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

A Prospective Study to Evaluate Biological and Clinical Effects of Significantly Corrected CFTR Function (The PROMISE Study)

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis

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.

• Study Type: Observational
• Enrollment (Actual): 490

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Providence Alaska Medical Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Palo Alto, California, United States, 94025
      • Stanford University Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta and Emory University
    • Atlanta, Georgia, United States, 30327
      • Emory University
    • Augusta, Georgia, United States, 30912
      • Augusta University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
    • Peoria, Illinois, United States, 61637
      • Saint Francis Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40506
      • University of Kentucky
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital, Brigham & Women's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
    • Detroit, Michigan, United States, 48201
      • Wayne State University Harper University Hospital
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • The Minnesota Cystic Fibrosis Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Kansas City
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nebraska
    • Omaha, Nebraska, United States, 69198
      • University of Nebraska Medical Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers Robert Wood Johnson Medical School
  • New York
    • Buffalo, New York, United States, 14203
      • The Cystic Fibrosis Center of Western New York
    • Lake Success, New York, United States, 11042
      • Cohen Children's Medical Center of New York
    • New York, New York, United States, 10032
      • Children's Hospital of New York
    • New York, New York, United States, 10021
      • Northwell CF Center
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center Strong Memorial
    • Valhalla, New York, United States, 10595
      • New York Medical College at Westchester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Cystic Fibrosis Program
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center/Rainbow Babies and Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma Cystic Fibrosis Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Hershey Medical Center Pennsylvania State University
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Intermountain Cystic Fibrosis Center
  • Virginia
    • Charlottesville, Virginia, United States, 22904
      • University of Virginia
    • Richmond, Virginia, United States, 23219
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Individuals with Cystic Fibrosis, prescribed the elexacaftor, tezacaftor and ivacaftor CFTR modulator therapy (TCT).

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Core; Cystic Fibrosis patients prescribed elexacaftor, tezacaftor and ivacaftor CFTR modulator therapy (TCT).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sweat Chloride at 6 months	Change in sweat chloride from Baseline to 6 months.	6 months
Forced expiratory volume at one second (FEV1) at 6 months	Change in FEV1 from Baseline to 6 months.	6 months
Sweat Chloride at 30 months	Change sweat chloride from Baseline to 30 months.	30 months
Forced expiratory volume at one second (FEV1) at 30 months	Change in FEV1 from Baseline to 30 months.	30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight at 6 Months	Change in weight from Baseline to 6 months.	6 months
BMI at 6 Months	Change in BMI from Baseline to 6 months.	6 months
Cystic Fibrosis Questionnaire Revised (CFQ-R) at 6 Months	Change in CFQ-R (respiratory domain) from Baseline to 6 months.	6 months
Weight at 30 Months	Change in weight from Baseline to 30 months.	30 months
BMI at 30 months	Change in BMI from Baseline to 30 months.	30 months
Cystic Fibrosis Questionnaire Revised (CFQ-R) at 30 months	Change in CFQ-R (respiratory domain) from Baseline to 30 months.	30 months

Collaborators and Investigators

• Sponsor: Nicole Hamblett
• Collaborators: Cystic Fibrosis Foundation
• Investigators: Principal Investigator: Steven Rowe, MD, University of Alabama at Birmingham; Principal Investigator: David Nichols, MD, University of Washington

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2019
• Primary Completion (Actual): December 23, 2024
• Study Completion (Actual): December 23, 2024

Study Registration Dates

• First Submitted: July 25, 2019
• First Submitted That Met QC Criteria: July 26, 2019
• First Posted (Actual): July 30, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 24, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: CF; triple combination therapy; CFTR modulator
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Infant, Newborn, Diseases; Pancreatic Diseases; Cystic Fibrosis
• Other Study ID Numbers: PROMISE-OB-18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No