's Medical Center of New York

Lake Success, New York, United States

Northwell CF Center

New York, New York, United States

Children's Hospital of New York

New York, New York, United States

University of Rochester Medical Center Strong Memorial

Rochester, New York, United States

New York Medical College at Westchester Medical Center

Valhalla, New York, United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Children's Hospital Medical Center of Akron

Akron, Ohio, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

University Hospitals Case Medical Center/Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States

Cleveland Clinic Cystic Fibrosis Program

Cleveland, Ohio, United States

Oklahoma Cystic Fibrosis Center

Oklahoma City, Oklahoma, United States

Oregon Health Sciences University

Portland, Oregon, United States

Hershey Medical Center Pennsylvania State University

Hershey, Pennsylvania, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Cook Children's Medical Center

Fort Worth, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

Intermountain Cystic Fibrosis Center

Salt Lake City, Utah, United States

University of Virginia

Charlottesville, Virginia, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Seattle Children's Hospital

Seattle, Washington, United States

University of Washington Medical Center

Seattle, Washington, United States

University of Wisconsin

Madison, Wisconsin, United States

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

Sagel SD, Poore TS, Wagner BD, Xie J, Heltshe SL, Cross M, Bratcher PE, Taylor-Cousar JL, Wilson A, McBennett K, Morgan SJ, Singh PK, Nichols DP, Kelly A, Solomon GM. Long-term Reductions in Inflammation in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor. Ann Am Thorac Soc. 2025 Sep 17:10.1513/AnnalsATS.202507-817OC. doi: 10.1513/AnnalsATS.202507-817OC. Online ahead of print.

Reference Type: DERIVED

PMID: 40961158 (View on PubMed)

Nichols DP, Morgan SJ, Skalland M, Vo AT, Van Dalfsen JM, Singh SB, Ni W, Hoffman LR, McGeer K, Heltshe SL, Clancy JP, Rowe SM, Jorth P, Singh PK; PROMISE-Micro Study Group. Pharmacologic improvement of CFTR function rapidly decreases sputum pathogen density, but lung infections generally persist. J Clin Invest. 2023 May 15;133(10):e167957. doi: 10.1172/JCI167957.

Reference Type: DERIVED

PMID: 36976651 (View on PubMed)

Schwarzenberg SJ, Vu PT, Skalland M, Hoffman LR, Pope C, Gelfond D, Narkewicz MR, Nichols DP, Heltshe SL, Donaldson SH, Frederick CA, Kelly A, Pittman JE, Ratjen F, Rosenfeld M, Sagel SD, Solomon GM, Stalvey MS, Clancy JP, Rowe SM, Freedman SD; Promise Study Group. Elexacaftor/tezacaftor/ivacaftor and gastrointestinal outcomes in cystic fibrosis: Report of promise-GI. J Cyst Fibros. 2023 Mar;22(2):282-289. doi: 10.1016/j.jcf.2022.10.003. Epub 2022 Oct 21.

Reference Type: DERIVED

PMID: 36280527 (View on PubMed)

Nichols DP, Paynter AC, Heltshe SL, Donaldson SH, Frederick CA, Freedman SD, Gelfond D, Hoffman LR, Kelly A, Narkewicz MR, Pittman JE, Ratjen F, Rosenfeld M, Sagel SD, Schwarzenberg SJ, Singh PK, Solomon GM, Stalvey MS, Clancy JP, Kirby S, Van Dalfsen JM, Kloster MH, Rowe SM; PROMISE Study group. Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial. Am J Respir Crit Care Med. 2022 Mar 1;205(5):529-539. doi: 10.1164/rccm.202108-1986OC.

Reference Type: DERIVED

PMID: 34784492 (View on PubMed)

Other Identifiers

PROMISE-OB-18

Identifier Type: -

Identifier Source: org_study_id