Study of Ataluren in Participants With Nonsense Mutation Aniridia

Study Overview
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Brief Summary
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This study is designed to evaluate the effect of ataluren on Maximum Reading Speed as measured using the Minnesota Low Vision Reading Test (MNREAD) Acuity Charts in participants with nonsense mutation aniridia. This study involves a 4-week screening period, a 144-week treatment period (Stage 1: Weeks 1 to 48 [double-masked treatment] and Stage 2: Weeks 49 to 144 [open label treatment]), an optional 96-week open label extension sub-study, and a 4-week post-treatment follow-up period (either study completion or early termination). Participants that choose not to participate in the sub-study will be required to complete the post-treatment follow-up visit at the end of the Stage 2 open-label extension.

Official Title
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A Phase 2, Multicenter, Randomized, Double-Masked, Placebo-Controlled Study of the Safety and Efficacy of Ataluren (PTC124) for the Treatment of Nonsense Mutation Aniridia

Conditions
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Aniridia

Intervention / Treatment
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* Drug: Ataluren
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of signed and dated informed consent document(s) indicating that the study candidate (and/or a parent/legal guardian) has been informed of all pertinent aspects of the study. Note: If the study candidate is considered a child under local regulation, a parent or legal guardian must provide written consent prior to initiation of study screening procedures and the study candidate may be required to provide written assent. The rules of the responsible institutional review board/independent ethics committee (IRB/IEC) regarding whether 1 or both parents must provide consent and the appropriate ages for obtaining consent and assent from the participant should be followed. Body weight greater than or equal to (>=) 12 kg. Documentation of the presence of a nonsense mutation in 1 allele of the PAX6 gene as determined by genotyping performed at a laboratory certified by the College of American Pathologists (CAP), or under the Clinical Laboratory Improvement Act/Amendment (CLIA), or by an equivalent organization. Clinical diagnosis of aniridia. Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, and study restrictions. Good general health, as determined at Screening by medical history and physical examination (including vital sign measurements). No clinically significant abnormality based upon laboratory assessments at Screening, in the opinion of the investigator. Female participants of childbearing potential are eligible for the study but must be willing to use adequate (at least 1 form of) contraceptive methods as described below during the study treatment period (starting from the day of first dose of study drug and ending 60 days after the last dose of study drug). Childbearing potential is defined as participants who have experienced menarche and who are neither postmenopausal nor have been permanently sterilized. Hormonal methods of contraception (including oral and transdermal contraceptives, injectable progesterone, progestin subdermal implants, progesterone-releasing intrauterine devices [IUDs]) initiated at least 14 days prior to the first dose of study drug Abstinence Placement of a copper-containing IUD Condom with spermicidal foam/gel/film/cream/suppository Postmenopausal at least 12 months prior to first dose of study drug or permanently sterilized (for example, tubal occlusion, hysterectomy, bilateral salpingectomy) Male partner who has had a vasectomy for at least 3 months prior to the first dose of study drug Male participants with partners of childbearing potential must agree to use adequate (at least 1 form of) contraception as described below during the study treatment period (starting from the day of first dose of study drug and ending 60 days after the last dose of study drug). Abstinence Vasectomy for at least 3 months prior to first dose of study drug or surgically sterile Without a vasectomy, must use a condom with spermicidal foam/gel/film/cream suppository Exclusion Criteria: Participants participating in any drug or device clinical investigation within 90 days prior to Screening or who anticipate participating in any other drug or device clinical investigation within the duration of this study. Exposure to ataluren within 90 days prior to Screening. Surgery within 30 days prior to enrollment. Female participants who are pregnant or breastfeeding. Female participants of childbearing potential must have a negative pregnancy test (beta-human chorionic gonadotropin [beta-HCG]) at screening and must use adequate (at least 1 form of) contraceptive methods. Active ocular infection or inflammation. Prior or ongoing medical condition (for example, concomitant illness, alcoholism, drug abuse, psychiatric condition), medical history, physical 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 study drug administration or follow-up would be completed, or could impair the assessment of study results. Participants with a positive result for hepatitis B, hepatitis C, or human immunodeficiency virus at Visit 1 (Screening). Ongoing warfarin, phenytoin, or tolbutamide therapy. Ongoing intravenous (IV) aminoglycoside or IV vancomycin use. Ongoing systemic cyclosporine therapy. Note: Topical cyclosporine therapy is permitted. Known hypersensitivity to any of the ingredients or excipients of the study drug (polydextrose, polyethylene glycol 3350, poloxamer 407, mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, vanilla, colloidal silica, or magnesium stearate). 20/200 or worse visual acuity in the better eye with best correction. Participants who are monocular. Participants with a history of complications due to ocular surgery that could interfere with the study procedures or assessment of study endpoints. Participants with any other significant ocular or systemic disease that the Investigator determines could interfere with the study.

Ages Eligible for Study
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Minimum Age: 2 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ataluren<br>Participants will receive ataluren orally 3 times a day (TID) at a dose of 10 milligrams per kilogram (mg/kg) in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 48 weeks in Stage 1 (double-masked period) and for additional 96 weeks in Stage 2 (open-label extension period). Participants, who complete Stage 2 and agree to continue in open-label sub-study, will continue to receive ataluren treatment at same dose as mentioned above, for 96 weeks or until commercial availability of ataluren for this indication, whichever is first, or until a positive risk-benefit assessment in this indication is not demonstrated. | Drug: Ataluren<br>* Ataluren oral suspension will be administered as per the dose and schedule specified in the respective arms.<br>* Other names: Translarna;|
| Placebo Comparator: Placebo<br>Participants will receive placebo matching to ataluren TID orally in the morning, at midday, and in the evening for 48 weeks in Stage 1 (double-masked period) and ataluren orally TID at a dose of 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for additional 96 weeks in Stage 2 (open-label extension period). Participants, who complete Stage 2 and agree to continue in open-label sub-study, will continue to receive ataluren treatment at same dose as mentioned above, for 96 weeks or until commercial availability of ataluren for this indication, whichever is first, or until a positive risk-benefit assessment in this indication is not demonstrated. | Drug: Ataluren<br>* Ataluren oral suspension will be administered as per the dose and schedule specified in the respective arms.<br>* Other names: Translarna;Drug: Placebo<br>* Placebo will be administered as per the schedule specified in the respective arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Maximum Reading Speed of Oculus Unitas (OU) (Both Eyes) at Week 48, as Measured Using the Minnesota Low Vision Reading Test (MNREAD) Acuity Charts | MNREAD Acuity Chart can only be used to assess participants ≥8 years old. MNREAD Acuity Chart measures reading speed as a function of print size in participants with normal and low vision. The test consists of short sentences with print size decreasing by 0.1 log unit steps from a maximum of 1.3 logarithm of the minimum angle of resolution (logMAR) (equivalent to 20/400 or 6/120 when viewed at 40 centimeters [cm]) to -0.5 logMAR (equivalent to 20/6 or 6/2). An MNREAD Acuity Chart curve of reading speed vs print size has a typical shape for normally sighted persons and many low-vision individuals. This curve is characterized by 3 summary values. At large print sizes, reading speed remains fairly constant, forming a plateau that represents the maximum reading speed. As the print size decreases, a critical print size (CPS) is reached at which reading speed begins to decline rapidly. Finally, the smallest print size that can be read is defined as the reading acuity (RA). | Baseline, Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Reading Accessibility Index of Both Eyes at Week 48 | Reading Accessibility Index is defined as the mean reading speed in words per minute (wpm) across the 10 largest physical print sizes on the MNREAD Acuity Chart, normalized by the value for a group of normally sighted young adults. For a viewing distance of 40 cm, this range of print sizes corresponds to 0.4 to 1.3 logMAR. This range of print sizes was chosen for 2 reasons. First, it sustains the manifest refraction spherical equivalent (MRS) in normally sighted persons. Second, it covers most contemporary printed text found in everyday life. Because the Reading Accessibility Index is normalized by the value for a group of normally sighted young adults (aged 18 to 39 years), a Reading Accessibility Index of 1.0 represents normal performance for this age group. Values less than 1.0 mean reduced accessibility to printed text within the range of print size encountered in daily life. Missing data was imputed using last observation carried forward (LOCF) method. | Baseline, Week 48 | 
| Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 48 | The BCVA was evaluated using the Early Treatment Diabetic Retinopathy Study (ETDRS) Method. Missing data was imputed using LOCF method. | Baseline, Week 48 | 
| Percent Change From Baseline in Maximum Reading Speed of Oculus Dexter (OD) (Right Eye) and Oculus Sinister (OS) (Left Eye) at Week 48 | Maximum Reading Speed was measured using the MNREAD Acuity Chart, which can only be used to assess participants ≥8 years old. The MNREAD Acuity Chart measures reading speed as a function of print size in participants with normal and low vision. The test consists of short sentences with print size decreasing by 0.1 log unit steps from a maximum of 1.3 logMAR (equivalent to 20/400 or 6/120 when viewed at 40 cm) to -0.5 logMAR (equivalent to 20/6 or 6/2). An MNREAD Acuity Chart curve of reading speed vs print size has a typical shape for normally sighted persons and many low-vision individuals. This curve is characterized by 3 summary values. At large print sizes, reading speed remains fairly constant, forming a plateau that represents the maximum reading speed. As the print size decreases, a CPS is reached at which reading speed begins to decline rapidly. Finally, the smallest print size that can be read is defined as the RA. | Baseline, Week 48 | 
| Change From Baseline in Reading Accessibility Index of Right Eye and Left Eye at Week 48 | Reading Accessibility Index is defined as the mean reading speed in wpm across the 10 largest physical print sizes on the MNREAD Acuity Chart, normalized by the value for a group of normally sighted young adults. For a viewing distance of 40 cm, this range of print sizes corresponds to 0.4 to 1.3 logMAR. This range of print sizes was chosen for 2 reasons. First, it sustains the MRS in normally sighted persons. Second, it covers most contemporary printed text found in everyday life. Because the Reading Accessibility Index is normalized by the value for a group of normally sighted young adults (aged 18 to 39 years), a Reading Accessibility Index of 1.0 represents normal performance for this age group. Values less than 1.0 mean reduced accessibility to printed text within the range of print size encountered in daily life. Missing data was imputed using LOCF method. | Baseline, Week 48 | 
| Change From Baseline in Critical Print Size (CPS) of Both Eyes, Right Eye, and Left Eye at Week 48 | The MNREAD Acuity Chart measures reading speed as a function of print size in participants with normal and low vision. The test consists of short sentences with print size decreasing by 0.1 log unit steps from a maximum of 1.3 logMAR (equivalent to 20/400 or 6/120 when viewed at 40 cm) to -0.5 logMAR (equivalent to 20/6 or 6/2). An MNREAD Acuity Chart curve of reading speed vs print size has a typical shape for normally sighted persons and many low-vision individuals. This curve is characterized by 3 summary values. At large print sizes, reading speed remains fairly constant, forming a plateau that represents the maximum reading speed. As the print size decreases, a CPS is reached at which reading speed begins to decline rapidly. Finally, the smallest print size that can be read is defined as the RA. Missing data was imputed using LOCF method. | Baseline, Week 48 | 
| Change From Baseline in Reading Acuity (RA) of Both Eyes, Right Eye, and Left Eye at Week 48 | The MNREAD Acuity Chart measures reading speed as a function of print size in participants with normal and low vision. The test consists of short sentences with print size decreasing by 0.1 log unit steps from a maximum of 1.3 logMAR (equivalent to 20/400 or 6/120 when viewed at 40 cm) to -0.5 logMAR (equivalent to 20/6 or 6/2). An MNREAD Acuity Chart curve of reading speed vs print size has a typical shape for normally sighted persons and many low-vision individuals. This curve is characterized by 3 summary values. At large print sizes, reading speed remains fairly constant, forming a plateau that represents the maximum reading speed. As the print size decreases, a CPS is reached at which reading speed begins to decline rapidly. Finally, the smallest print size that can be read is defined as the RA. Missing data was imputed using LOCF method. | Baseline, Week 48 | 
| Number of Participants With Change From Baseline in Severity of Corneal Keratopathy at Week 48 | The severity of corneal keratopathy was reported as worsened, not change, or improve. Missing data were imputed using LOCF. | Baseline to Week 48 | 
| Change From Baseline in Iris Area at Week 48 | Missing data were imputed using LOCF. | Baseline, Week 48 | 
| Change From Baseline in BCVA at Week 240 | The BCVA was evaluated using the ETDRS Method. Missing data were imputed using LOCF method. | Baseline, Week 240 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. AEs were summarized separately for Stage 1 and for the overall ataluren experience, which included all participants who received ataluren throughput the study (Stage 1, open-label extension period [Stage 2], and sub-study). | Baseline up to Week 244 |