Pilot Study Testing the Effect of Ivacaftor on Lung Function in Subjects With Cystic Fibrosis and Residual CFTR Function

• ClinicalTrials.gov Identifier: NCT01685801
• Recruitment Status: Completed
• First Posted: September 14, 2012
• Results First Posted: May 19, 2015
• Last Update Posted: May 19, 2015
• Sponsor: Vertex Pharmaceuticals Incorporated
• Information provided by (Responsible Party): Vertex Pharmaceuticals Incorporated

Study Description

Brief Summary:

This study is a multiple within participant crossover study to evaluate the effect of ivacaftor on lung function in participants aged 12 years and older with cystic fibrosis (CF) who have phenotypic or molecular evidence of residual CF transmembrane conductance regulator (CFTR) function.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Drug: Ivacaftor; Drug: Placebo-matched-to-ivacaftor tablet	Phase 2

Detailed Description:

CFTR Mutations associated with residual function or defective messenger ribonucleic acid (mRNA) splicing include the following:

R117H, E56K, P67L, D110E, D110H, R117C, R347H, R352Q, A455E, D579G, S945L, L206W, R1070W, F1074L, D1152H, S1235R, D1270N, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1898+1G->A, 1717-1G->A, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G/A 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, 621+3A->G, 621+1G->T.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: A Pilot Study Testing the Effect of Ivacaftor on Lung Function in Subjects With Cystic Fibrosis, Residual CFTR Function, and FEV1 ≥40% Predicted
• Study Start Date: September 2012
• Actual Primary Completion Date: April 2014
• Actual Study Completion Date: April 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ivacaftor, Placebo, Ivacaftor, Placebo (IPIP); During the Crossover Period, study drug was administered in 2-week alternating cycles with a minimum of 4-week washout period between Cycle 1 [(Period 1 - Day 1 to 14) (Period 2 - Day 15 to 29)] and Cycle 2 [(Period 1 - Day 1 to 14) (Period 2 - Day 15 to 29)] and between Cycle 2 and the Open-label Period (Day 1 to 57). During the Open-label Period, all participants received ivacaftor.	Drug: Ivacaftor; 150 milligram (mg) tablet orally every 12 hours up to 12 weeks.; Other Name: Kalydeco, VX-770; Drug: Placebo-matched-to-ivacaftor tablet; Orally every 12 hours up to 4 weeks.
Experimental: Ivacaftor, Placebo, Placebo, Ivacaftor (IPPI); During the Crossover Period, study drug was administered in 2-week alternating cycles with a minimum of 4-week washout period between Cycle 1 [(Period 1 - Day 1 to 14) (Period 2 - Day 15 to 29)] and Cycle 2 [(Period 1 - Day 1 to 14) (Period 2 - Day 15 to 29)] and between Cycle 2 and the Open-label Period (Day 1 to 57). During the Open-label Period, all participants received ivacaftor.	Drug: Ivacaftor; 150 milligram (mg) tablet orally every 12 hours up to 12 weeks.; Other Name: Kalydeco, VX-770; Drug: Placebo-matched-to-ivacaftor tablet; Orally every 12 hours up to 4 weeks.
Experimental: Placebo, Ivacaftor, Ivacaftor, Placebo (PIIP); During the Crossover Period, study drug was administered in 2-week alternating cycles with a minimum of 4-week washout period between Cycle 1 [(Period 1 - Day 1 to 14) (Period 2 - Day 15 to 29)] and Cycle 2 [(Period 1 - Day 1 to 14) (Period 2 - Day 15 to 29)] and between Cycle 2 and the Open-label Period (Day 1 to 57). During the Open-label Period, all participants received ivacaftor.	Drug: Ivacaftor; 150 milligram (mg) tablet orally every 12 hours up to 12 weeks.; Other Name: Kalydeco, VX-770; Drug: Placebo-matched-to-ivacaftor tablet; Orally every 12 hours up to 4 weeks.
Experimental: Placebo, Ivacaftor, Placebo, Ivacaftor (PIPI); During the Crossover Period, study drug was administered in 2-week alternating cycles with a minimum of 4-week washout period between Cycle 1 [(Period 1 - Day 1 to 14) (Period 2 - Day 15 to 29)] and Cycle 2 [(Period 1 - Day 1 to 14) (Period 2 - Day 15 to 29)] and between Cycle 2 and the Open-label Period (Day 1 to 57). During the Open-label Period, all participants received ivacaftor.	Drug: Ivacaftor; 150 milligram (mg) tablet orally every 12 hours up to 12 weeks.; Other Name: Kalydeco, VX-770; Drug: Placebo-matched-to-ivacaftor tablet; Orally every 12 hours up to 4 weeks.

Outcome Measures

Primary Outcome Measures :

1. Cycle 1 and Cycle 2: Absolute Change From Cycle Baseline In Percent Predicted Forced Expiratory Volume In 1 Second (FEV1) After 2 Weeks of Treatment [ Time Frame: Cycle 1 baseline, Cycle 1 Day 15 (for Cycle 1 reporting arms); Cycle 2 baseline, Cycle 2 Day 15 (for Cycle 2 reporting arms) ]
   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Data was to be reported for each cycle (Cycle 1 and Cycle 2) and as per drug treatment, for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Secondary Outcome Measures :

1. Cycle 1 and Cycle 2: Absolute Change From Cycle Baseline In Lung Clearance Index (LCI) After 2 Weeks of Treatment [ Time Frame: Cycle 1 baseline, Cycle 1 Day 15 (for Cycle 1 reporting arms); Cycle 2 baseline, Cycle 2 Day 15 (for Cycle 2 reporting arms) ]
   LCI is a measure of ventilation inhomogeneity that is derived from a multiple-breath washout test. The LCI was calculated as the number of lung volume turnovers (cumulative expired volume divided by the functional residual capacity [FRC]) required to reduce end-tidal concentration of an inert gas to 1/40th of the starting value. Data was to be reported for each cycle (Cycle 1 and Cycle 2) and as per drug treatment. Data was to be reported for each cycle (Cycle 1 and Cycle 2) and as per drug treatment, for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).
2. Open-label Period: Absolute Change From Open-label Baseline In Percent Predicted Forced Expiratory Volume In 1 Second (FEV1) at Day 57 [ Time Frame: Open-label Baseline, Open-label Day 57 ]
   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Data was to be reported for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).
3. Open-label Period: Absolute Change From Open-label Baseline In Lung Clearance Index (LCI) at Day 57 [ Time Frame: Open-label Baseline, Open-label Day 57 ]
   LCI is a measure of ventilation inhomogeneity that is derived from a multiple-breath washout test. The LCI was calculated as the number of lung volume turnovers (cumulative expired volume divided by the functional residual capacity [FRC]) required to reduce end-tidal concentration of an inert gas to 1/40th of the starting value. Data was to be reported for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).
4. Open-label Period: Absolute Change From Study Baseline In Sweat Chloride at Day 57 [ Time Frame: Study Baseline, Open-label Day 57 ]
   Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Data was to be reported for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).
5. Open-label Period: Absolute Change From Open-label Baseline In Weight at Day 57 [ Time Frame: Open-label Baseline, Open-label Day 57 ]
   Data was to be reported for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).
6. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From first dose of study drug through completion of follow-up visit (up to 26 weeks) ]
   Adverse events (AEs) that started (or increased in severity) from first dose of study drug through completion of Follow-up were considered TEAEs, with exception that if an AE started during a Washout Period and was beyond 14 days from last dose date of preceding cycle, AE was considered as a "Washout Period" AE, and hence not TEAE. A TEAE was attributed to treatment in which it started or to the treatment in second cycling period of previous Crossover Period if it started during a Washout Period. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Data was to be reported by drug treatment for double-blind crossover period (Cycle 1 up to Washout Period 2) and open-label period.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Male or female participants with confirmed diagnosis of CF
• Clinical evidence of residual CFTR function based on any 1 of the following: 1) Clinically documented residual exocrine pancreatic function, 2) Sweat chloride value less than equal to (<=) 80 millimole per liter (mmol/L) at screening, or 3) Age of diagnosis greater than equal to (>=) 12 years and at least 1 copy of a CFTR mutation associated with residual CFTR function or defective mRNA splicing
• FEV1 >= 40 percent (%)
• 12 years of age or older
• Willing to agree to meet the contraception requirements
• Able to swallow tablets

Exclusion Criteria:

• A copy of any of the following CFTR mutations: G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, or G1349D
• Unable to perform spirometry
• An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1
• Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening

Contacts and Locations

Locations

United States, Colorado

Denver, Colorado, United States

Sponsors and Collaborators

Vertex Pharmaceuticals Incorporated

Investigators

• Principal Investigator: Jerry Nick, MD; National Jewish Health

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nick JA, St Clair C, Jones MC, Lan L, Higgins M; VX12-770-113 Study Team. Ivacaftor in cystic fibrosis with residual function: Lung function results from an N-of-1 study. J Cyst Fibros. 2020 Jan;19(1):91-98. doi: 10.1016/j.jcf.2019.09.013. Epub 2019 Nov 26.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT01685801
• Other Study ID Numbers: VX12-770-113
• First Posted: September 14, 2012
• Results First Posted: May 19, 2015
• Last Update Posted: May 19, 2015
• Last Verified: April 2015

Additional relevant MeSH terms:

Cystic Fibrosis; Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Ivacaftor; Chloride Channel Agonists; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action