Trikafta in Cystic Fibrosis Patients

iPS Cell Response to CFTR Modulators: Study of Trikafta in CF Patients Carrying Partial Function Mutations or N1303K CFTR

This clinical study will enroll 42 participants without the F508del mutation, carrying partial function or N1303K mutations not approved for Trikafta, and who are not expected to be approved for CFTR modulator treatment in the immediate future. Each participant will be given Trikafta for approximately four weeks. The study researchers will monitor clinical endpoints that include forced expiratory volume (FEV1) and sweat chloride. Additionally, the researchers will obtain skin biopsy material and/or blood sample from each subject so that induced pluripotent stem (iPS) cells can be modified into airway cell monolayers and tested for response to Trikafta. In this way, the study will evaluate an emerging and readily accessible in vitro endpoint as a predictor of clinical response. This study will serve as a pilot/test case for other clinical protocols relevant to patients with rare CFTR variants who do not currently receive modulator therapies.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Trikafta

Detailed Description

Cystic Fibrosis (CF) is a life threatening genetic disorder resulting from mutations found in the gene known as the cystic fibrosis transmembrane conductance regulator (CFTR). Defects in this gene prevent correct chloride and bicarbonate transport in and out of cells. It has become increasingly important to develop new in vitro model systems capable of predicting in vivo clinical effectiveness of modulator therapy among patients with CF. This objective represents a significant and unmet need for advancing personalized therapeutics in the disease.

Trikafta is currently approved for patients with CF carrying at least one copy of the common F508del variant and over 250 other CFTR abnormalities. Because approximately 90% of CF patients in the United States meet these criteria, pharmacotherapies (Trikafta in particular) are now available to a sizable majority of those with the disease. However, thousands of patients harboring relatively common variants will remain without effective drug therapy. Others with ultra-rare or private CFTR mutations have forms of the disease that are very likely to benefit from available drugs, but do not have access to these therapies. It has been estimated that over 1,000 CFTR mutations are represented by less than 5 patients each. Establishing processes so that individuals with very rare and/or poorly characterized alleles can gain access to effective modulator treatment remains one of the predominant challenges in the field.

This clinical study will enroll 42 participants without the F508del mutation, carrying partial function or N1303K mutations not approved for Trikafta. Substudy 1 will comprise an open-label, two center trial of orally administered elexacaftor, tezacaftor and ivacaftor (Trikafta) that will enroll 22 patients with rare/orphan genotypes. Substudy 2 will enroll 20 participants who encode the N1303K variant as emblematic of a mutation not approved for Trikafta, but are likely to respond to the treatment.

Each participant will have clinical and/or preclinical evidence that Trikafta should offer benefit, and each will be given Trikafta for approximately four weeks. The researchers will monitor clinical endpoints that include FEV1, sweat chloride, quality of life, and weight. The study will differentiate iPS cells from each subject to generate airway epithelial monolayers that can be tested for response to Trikafta. This trial will serve as a pilot/test case for other clinical protocols relevant to patients with rare CFTR variants and evidence of residual function who do not have an approved modulator therapy, due to rarity of their mutation. It is hypothesized that a correlation will be established between in vitro Trikafta responsiveness of iPS cells and in vivo benefit (FEV1) in patients, and provide a tool for utilizing iPS cells to identify rare CF patient populations most suitable for cystic fibrosis modulator therapy.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama Cystic Fibrosis Research Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Children's Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Provision of signed and dated informed consent form or assent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male or female age ≥12
• A clinical diagnosis of CF or CFTR-related disease and either: 1) evidence for a partial function mutation not currently covered or likely to be covered for treatment with a CFTR modulator (Substudy 1), or 2) N1303K CFTR and a minimal function mutation (Substudy 2)
• Sweat Chloride < 80 mmol/L and/or pancreatic sufficiency (no exogenous pancreatic enzyme supplement therapy) or carrying the N1303K CFTR variant
• Able to perform spirometry meeting American Thoracic Society (ATS) criteria for acceptability and repeatability
• Clinically stable in the past 4 weeks with no evidence of CF exacerbation (prior to screening and study Day 1)
• Willingness to use at least one form of acceptable birth control including abstinence or condom with spermicide. This will include birth control for at least one month prior to screening and agreement to use such a method during study participation for an additional four weeks after the last administration of study drug
• Ability to take Trikafta
• Agreement to adhere to all current medical therapies as designated by the CF care center physician

Exclusion Criteria:

• Documented history of drug or alcohol abuse within the last year
• Subjects should not have a pulmonary exacerbation or changes in therapy for pulmonary disease in the 4 weeks prior to screening
• Listed for lung or liver transplant at the time of screening
• Cirrhosis or elevated liver transaminases > 3 times the upper limit of normal
• Pregnant or breastfeeding
• Inhibitors or inducers of CYP3A4, including certain herbal medications and grapefruit/grapefruit juice, or other medicines known to negatively influence Trikafta administration
• History of solid organ transplant
• Active therapy for non-tuberculosis mycobacterial infection or any plan to initiate non-tuberculosis mycobacterial therapies during the study period
• Known allergy to Trikafta
• Treatment in the last 6 months with an approved CFTR modulator
• Any other condition that in the opinion of the lead investigators might confound results of the study or pose an additional risk from administering study drug
• Treatment with another investigational drug or other intervention within one month prior to enrollment, throughout the duration of study participation, and for an additional four weeks following final drug administration
• Evidence of cataract/lens opacity determined to be clinically significant by an ophthalmologist at or within 3 months prior to the Screening Visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Substudy 1 - Participants With Evidence of Partial Function; Participants with CF with evidence of partial function (sweat chloride < 80 milliequivalents per liter (mEq/L) or pancreatic sufficiency) will receive Trikafta for 28 days.	Drug: Trikafta; Participants will take Trikafta which is a combination tablet comprised of 100 milligrams (mg) of elexacaftor, 50 mg of tezacaftor and 75 mg of ivacaftor (2 tablets taken in the morning), and 150 mg of ivacaftor taken in the evening.; Other Names: ivacaftor; elexacaftor; tezacaftor
Experimental: Substudy 2 - Participants who Encode the N1303K Variant; Participants with CF who encode the N1303K variant will receive Trikafta for 28 days.	Drug: Trikafta; Participants will take Trikafta which is a combination tablet comprised of 100 milligrams (mg) of elexacaftor, 50 mg of tezacaftor and 75 mg of ivacaftor (2 tablets taken in the morning), and 150 mg of ivacaftor taken in the evening.; Other Names: ivacaftor; elexacaftor; tezacaftor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Predicted Forced Expiratory Volume in One Second (FEV1) Among Participants With Evidence of Partial Function	FEV1 provides a direct measurement of patient health among individuals with cystic fibrosis and declines in FEV1 are associated with poor outcomes among those with CF. FEV1 is measured by spirometry and is the maximum amount of air the participant can blow out in one second.	Baseline, Day 28
Sweat Chloride Among Participants Who Encode the N1303K Variant	Persons with CF have higher levels of chloride in their sweat. Sweat chloride concentrations of less than or equal to 29 mmol/L are considered normal, concentrations of 30-59 mmol/L are considered intermediate and indicate that the individual may have CF. Concentrations of 60 mmol/L and greater mean that a diagnosis of CF is likely.	Baseline, Day 28
Number of Participants With Induced Pluripotent Stem (iPS) Cells Predicting Response to Treatment Among Participants With Evidence of Partial Function	Response of iPS cells (iPSc) to treatment among participants with evidence of partial function was examined to determine whether iPS derived monolayers could predict "personalized" clinical benefit. Cutaneous punch biopsy material was collected from each participant so that iPS cells could be differentiated into airway epithelial monolayers and tested for response to treatment in vitro - as a potential way to predict improvement from Trikafta in vivo.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Predicted Forced Expiratory Volume in One Second (FEV1) Among Participants Who Encode the N1303K Variant	FEV1 provides a direct measurement of patient health among individuals with cystic fibrosis and declines in FEV1 are associated with poor outcomes among those with CF. FEV1 is measured by spirometry and is the maximum amount of air the participant can blow out in one second.	Baseline, Day 28
Sweat Chloride Among Participants With Evidence of Partial Function	Persons with CF have higher levels of chloride in their sweat. Sweat chloride concentrations of less than or equal to 29 mmol/L are considered normal, concentrations of 30-59 mmol/L are considered intermediate and indicate that the individual may have CF. Concentrations of 60 mmol/L and greater mean that a diagnosis of CF is likely.	Baseline, Day 28
Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score	Participants take the CFQ-R corresponding to their age for assessing quality of life. Responses to questions are coded as 1 = very true or always, 2 = mostly true or often, 3 = somewhat true or sometimes, and 4 = not at all true or never. Some items are reverse scored so that higher scores indicate increased ability and higher quality of life. Scores for items in the respiratory domain are summed and standardized and the standardized score ranges from 1 to 100. A minimum clinically important difference (MCID) of 4 or more points represents improved respiratory-related quality of life.	Baseline, Day 28
Weight	Weight is measured in kilograms.	Baseline, Day 28
Body Mass Index (BMI)	Body mass index is calculated as weight in kilograms divided by height in meters squared.	Baseline, Day 28
Number of Participants With iPS Cells Predicting Response to Treatment Among Participants Encoding N1303K	Cutaneous punch biopsy material was collected from each participant so that iPS cells could be differentiated into airway epithelial monolayers and tested for response to treatment in vitro - i.e., as a potential way to predict benefit from Trikafta in vivo. By using iPS cells differentiated to exhibit a respiratory epithelial phenotype, the study aims to determine whether iPScs can be used to predict clinical improvement due to Trikafta.	Baseline

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: The University of Texas Health Science Center, Houston; National Heart, Lung, and Blood Institute (NHLBI); Cystic Fibrosis Foundation
• Investigators: Principal Investigator: Eric Sorscher, MD, Emory University

Publications and helpful links

General Publications

• Solomon GM, Linnemann RW, Rich R, Streby A, Buehler B, Hunter E, Vijaykumar K, Hunt WR, Brewington JJ, Rab A, Bai SP, Westbrook AL, McNicholas-Bevensee C, Hong J, Manfredi C, Barilla C, Suzuki S, Davis BR, Sorscher EJ. Evaluation of elexacaftor-tezacaftor-ivacaftor treatment in individuals with cystic fibrosis and CFTRN1303K in the USA: a prospective, multicentre, open-label, single-arm trial. Lancet Respir Med. 2024 Dec;12(12):947-957. doi: 10.1016/S2213-2600(24)00205-4. Epub 2024 Aug 26.

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2019
• Primary Completion (Actual): February 13, 2024
• Study Completion (Actual): February 13, 2024

Study Registration Dates

• First Submitted: April 13, 2018
• First Submitted That Met QC Criteria: April 13, 2018
• First Posted (Actual): April 23, 2018

Study Record Updates

• Last Update Posted (Estimated): September 11, 2025
• Last Update Submitted That Met QC Criteria: August 22, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Infant, Newborn, Diseases; Pancreatic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Chloride Channel Agonists; elexacaftor, ivacaftor, tezacaftor drug combination; elexacaftor; tezacaftor; ivacaftor
• Other Study ID Numbers: IRB00108656; 300001205 (Other Identifier: University of Alabama); R01HL139876 (U.S. NIH Grant/Contract)

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