Cystic Fibrosis Related Bone Disease: the Role of CFTR

The purpose of this study is to determine whether ivacaftor, a recently FDA-approved CFTR potentiator, improves bone micro-architecture and strength in patients with cystic fibrosis with at least one G551D CFTR mutation.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis Related Bone Disease

Detailed Description

Ivacaftor, a CFTR potentiator, has recently been FDA approved for the treatment of cystic fibrosis in patients with at least one G551D CFTR mutation. Given the possible role of CFTR in bone, we hypothesize that this medication may also improve bone health in CF patients. The purpose of this study is to test this hypothesis using high resolution peripheral quantitative computed tomography, a research tool that measures bone micro-architecture and volumetric bone density and has the ability to detect small changes in bone that might otherwise be missed with standard bone imaging techniques such as bone density testing.

• Study Type: Observational
• Enrollment (Actual): 79

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Subjects with CF will be recruited from the Cystic Fibrosis Centers at Children's Hospital Boston and Massachusetts General Hospital. Healthy subjects will be a community sample recruited from nearby communities.

Description

COHORT 1

Inclusion Criteria:

• Age 6 to 75 years old
• Established diagnosis of CF with at least one abnormal G551D-CFTR allele
• Eligibility for and intent to start treatment with ivacaftor or started treatment with ivacaftor within previous 6 months

Exclusion Criteria:

• Psychiatric or mental incapacity that would preclude subject from assenting to study participation
• Current pregnancy
• History of organ transplantation
• History of Burkholderia dolosa infection

COHORT 2:

Subjects will be grouped by gender, age and race to match subjects in Cohort 1 within two years. Pubertal subjects will be matched by Tanner stage.

Inclusion Criteria:

• Age 6 to 75 years old
• Established diagnosis of CF

Exclusion Criteria:

• Psychiatric or mental incapacity that would preclude subject from assenting to study participation
• Current pregnancy
• History of organ transplantation
• History of Burkholderia dolosa infection

COHORT 3:

Subjects will be grouped by gender, age and race to match subjects in Cohort 2 within two years. Pubertal subjects will be matched by Tanner stage.

Inclusion criteria:

• Age 6 to 75 years old
• Clinically stable, deemed able to complete the screening, baseline, and scheduled study visits.

Exclusion criteria:

• History of significant cardiac, renal, pulmonary, hepatic, or malignant disease, current alcohol or illicit drug abuse, or major psychiatric disorder
• Current diagnoses known to affect bone metabolism, including cystic fibrosis, osteoporosis, amenorrhea >3 months (in menstruating women who are not taking oral contraceptives or have an IUD), hyperthyroidism, diabetes, hyperparathyroidism, Paget's disease, kidney stones, chronic inflammatory diseases, malabsorptive disorders, malnutrition, prolonged immobility, and skeletal dysplasias
• History of a non-digital fracture in the previous 6 months, history of one pathologic fracture, or greater than four total lifetime non-digital fractures
• Cumulative lifetime use of oral glucocorticoids for greater than 2 months
• Current or prior use of medications known to affect bone metabolism including hormone replacement therapy, anti-estrogens, bisphosphonates, calcitonin, fluoride, lithium, suppressive doses of levothyroxine, or anticonvulsants.
• Pregnancy
• BMI less than 18.5 or greater than 30 kg/m2 in subjects 18 years and older, or BMI less than 5th or greater than 95th percentile in subjects under the age of 18 years.
• Any medical or psychiatric condition or situation that would compromise subject safety, informed consent/assent, treatment compliance, follow-up measurements, or data quality

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Subjects with CF taking ivacaftor; Subjects with CF ages 6 to 75 years old who will be or have started taking ivacaftor within the previous 6 months
Subjects with CF not taking ivacaftor; Subjects with CF ages 6 to 75 years old who will not be taking ivacaftor, matched for age, race, and gender with cohort 1
Healthy subjects; Healthy subjects with no medical conditions known to affect bone between the ages of 6 to 75 years old, matched for age, race, and gender with cohort 2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone Microarchitecture and Strength Measures of the Radius and Tibia	Change in cortical volumetric bone mineral density at the radius	Baseline and 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Areal Bone Mineral Density as Measured by DXA	Change in PA spine bone mineral density	Baseline and 24 months
Bone Turnover Markers	Change in osteocalcin	Baseline and 24 months

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Boston Children's Hospital
• Investigators: Principal Investigator: Joel Finkelstein, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Aris RM, Merkel PA, Bachrach LK, Borowitz DS, Boyle MP, Elkin SL, Guise TA, Hardin DS, Haworth CS, Holick MF, Joseph PM, O'Brien K, Tullis E, Watts NB, White TB. Guide to bone health and disease in cystic fibrosis. J Clin Endocrinol Metab. 2005 Mar;90(3):1888-96. doi: 10.1210/jc.2004-1629. Epub 2004 Dec 21.
• Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordonez C, Elborn JS; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011 Nov 3;365(18):1663-72. doi: 10.1056/NEJMoa1105185.
• Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordonez CL, Campbell PW, Ashlock MA, Ramsey BW. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010 Nov 18;363(21):1991-2003. doi: 10.1056/NEJMoa0909825.
• MacNeil JA, Boyd SK. Accuracy of high-resolution peripheral quantitative computed tomography for measurement of bone quality. Med Eng Phys. 2007 Dec;29(10):1096-105. doi: 10.1016/j.medengphy.2006.11.002. Epub 2007 Jan 16.
• Shead EF, Haworth CS, Condliffe AM, McKeon DJ, Scott MA, Compston JE. Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human bone. Thorax. 2007 Jul;62(7):650-1. doi: 10.1136/thx.2006.075887. No abstract available.
• Putman MS, Greenblatt LB, Bruce M, Joseph T, Lee H, Sawicki G, Uluer A, Sicilian L, Neuringer I, Gordon CM, Bouxsein ML, Finkelstein JS. The Effects of Ivacaftor on Bone Density and Microarchitecture in Children and Adults with Cystic Fibrosis. J Clin Endocrinol Metab. 2021 Mar 8;106(3):e1248-e1261. doi: 10.1210/clinem/dgaa890.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2012
• Primary Completion (Actual): May 1, 2018
• Study Completion (Actual): February 1, 2020

Study Registration Dates

• First Submitted: March 2, 2012
• First Submitted That Met QC Criteria: March 6, 2012
• First Posted (Estimate): March 9, 2012

Study Record Updates

• Last Update Posted (Actual): April 1, 2020
• Last Update Submitted That Met QC Criteria: March 24, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Cystic fibrosis; Ivacaftor; Cystic fibrosis related bone disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Bone Diseases
• Other Study ID Numbers: MGH 2012P000269