A Study of Ataluren in Pediatric Participants With Cystic Fibrosis

Study Overview
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Brief Summary
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In some participants with cystic fibrosis (CF), the disease is caused by a nonsense mutation (premature stop codon) in the gene that makes the cystic fibrosis transmembrane regulator (CFTR) protein. Ataluren has been shown to partially restore CFTR production in animals with CF due to a nonsense mutation. The main purpose of this study is to understand whether ataluren can safely increase functional CFTR protein in the cells of participants with CF due to a nonsense mutation.

Detailed Description
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In this study, participants with CF due to a nonsense mutation will be treated with a new investigational drug called ataluren. Evaluation procedures (history, physical examination, blood and urine tests to assess organ function, electrocardiogram [ECG], chest x-ray, and CF-specific tests) to determine if a participant qualifies for the study will be performed within 21 days prior to the start of treatment. Eligible participants with nonsense-mutation-mediated CF will receive 2 repeated 28-day cycles, each comprising of 14 days on therapy and 14 days off therapy. In a crossover design, participants will be randomized to receive ataluren treatment in Cycle 1 by either of the following regimens: Ataluren, given 3 times per day (TID) with a regimen of 4 milligrams/kilograms (mg/kg) at breakfast, 4 mg/kg at lunch, and 8 mg/kg at dinner, or Ataluren, given 3 TID with a regimen of 10 mg/kg at breakfast, 10 mg/kg at lunch and 20 mg/kg at dinner. In Cycle 2, participants will then receive the drug according to the regimen opposite from that given in Cycle 1. There will be a 2-night stay at the clinical research center at the beginning and at the end of each 14 days of ataluren treatment, which means that there will be four 2-night stays at the clinical research center during the study. During the study, ataluren efficacy, safety, and pharmacokinetics (PK) will be evaluated periodically with measurements of transepithelial potential difference (TEPD), nasal mucosal brushing to assess for cellular CFTR messenger ribonucleic acid (mRNA) and protein, medical history, physical examinations, blood tests, sputum test, urinalysis, ECGs, chest x-ray, and pulmonary function tests. The measurement of TEPD, also known as nasal potential difference, provides a sensitive evaluation of sodium and chloride transport directly in secretory epithelial cells. TEPD assessments are made on the nasal epithelium cells lining the inferior turbinate because these cells are easier to access than the respiratory epithelial cells lining the lower airways and have been shown to have the same ion transport characteristics. As an endpoint, TEPD has the advantage that it can detect chloride transport changes that are a quantitative integration of the presence, functional activity, and apical location of the CFTR in airway cells. Furthermore, it is a direct measure of CFTR activity that is not likely to be affected by supportive or palliative treatments for CF (with the possible exception of systemically administered aminoglycoside antibiotics).

Official Title
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A Phase 2 Study of PTC124 as an Oral Treatment for Nonsense-Mutation-Mediated Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Ataluren


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must meet all of the following conditions to be eligible for enrollment into the study: Diagnosis of CF based on conclusively abnormal sweat test (sweat chloride >35 milliequivalents [mEq]/liter). Abnormal nasal epithelial TEPD total chloride conductance (a more electrically negative value than 5 mV for Δchloride-free+isoproterenol). Presence of a mutation in both alleles. Documentation that a blood sample has been drawn for reconfirmation of the presence of a nonsense mutation in the CFTR gene. Age ≥6 years. Body weight ≥25 kg. FEV1 ≥40% of predicted for age, gender, and height. Oxygen saturation ≥92% on room air. Willingness of male and female participants, if not surgically sterile, to abstain from sexual intercourse or employ a barrier or medical method of contraception during the study drug administration and follow-up periods. Negative pregnancy test (for females of childbearing potential). Willingness and ability to comply with scheduled visits, drug administration plan, study procedures (including TEPD measurements, clinical laboratory tests, pulmonary function tests, and PK sampling), and study restrictions. Ability to provide written informed consent and/or assent. Evidence of signed and dated informed consent document (by the participant or a legal guardian) indicating that the participant and/or the legal guardian has been informed of all pertinent aspects of the trial. Exclusion Criteria: The presence of any of the following conditions will exclude a participant from enrollment in the study: Prior exposure to ataluren. Prior or ongoing medical condition (for example, concomitant illness, alcoholism, drug abuse, psychiatric condition), medical history, physical findings, ECG findings, or laboratory abnormality that, in the Investigator's opinion, could adversely affect the safety of the participant, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results. Ongoing acute illness including acute upper or lower respiratory infections within 2 weeks before start of study treatment. History of major complications of lung disease (including recent massive hemoptysis or pneumothorax) within 2 months prior to start of study treatment. Abnormalities on screening chest x-ray suggesting clinically significant active pulmonary disease other than CF, or new, significant abnormalities such as atelectasis or pleural effusion which may be indicative of clinically significant active pulmonary involvement secondary to CF. Positive hepatitis B surface antigen, hepatitis C antibody test, or human immunodeficiency virus (HIV) test. Hemoglobin <10 grams/deciliter (g/dL). Serum albumin <2.5 g/dL. Abnormal liver function (serum total bilirubin > the upper limit of normal, or serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or gamma-glutamyl transferase (GGT) >2.0 times the upper limit of normal). Abnormal renal function (serum creatinine >1.5 times upper limit of normal). Pregnancy or breast-feeding. History of solid organ or hematological transplantation. Exposure to another investigational drug within 14 days prior to start of study treatment. Ongoing participation in any other therapeutic clinical trial. Ongoing use of thiazolidinedione peroxisome proliferator-activated receptor gamma (PPAR γ) agonists, for example, rosiglitazone (Avandia® or equivalent) or pioglitazone (Actos® or equivalent). Change in intranasal medications (including use of corticosteroids, cromolyn, ipratropium bromide, phenylephrine, or oxymetazoline) within 14 days prior to start of study treatment. Change in treatment with systemic or inhaled corticosteroids within 14 days prior to start of study treatment. Use of or requirement for inhaled gentamicin or amikacin within 14 days prior to start of study treatment or during study treatment. Requirement for systemic aminoglycoside antibiotics within 14 days prior to start of study treatment.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ataluren 4, 4, and 8 mg/kg, then ataluren 10, 10, and 20 mg/kg<br>During Cycle 1, participants will receive ataluren at 4 mg/kg in the morning, 4 mg/kg at midday, and 8 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants will crossover to the other ataluren dose regimen (ataluren 10, 10, and 20 mg/kg) for Cycle 2. | Drug: Ataluren<br>* Ataluren will be provided as a vanilla-flavored powder to be mixed with water, milk, or apple juice. Participants are to receive a total of 42 doses of ataluren during each cycle, for a total of 84 doses of ataluren in both cycles.<br>* Other names: PTC124;|
| Experimental: Ataluren 10, 10, and 20 mg/kg, then ataluren 4, 4, and 8 mg/kg<br>During Cycle 1, participants will receive ataluren at 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants will crossover to the other ataluren dose regimen (ataluren 4, 4, and 8 mg/kg) for Cycle 2. | Drug: Ataluren<br>* Ataluren will be provided as a vanilla-flavored powder to be mixed with water, milk, or apple juice. Participants are to receive a total of 42 doses of ataluren during each cycle, for a total of 84 doses of ataluren in both cycles.<br>* Other names: PTC124;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Chloride Transport at Day 14 of Cycles 1 and 2 | Nasal transepithelial potential difference (TEPD) was assessed in each participant using standardized techniques. Warmed solutions of Ringer's solution, amiloride, chloride-free gluconate, isoproterenol, and adenosine triphosphate (ATP) were perfused for ≥3-minute sequentially through a nasal catheter while a voltage tracing was recorded. Total chloride transport was computed for each nostril. The total chloride transport values were calculated by subtracting the voltages at the end of a perfusion from the voltage at the end of an earlier perfusion (isoproterenol - amiloride). The average of the values for each nostril was computed. If the assessment was available in only 1 nostril, this value was used as if it were the average of both nostrils. Baseline data for Cycle 1 and Cycle 2 and change from Baseline data at Day 14 of Cycles 1 and 2 are presented. | Baseline of Cycle 1 and Cycle 2, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days) | 
| Number of Participants With a Chloride Transport Response at Day 14 of Cycles 1 and 2 | Nasal TEPD was assessed in each participant using standardized techniques. Warmed solutions of Ringer's solution, amiloride, chloride-free gluconate, isoproterenol, and ATP were perfused for ≥3-minute sequentially through a nasal catheter while a voltage tracing was recorded. Total chloride transport was computed for each nostril. The total chloride transport values were calculated by subtracting the voltages at the end of a perfusion from the voltage at the end of an earlier perfusion (isoproterenol - amiloride). The average of the values for each nostril was computed. If the assessment was available in only 1 nostril, this value was used as if it were the average of both nostrils. Response to study treatment defined as an increase in total chloride transport as indicated by a change of at least -5 mV in nasal TEPD. | Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days) | 
| Number of Participants With Normalization of Chloride Transport Between Baseline and Day 14 of Cycles 1 and 2 | Nasal TEPD was assessed in each participant using standardized techniques. Warmed solutions of Ringer's solution, amiloride, chloride-free gluconate, isoproterenol, and ATP were perfused for ≥3-minute sequentially through a nasal catheter while a voltage tracing was recorded. Total chloride transport was computed for each nostril. The total chloride transport values were calculated by subtracting the voltages at the end of a perfusion from the voltage at the end of an earlier perfusion (isoproterenol - amiloride). The average of the values for each nostril was computed. If the assessment was available in only 1 nostril, this value was used as if it were the average of both nostrils. Normalization of chloride transport (normal range [NR]) was defined as nasal TEPD that was at least as electrically negative as -5 mV. Normalization in chloride transport can also be referred to as hyperpolarization. | Overall Baseline and Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Parameters of Transepithelial Difference at Day 14 of Cycles 1 and 2 | To assess TEPD, warmed solutions of Ringer's solution, amiloride, chloride-free gluconate, isoproterenol and ATP were perfused for ≥3-minutes sequentially through a nasal catheter while a voltage tracing was recorded. Total chloride transport was computed per nostril. Totals were calculated by subtracting voltages at end of perfusion from voltage at end of earlier perfusion for: sodium transport (amiloride-Ringer's solution), intrinsic chloride transport (chloride-free gluconate-amiloride), stimulated chloride transport (isoproterenol-chloride-free gluconate), total potential difference (isoproterenol-Ringer's solution), and ATP-mediated chloride transport (ATP-isoproterenol). Basal potential difference voltage was obtained at end of Ringer's solution perfusion. Average values per nostril were computed. If assessment was available in only 1 nostril, the value was used as if it's the average of both nostrils. Baseline data for Cycles 1 and 2 and change from Baseline data are presented. | Baseline of Cycle 1 and Cycle 2, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days) | 
| Change From Baseline in CFTR Protein in Nasal Mucosa as Determined by Immunofluorescence at Overall Day 56 | The immunofluorescence staining of normal epithelial cells (for example, from nasal mucosal curettage) reveals the presence of cystic fibrosis transmembrane regulator (CFTR) protein at the apical surface. Cells were stained with antibodies that recognized an epitope in the C-terminal portion of the CFTR protein, and the cells were imaged microscopically. The percentage of epithelial cells that showed apical CFTR staining was determined by 2 expert readers who were blinded to the timepoint at which the samples were obtained. The scores of the reviewers were averaged to determine the final percentage of cells with apical CFTR. Overall Baseline data for the study and change from overall Baseline data at overall Day 56 are presented. | Overall Baseline, Overall Day 56 | 
| Change From Baseline in Nonsense Mutation CFTR mRNA in Nasal Mucosa as Determined by Quantitative Real-Time Polymerase Chain Reaction (RT-PCR) Assay at Overall Day 42 | The collection and processing of the nasal mucosal curettage from each nostril of each participant for measurement of CFTR protein by immunofluorescence and for quantification of CFTR messenger ribonucleic acid (mRNA) was performed using standardized techniques. The slides were processed and immunostained for detection of CFTR protein. Microscopic images were to be captured photographically for analysis. Because the nasal brushing used to collect nasal mucosal epithelial cells did not result in collection of sufficient cells for RT-PCR to be performed, an insufficient number of paired baseline and follow-up samples were available for analysis. As a result, no data were available to evaluate the effects of ataluren on CFTR mRNA. | Overall Baseline, Overall Day 42 | 
| Change From Baseline in Pulmonary Function as Measured by Spirometry at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | Pulmonary function tests, including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and forced expiratory flow25-75 (FEF25-75), were measured using standard spirometry techniques. Overall Baseline data for the study and change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented. | Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56 | 
| Change From Baseline in Sputum Markers of Inflammation (Free Elastase) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | The inflammatory marker free elastase was measured in induced sputum from each participant. Hypertonic saline (3%) inhalation was used to induce the sputum (with efforts made to avoid oropharyngeal contamination). The sputum sample was divided into 4 aliquots (1 aliquot each for determination of cell count, IL-8 level, and elastase activity and 1 aliquot for potential future viscosity measurements). Change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented. | Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56 | 
| Change From Baseline in Sputum Markers of Inflammation (Matrix Metalloproteinase 9 [MMP-9] Active) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | The inflammatory marker MMP-9 active was measured in induced sputum from each participant. Hypertonic saline (3%) inhalation was used to induce the sputum (with efforts made to avoid oropharyngeal contamination). The sputum sample was divided into 4 aliquots (1 aliquot each for determination of cell count, IL-8 level, and elastase activity and 1 aliquot for potential future viscosity measurements). Change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented. | Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56 | 
| Change From Baseline in Sputum Markers of Inflammation (Tumor Necrosis Factor-Alpha [TNF-α], Interleukin-8 [IL-8], Transforming Growth Factor Beta 1 [TGF-β1]) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | The inflammatory markers TNF-α, IL-8, and TGF-β1 were measured in induced sputum from each participant. Hypertonic saline (3%) inhalation was used to induce the sputum (with efforts made to avoid oropharyngeal contamination). The sputum sample was divided into 4 aliquots (1 aliquot each for determination of cell count, IL-8 level, and elastase activity and 1 aliquot for potential future viscosity measurements). Change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented. | Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56 | 
| Change From Baseline in Sputum Markers of Inflammation (Uridine-5'-Triphosphate [UTP]) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | The inflammatory marker UTP was measured in induced sputum from each participant. Hypertonic saline (3%) inhalation was used to induce the sputum (with efforts made to avoid oropharyngeal contamination). The sputum sample was divided into 4 aliquots (1 aliquot each for determination of cell count, IL-8 level, and elastase activity and 1 aliquot for potential future viscosity measurements). Change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented. | Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56 | 
| Change From Baseline in Clinically Significant Neutrophil Levels in Blood at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | To assess inflammatory markers in the blood, neutrophil levels in the blood were measured. Higher levels of neutrophils are indicative of more inflammation. Change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented. | Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56 | 
| Change From Baseline in Clinically Significant Serum Levels of C-Reactive Protein at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | To assess inflammatory markers in the blood, serum levels of C-reactive protein were measured. Higher levels of C-reactive protein are indicative of more inflammation. Change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented. | Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56 | 
| Change From Baseline in Body Weight at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | Body weight were measured for each participant in kilograms (kg). Overall Baseline data for the study and change from overall Baseline data at Day 14 of Cycles 1 and 2 and at overall Day 56 are presented. | Overall Baseline, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56 | 
| Change From Baseline in the CF-Related Symptom Scores, as Assessed Using a Participant-Reported Questionnaire at Day 14 of Cycles 1 and 2 and Overall Day 56 | The CF symptom questionnaire includes questions related to daytime cough, nighttime cough, sputum volume, sputum clearance, physical fatigue, and shortness of breath. The participants (or their guardians) completed the CF symptom questionnaire, under the Investigator's supervision, before the TEPD, nasal mucosal curettage, pulmonary function tests, or sputum induction procedures were performed. For each symptom, the participants were asked to choose the response that best matched their experience during the 3 days before the questionnaire was completed. The scale of the 4 possible responses for each question was 0 (best response) to 4 (worse response). The sum of the scores for all of the questions was calculated. The scale for the sum of the scores was 0 (best response) to 24 (worse response). Overall Baseline data for the study and change from overall Baseline data at Day 14 of Cycles 1 and 2 and at overall Day 56 are presented. | Overall Baseline, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56 | 
| PK: Area Under the Concentration Time Curve From Time 0 (Dosing) to 24 Hours (AUC0-24) of Ataluren | All PK parameters were calculated using the actual postdose blood sampling times in relationship to the time of the first dose (morning dose) on Day 14 of each treatment cycle. AUC0-24 values were calculated by WinNonlin by extrapolation to 24 hours if the last sampling timepoint was before 24 hours and by interpolation if the last sampling timepoint was after 24 hours. Extrapolation of AUC to 24 hours was performed only if the last sampling timepoint did not deviate from the nominal collection time by more than approximately 10%. | 0 (predose), 2 and 3 hours postdose of the morning dose; 0 (predose), 2 and 3 hours postdose of the midday dose; and 0 hours (predose), 2, 3, and 12 hours postdose of the evening dose on Day 14 of Cycle 1 and Cycle 2 | 
| Compliance With Study Treatment | For each participant, compliance was described in terms of the percentage of drug actually taken relative to the amount that was prescribed (taking into account physician-prescribed reductions and interruptions). The number of doses described as taken less than planned includes cases in which the participants took less than the prescribed dose and/or cases in which the Investigator reduced the dose. | Baseline up to Day 14 in Cycle 1 and Cycle 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic fibrosis, Nonsense mutation, Premature stop codon