Cystic Fibrosis
Conditions
Brief summary
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.
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.
Interventions
DRUGTrikafta
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.
Sponsors
Emory University
National Heart, Lung, and Blood Institute (NHLBI)
Cystic Fibrosis Foundation
The University of Texas Health Science Center, Houston
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Predicted Forced Expiratory Volume in One Second (FEV1) Among Participants With Evidence of Partial Function | Baseline, Day 28 | 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. |
| Sweat Chloride Among Participants Who Encode the N1303K Variant | Baseline, Day 28 | 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. |
| Number of Participants With Induced Pluripotent Stem (iPS) Cells Predicting Response to Treatment Among Participants With Evidence of Partial Function | Baseline | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Predicted Forced Expiratory Volume in One Second (FEV1) Among Participants Who Encode the N1303K Variant | Baseline, Day 28 | 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. |
| Sweat Chloride Among Participants With Evidence of Partial Function | Baseline, Day 28 | 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. |
| Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score | Baseline, Day 28 | 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. |
| Weight | Baseline, Day 28 | Weight is measured in kilograms. |
| Body Mass Index (BMI) | Baseline, Day 28 | Body mass index is calculated as weight in kilograms divided by height in meters squared. |
| Number of Participants Where the Assay Successfully Predicted Treatment Response Using iPS Cells Among Participants Encoding N1303K | Baseline | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATOREric Sorscher, MD
Emory University
Participant flow
Recruitment details
Participants were enrolled at two sites in the United States: The Emory Children's Center in Atlanta, Georgia, and The University of Alabama Cystic Fibrosis Center in Birmingham, Alabama. Participant enrollment began September 4, 2019 and all follow-up assessments were completed by February 13, 2024.
Participants by arm
| Arm | Count |
|---|---|
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) Participants with cystic fibrosis (CF) with evidence of partial function (sweat chloride \< 80 milliequivalents per liter (mEq/L) or pancreatic sufficiency) receiving Trikafta for 28 days. | 22 |
| Participants Who Encode the N1303K Variant Participants with cystic fibrosis (CF) who encode the N1303K variant receiving Trikafta for 28 days. | 20 |
| Total | 42 |
Baseline characteristics
| Characteristic | Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Participants Who Encode the N1303K Variant | Total |
|---|---|---|---|
| Age, Customized 12 to <18 years old | 4 Participants | 8 Participants | 12 Participants |
| Age, Customized 18 or more years old | 18 Participants | 12 Participants | 30 Participants |
| CF Medical History CF-related Diabetes | 3 Participants | 4 Participants | 7 Participants |
| CF Medical History Chronic Sinusitis | 12 Participants | 12 Participants | 24 Participants |
| CF Medical History Pancreatic Insufficiency | 3 Participants | 20 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 18 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Percent of Predicted FEV1 100% or More | 4 Participants | 0 Participants | 4 Participants |
| Percent of Predicted FEV1 50% up to 75% | 4 Participants | 3 Participants | 7 Participants |
| Percent of Predicted FEV1 75% up to 100% | 8 Participants | 13 Participants | 21 Participants |
| Percent of Predicted FEV1 Less than 50% | 6 Participants | 4 Participants | 10 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Southeast Asian | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White or Caucasian | 17 Participants | 18 Participants | 35 Participants |
| Region of Enrollment United States | 22 Participants | 20 Participants | 42 Participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 21 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 20 |
| other Total, other adverse events | 17 / 22 | 14 / 20 |
| serious Total, serious adverse events | 0 / 22 | 1 / 20 |
Outcome results
Primary
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.
Time frame: Baseline
Population: Participants with evidence of partial function were included for the primary outcome measure of examining response of iPS cell derived epithelial monolayers. This analysis includes participants from which samples were successfully obtained, differentiated, and examined using bioelectric measurements.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Number of Participants With Induced Pluripotent Stem (iPS) Cells Predicting Response to Treatment Among Participants With Evidence of Partial Function | 0 Participants |
Primary
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.
Time frame: Baseline, Day 28
Population: The Analysis Population includes the intended use population. Two participants with evidence of partial function were found to have cystic fibrosis transmembrane conductance regulator (CFTR) genotypes that were approved by the FDA to use elexacaftor-tezacaftor-ivacaftor while the study was ongoing; these participants were removed from data analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Percent Predicted Forced Expiratory Volume in One Second (FEV1) Among Participants With Evidence of Partial Function | Baseline | 74.8 percent of predicted FEV1 |
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Percent Predicted Forced Expiratory Volume in One Second (FEV1) Among Participants With Evidence of Partial Function | Day 28 | 76 percent of predicted FEV1 |
Primary
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.
Time frame: Baseline, Day 28
Population: The Analysis Population includes the intended use population.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Sweat Chloride Among Participants Who Encode the N1303K Variant | Baseline | 109 mmol/liter |
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Sweat Chloride Among Participants Who Encode the N1303K Variant | Day 28 | 107.9 mmol/liter |
Secondary
Body Mass Index (BMI)
Body mass index is calculated as weight in kilograms divided by height in meters squared.
Time frame: Baseline, Day 28
Population: The Analysis Population includes the intended use population. Two participants with evidence of partial function were found to have cystic fibrosis transmembrane conductance regulator (CFTR) genotypes that were approved by the FDA to use elexacaftor-tezacaftor-ivacaftor while the study was ongoing; these participants were removed from data analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Body Mass Index (BMI) | Day 28 | 25.7 kg/m^2 |
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Body Mass Index (BMI) | Baseline | 25.4 kg/m^2 |
| Participants Who Encode the N1303K Variant | Body Mass Index (BMI) | Day 28 | 22.5 kg/m^2 |
| Participants Who Encode the N1303K Variant | Body Mass Index (BMI) | Baseline | 22.1 kg/m^2 |
Secondary
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.
Time frame: Baseline, Day 28
Population: The Analysis Population includes the intended use population. Two participants with evidence of partial function were found to have cystic fibrosis transmembrane conductance regulator (CFTR) genotypes that were approved by the FDA to use elexacaftor-tezacaftor-ivacaftor while the study was ongoing; these participants were removed from data analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score | Baseline | 66.4 score on a scale |
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score | Day 28 | 74.1 score on a scale |
| Participants Who Encode the N1303K Variant | Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score | Baseline | 60.6 score on a scale |
| Participants Who Encode the N1303K Variant | Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score | Day 28 | 81.4 score on a scale |
Secondary
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.
Time frame: Baseline
Secondary
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.
Time frame: Baseline, Day 28
Population: The Analysis Population includes the intended use population.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Percent Predicted Forced Expiratory Volume in One Second (FEV1) Among Participants Who Encode the N1303K Variant | Baseline | 75.8 percent predicted FEV1 |
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Percent Predicted Forced Expiratory Volume in One Second (FEV1) Among Participants Who Encode the N1303K Variant | Day 28 | 85.3 percent predicted FEV1 |
Secondary
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.
Time frame: Baseline, Day 28
Population: The Analysis Population includes the intended use population. Two participants with evidence of partial function were found to have cystic fibrosis transmembrane conductance regulator (CFTR) genotypes that were approved by the FDA to use elexacaftor-tezacaftor-ivacaftor while the study was ongoing; these participants were removed from data analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Sweat Chloride Among Participants With Evidence of Partial Function | Baseline | 66.9 mmol/liter |
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Sweat Chloride Among Participants With Evidence of Partial Function | Day 28 | 57.8 mmol/liter |
Secondary
Weight
Weight is measured in kilograms.
Time frame: Baseline, Day 28
Population: The Analysis Population includes the intended use population. Two participants with evidence of partial function were found to have cystic fibrosis transmembrane conductance regulator (CFTR) genotypes that were approved by the FDA to use elexacaftor-tezacaftor-ivacaftor while the study was ongoing; these participants were removed from data analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Weight | Baseline | 75 kilograms |
| Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) | Weight | Day 28 | 75.8 kilograms |
| Participants Who Encode the N1303K Variant | Weight | Baseline | 57.5 kilograms |
| Participants Who Encode the N1303K Variant | Weight | Day 28 | 58.5 kilograms |