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Safety Study of Ivacaftor in Subjects With Cystic Fibrosis

Primary Purpose

Cystic Fibrosis

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Ivacaftor 25 mg/75 mg

Ivacaftor 75 mg/150 mg

Ivacaftor 150 mg or 250 mg

Placebo

About this trial

This is an interventional treatment trial for Cystic Fibrosis focused on measuring G551D mutation, Fibrosis, Pancreatic Diseases, Digestive System Diseases, Lung Diseases, Respiratory Tract Diseases, Genetic Diseases, Inborn, Infant, Newborn, Diseases, Pathologic Processes

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Weighing at least 40 kg
Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele
Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height
Willing to remain on stable medication regimen for the duration of study participation
No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of the study
No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator

Exclusion Criteria:

History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject
Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study
History of alcohol, medication or illicit drug abuse within one year prior to Day 1
Abnormal liver function ≥ 3x the upper limit of normal
History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation)
History of solid organ or hematological transplantation
Pregnant or breast-feeding (for women)
Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout
Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4)

Sites / Locations

University of Alabama Hospital
Stanford University Medical Center
The Children's Hospital
Roy J. and Lucille A. Carver College of Medicine, The University of Iowa
Johns Hopkins Hospital
Pulmonary and Critical Care Medicine, Massachusetts General Hospital
Children's Hospital of Boston
Division of Pulmonary, Allergy and Critical Care Medicine, University of Minnesota
Cystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill
Rainbow Babies and Children's Hospital
The Children's Hospital of Philadelphia
University of Pittsburgh
Pulmonary Critical Care, University of Washington
Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children
CF Clinic, Pediatric Pulmonology and Neonatology, Medical School of Hannover

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Arm Label

Ivacaftor Group A

Ivacaftor Group B

Ivacaftor Group C

Placebo

Arm Description

Subjects in Part 1 who first received 25 mg or 75 mg of ivacaftor every 12 hours (q12h) for 14 days, then crossed over to receive the alternate dose for another 14 days.

Subjects in Part 1 who first received 75 mg or 150 mg of ivacaftor q12h for 14 days then crossed over to receive the alternate dose for another 14 days.

Subjects in Part 2 who received 150 mg or 250 mg of ivacaftor q12h for 28 days.

Subjects who received placebo in Part 1 and subjects who received placebo in Part 2.

Outcomes

Primary Outcome Measures

Number of Subjects With Adverse Events (Combined Part 1 and Part 2)

Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.

Number of Adverse Events (Combined Part 1 and Part 2)

Secondary Outcome Measures

Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2)

The transepithelial nasal potential difference (NPD) is a direct measure of transepithelial ion transport. NPD under conditions of zero chloride concentration perfusion solution in the presence of isoproterenol was of primary interest.

Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2)

Spirometry is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. Relative change reflects the percent change from the baseline values [100% * (X-Y)/Y], where X and Y are post-baseline and baseline values, respectively.

Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score)

The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID).

Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2)

The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.

Full Information

NCT ID

NCT00457821

First Posted

April 5, 2007

Last Updated

October 3, 2012

Sponsor

Vertex Pharmaceuticals Incorporated

Collaborators

Cystic Fibrosis Foundation

1. Study Identification

Unique Protocol Identification Number

NCT00457821

Brief Title

Safety Study of Ivacaftor in Subjects With Cystic Fibrosis

Official Title

A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study of VX-770 to Evaluate Safety, Pharmacokinetics, and Biomarkers of CFTR Activity in Cystic Fibrosis (CF) Subjects With Genotype G551D

Study Type

Interventional

2. Study Status

Record Verification Date

October 2012

Overall Recruitment Status

Completed

Study Start Date

May 2007 (undefined)

Primary Completion Date

August 2008 (Actual)

Study Completion Date

August 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Vertex Pharmaceuticals Incorporated

Collaborators

Cystic Fibrosis Foundation

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study was to evaluate the safety and tolerability of ivacaftor in patients with cystic fibrosis (CF) who were aged 18 years or older and have a G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. Potentiators are pharmacological agents that increase the chloride ion transport properties of the channel in the presence of cyclic AMP-dependent protein kinase A (PKA) activation.

Detailed Description

This was a double-blind, placebo-controlled, cross-over, multiple dose study of up to 28 days of dosing, in subjects with cystic fibrosis (CF) who have a G551D-CTFR gene mutation. Enrollment of 39 subjects occurred at 15 centers in the US, Canada, and Germany. The study was conducted in 2 parts: Part 1 consisted of Group A and Group B. Subjects in Group A (10 subjects) were randomized to receive 25 mg of ivacaftor every 12 hours [q12h] (4 subjects), 75 mg of ivacaftor q12h (4 subjects), or placebo (2 subjects) for 14 days. Following a 7- to 28-day washout period, subjects who received active study drug crossed over to the alternate dose strength of ivacaftor for an additional 14 days. Placebo subjects continued to receive placebo for an additional 14 days. Subjects in Group B (10 subjects) were randomized to receive 75 mg of ivacaftor q12h (4 subjects), 150 mg of ivacaftor q12h (4 subjects), or placebo (2 subjects) for 14 days. Following a 7- to 28-day washout period, the subjects who received active study drug crossed over to the alternate dose strength of ivacaftor for an additional 14 days. Placebo subjects continued to receive placebo for an additional 14 days. Part 2 consisted of Group C; these subjects did not participate in Part 1. Subjects were randomized to receive 150 mg of ivacaftor q12h (7 subjects), 250 mg of ivacaftor q12h (7 subjects), or placebo (4 subjects) for a total of 28 days. Ivacaftor doses studied in Part 2 were selected following an interim pharmacokinetic/pharmacodynamic (PK/PD) and statistical analyses of data from Part 1. The 2 doses selected for Part 2 were anticipated to enable better definition of the optimal therapeutic dose.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cystic Fibrosis

Keywords

G551D mutation, Fibrosis, Pancreatic Diseases, Digestive System Diseases, Lung Diseases, Respiratory Tract Diseases, Genetic Diseases, Inborn, Infant, Newborn, Diseases, Pathologic Processes

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

39 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ivacaftor Group A

Arm Type

Experimental

Arm Description

Subjects in Part 1 who first received 25 mg or 75 mg of ivacaftor every 12 hours (q12h) for 14 days, then crossed over to receive the alternate dose for another 14 days.

Arm Title

Ivacaftor Group B

Arm Type

Experimental

Arm Description

Subjects in Part 1 who first received 75 mg or 150 mg of ivacaftor q12h for 14 days then crossed over to receive the alternate dose for another 14 days.

Arm Title

Ivacaftor Group C

Arm Type

Experimental

Arm Description

Subjects in Part 2 who received 150 mg or 250 mg of ivacaftor q12h for 28 days.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Subjects who received placebo in Part 1 and subjects who received placebo in Part 2.

Intervention Type

Drug

Intervention Name(s)

Ivacaftor 25 mg/75 mg

Other Intervention Name(s)

VX-770

Intervention Description

25 mg or 75 mg q12h for a total of 28 days (Part 1)

Intervention Type

Drug

Intervention Name(s)

Ivacaftor 75 mg/150 mg

Other Intervention Name(s)

VX-770

Intervention Description

75 mg or 150 mg q12h for a total of 28 days (Part 1)

Intervention Type

Drug

Intervention Name(s)

Ivacaftor 150 mg or 250 mg

Other Intervention Name(s)

VX-770

Intervention Description

150 mg or 250 mg of ivacaftor q12h for 28 days (Part 2)

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Given q12h for 28 days each in Part 1 and Part 2 of the study

Primary Outcome Measure Information:

Title

Number of Subjects With Adverse Events (Combined Part 1 and Part 2)

Description

Time Frame

Baseline to Follow-up

Title

Number of Adverse Events (Combined Part 1 and Part 2)

Description

Time Frame

Baseline to Follow-up

Secondary Outcome Measure Information:

Title

Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2)

Description

Time Frame

14 days and 28 days

Title

Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2)

Description

Time Frame

14 days and 28 days

Title

Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score)

Description

Time Frame

14 days and 28 days

Title

Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2)

Description

Time Frame

14 days and 28 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Weighing at least 40 kg Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height Willing to remain on stable medication regimen for the duration of study participation No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of the study No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study History of alcohol, medication or illicit drug abuse within one year prior to Day 1 Abnormal liver function ≥ 3x the upper limit of normal History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation) History of solid organ or hematological transplantation Pregnant or breast-feeding (for women) Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Monitor

Organizational Affiliation

Vertex Pharmaceuticals Incorporated

Official's Role

Study Director

Facility Information:

Facility Name

University of Alabama Hospital

City

Birmingham

State/Province

Alabama

ZIP/Postal Code

35211

Country

United States

Facility Name

Stanford University Medical Center

City

Palo Alto

State/Province

California

ZIP/Postal Code

34304

Country

United States

Facility Name

The Children's Hospital

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

Roy J. and Lucille A. Carver College of Medicine, The University of Iowa

City

Iowa City

State/Province

Iowa

ZIP/Postal Code

52242-1083

Country

United States

Facility Name

Johns Hopkins Hospital

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21287

Country

United States

Facility Name

Pulmonary and Critical Care Medicine, Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Facility Name

Children's Hospital of Boston

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

Division of Pulmonary, Allergy and Critical Care Medicine, University of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

Facility Name

Cystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27599

Country

United States

Facility Name

Rainbow Babies and Children's Hospital

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44106

Country

United States

Facility Name

The Children's Hospital of Philadelphia

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104-4399

Country

United States

Facility Name

University of Pittsburgh

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15213

Country

United States

Facility Name

Pulmonary Critical Care, University of Washington

City

Seattle

State/Province

Washington

ZIP/Postal Code

98195

Country

United States

Facility Name

Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 1X8

Country

Canada

Facility Name

CF Clinic, Pediatric Pulmonology and Neonatology, Medical School of Hannover

City

Strasse

State/Province

Hannover

ZIP/Postal Code

D-30625

Country

Germany

12. IPD Sharing Statement

Citations:

PubMed Identifier

21083385

Citation

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.

Results Reference

result

PubMed Identifier

24660233

Citation

Accurso FJ, Van Goor F, Zha J, Stone AJ, Dong Q, Ordonez CL, Rowe SM, Clancy JP, Konstan MW, Hoch HE, Heltshe SL, Ramsey BW, Campbell PW, Ashlock MA. Sweat chloride as a biomarker of CFTR activity: proof of concept and ivacaftor clinical trial data. J Cyst Fibros. 2014 Mar;13(2):139-47. doi: 10.1016/j.jcf.2013.09.007.

Results Reference

derived

Links:

URL

http://ghr.nlm.nih.gov/

Description

Genetics Home Reference

URL

http://www.nlm.nih.gov/medlineplus/

Description

Medline Plus

URL

http://www.clinicaltrials.gov/ct2/info/fdalinks

Description

U.S. FDA Resources

Learn more about this trial

Safety Study of Ivacaftor in Subjects With Cystic Fibrosis

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