A Two-Part Multicenter Prospective Longitudinal Study of CFTR-dependent Disease Profiling in Cystic Fibrosis (PROSPECT) (PROSPECT)

identify and validate biomarkers that might reflect partial restoration of CFTR function and can be used to monitor disease progression, and ii) evaluate the mechanistic effects of CFTR modulators and other relevant therapies in individuals with CF

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Other: Observational

Detailed Description

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Over 1,900 mutations, categorized into five genotypic or functional classes are implicated in causing CF. Severity of disease varies widely in CF based on CFTR-dependent and independent factors. Progressive obstructive lung disease is the main determinant of morbidity and mortality in CF; therefore it is critical to identify biomarker profiles that reflect and predict this phenotypic variability, and understand their relationship to residual CFTR activity. Emerging CFTR modulator therapies that directly target defective CFTR are being evaluated in pivotal clinical trials and may become available in the next few years. It is not known how partial restoration of CFTR function might impact CF disease progression and disease-related biomarkers. Thus there is urgent need to i) identify and validate biomarkers that might reflect partial restoration of CFTR function and can be used to monitor disease progression, and ii) evaluate the mechanistic effects of CFTR modulators and other relevant therapies in individuals with CF

• Study Type: Observational
• Enrollment (Actual): 452

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90027
      • Childrens Hospital Los Angeles
    • Palo Alto, California, United States, 94394
      • Lucile S. Packard Children's Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital Colarado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Illinois
    • Chicago, Illinois, United States, 60611-2605
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States
      • Indianapolis University Hospital; James Whitcomb Riley Hospital for Children
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • The University of Kansas Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Devon Children's Hospital at Spectrum Health
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Medical Center
    • Saint Louis, Missouri, United States
      • St. Louis Children's Hospital
  • New Hampshire
    • Lebanon, New Hampshire, United States
      • Dartmouth Hitchcock Medical Center
  • New York
    • Buffalo, New York, United States, 14222
      • Women and Children's Hospital of Buffalo
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Valhalla, New York, United States, 10595
      • Maria Fareri Children's Hospital; 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
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • University Hospital of Cleveland
    • Columbus, Ohio, United States
      • Nation Wide Childrens Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Sciences University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Hershey Medical Center; Penn State Children's Hospital
    • Philadelphia, Pennsylvania, United States
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh of UPMC
  • South Carolina
    • Charleston, South Carolina, United States, 29403
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232-9500
      • The Children's Hospital at Vanderbilt
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Primary Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
    • Seattle, Washington, United States, 98145-9807
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital
    • Milwaukee, Wisconsin, United States, 55455
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Part A N = 260 (210 CF, 50 non-CF controls)

• Cohort 1: 50 non-CF control subjects ≥ 12 years of age, with at least 15 subjects 12 - 21 yrs of age
• Cohort 2: 50 Partial CFTR Function CF subjects with at least one class IV/V CFTR mutation, ≥ 12 years of age
• Cohort 3 160 Absent CFTR Function CF subjects with two class I/II mutations ≥ 12 years of age

Part B

Up to 250 CF subjects who are homozygous for F508del mutation and who are prescribed ivacaftor/lumacafor for clinical care will be allowed to enroll. This will include :

• Cohort 3 subjects homozygous for F508del mutation from Part A who are prescribed ivacaftor/lumacaftor will be invited to participate in Part B (up to 100 potential subjects).
• Up to 150 additional CF subjects homozygous for F508del mutation ≥ 12 years of age who did not participate in Part A but are otherwise eligible for participation in Part B.

Description

Inclusion Criteria Part A COHORT 1:

• 1. Written informed consent (and assent when applicable) obtained from subject or subject's legal representative.

  2. Be willing and able to adhere to the study visit schedule and other protocol requirements 3. Male or female ≥ 12 years of age at Visit 1. 4. Have a body mass index (BMI) of:

  • For subjects ≥ 18 years of age: ≤ 30 kg/m2

  • For subjects 12 - 17 years of age: ≤ 95th percentile 5. Be a non-smoker for ≥ 1 year at screening and have ≤ 10 pack-year history of smoking.

    6. To participate in the optional DNA banking component of this study, subject must have signed the informed consent indicating willingness to participate in the genomic component of the study. Refusal to give consent for this component does not exclude a subject from participation in the study.

Inclusion Cohorts 2-3

1. Written informed consent (and assent when applicable) obtained from subject or subject's legal representative.
2. Male or female ≥ 12 years of age at Visit 1.

3. Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and the following criteria: Cohort 2: (Partial Function CFTR CF)

   • Two mutations in the CFTR gene:

     • At least one allele must be a Class IV or V mutation
     • The second allele can be within any CFTR mutation class.
   • Pancreatic sufficient (based on the absence of daily PERT use)
   • At least one historic sweat chloride ≥60 mEq/L by quantitative pilocarpine iontophoresis test (QPIT) OR sweat chloride results ≥ 40, but < 60mEQ/L upon permission of the PROSPECT Investigator-Sponsors.

   Cohort 3: (Absent Function CF)

   • Two class I or II CFTR mutations

4. Enrolled in the Cystic Fibrosis Foundation Patient Registry. Patients may enroll in the Registry at Visit 1 if not previously enrolled.
5. Clinically stable with no significant changes in health status within 2 weeks prior to Visit 1.
6. Be a non-smoker for ≥ 1 year at screening and have ≤ 10 pack-year history of smoking.
7. To participate in the optional DNA banking component of this study, subject must have signed the informed consent indicating willingness to participate in the genomic component of the study. Refusal to give consent for this component does not exclude a subject from participation in the study

Part B Inclusion

1. Written informed consent (and assent when applicable) obtained from subject or subject's legal representative.
2. Physician decision to treat with ivacaftor/lumacaftor.
3. Completion of at least Visit 1 and Visit 2 of Part A

Exclusion Criteria PART A COHORT 1

1. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
2. A history of any clinically significant medical illness or medical disorder that requires ongoing systemic medical therapy, including (but not limited to) cardiovascular disease, neuromuscular disease, hematological disease including bleeding disorders, chronic respiratory disease (including persistent asthma), hepatic or gastrointestinal (GI) disease, neurological disease, neoplastic disease, renal diseases, or endocrine disorders including diabetes.
3. Acute illness requiring any new prescription or over-the-counter treatment within 14 days prior to Visit 1.
4. Major or traumatic surgery within 12 weeks prior to Visit 1.
5. For females of child-bearing potential: a positive pregnancy test at Visit 1.
6. Initiation of any new chronic therapy within 28 days prior to Visit 1.
7. Use of an investigational agent within 28 days prior to Visit 1.

Exclusion Part A COHORTS 2-3

1. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
2. Initiation of newly prescribed antibiotics [oral, intravenous (IV), and/or inhaled] for acute respiratory symptoms within 2 weeks of Visit 1.
3. Major or traumatic surgery within 12 weeks prior to Visit 1.
4. For females of child-bearing potential: a positive pregnancy test at Visit 1.
5. Initiation of any new chronic therapy (e.g., ibuprofen Pulmozyme®, hypertonic saline, azithromycin, TOBI®, Cayston®) within 4 weeks prior to Visit 1.
6. Use of an investigational agent within 28 days prior to Visit 1.
7. Use of oral corticosteroids in doses exceeding 10 mg prednisone/day or 20 mg prednisone/every other day (subjects on oral steroids will be on stable doses for > 12 weeks prior to visit 1).
8. Active treatment for nontuberculous mycobacterial (NTM) infection, consisting of ≥ two antibiotics (oral, IV, and/or inhaled).
9. Use of CFTR modulator therapy such as ivacaftor (Kalydeco®) within 28 days prior to Visit 1.
10. History of lung or liver transplantation, or listing for organ transplantation.

Exclusion PART B

1. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
2. Initiation of newly prescribed antibiotics [oral, intravenous (IV), and/or inhaled] for acute respiratory symptoms within 2 weeks of Visit 4.
3. Initiation of any new chronic therapy (e.g., ibuprofen, Pulmozyme®, hypertonic saline, azithromycin, TOBI®, Cayston®) within 4 weeks prior to Visit 4.
4. Use of an investigational agent within 28 days prior to Visit 4.
5. Use of oral corticosteroids in doses exceeding 10 mg prednisone/day or 20 mg prednisone/every other day (subjects on oral steroids will be on stable doses for > 12 weeks prior to Visit 4).
6. Active treatment for nontuberculous mycobacterial (NTM) infection, consisting of ≥ two antibiotics (oral, IV, and/or inhaled).
7. Use of CFTR modulator therapy such as ivacaftor (Kalydeco®) within 28 days prior to Visit 4.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Part A; Cohort 1: Healthy Controls; Cohort 2: Partial CFTR function CF (class IV/V); Cohort 3: Absent CFTR function CF (Class I/II)	Other: Observational
Part B; CF patients who are homozygous for the F508del	Other: Observational

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sweat Chloride by Cohort (Part A Only)	This is the primary endpoint for Part A per the PROSPECT protocol. Mean sweat chloride was not reported for Part B, as it is not a relevant statistic. For cohort 1, sweat chloride is from day 0 only. For cohorts 2-3, sweat chloride was averaged from days 0, 14, 90 via a random intercept longitudinal model.	For cohort 1, sweat chloride at Day 0 is time frame. For cohorts 2-3, sweat chloride averaged across all 3 visits at days 0, 14 and 90 is time frame.
6 Month Change in FEV1 Percent Predicted (Part B Only)	This is the primary endpoint for Part B per the PROSPECT protocol. Change in FEV1 Percent Predicted is only relevant for Part B as it captures changes in lung function post-initiation of Ivacaftor/Lumacaftor.	Baseline and 6 months

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Cystic Fibrosis Foundation

Publications and helpful links

General Publications

• Sagel SD, Khan U, Heltshe SL, Clancy JP, Borowitz D, Gelfond D, Donaldson SH, Moran A, Ratjen F, VanDalfsen JM, Rowe SM. Clinical Effectiveness of Lumacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR. A Clinical Trial. Ann Am Thorac Soc. 2021 Jan;18(1):75-83. doi: 10.1513/AnnalsATS.202002-144OC.

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): April 25, 2018
• Study Completion (Actual): July 27, 2018

Study Registration Dates

• First Submitted: May 22, 2015
• First Submitted That Met QC Criteria: June 19, 2015
• First Posted (Estimate): June 22, 2015

Study Record Updates

• Last Update Posted (Actual): May 20, 2020
• Last Update Submitted That Met QC Criteria: May 12, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: PROSPECT