An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy

A Phase 3 Extension Study of Ataluren (PTC124) in Patients With Nonsense Mutation Dystrophinopathy

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02090959

Enrollment

219

Registered

2014-03-19

Start date

2014-03-20

Completion date

2018-06-12

Last updated

2020-08-11

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Genetic Diseases, Inborn, Genetic Diseases, X-Linked, Muscular Diseases, Muscular Disorders, Atrophic, Muscular Dystrophies, Muscular Dystrophy, Duchenne, Musculoskeletal Diseases, Nervous System Diseases, Neuromuscular Diseases

Keywords

Duchenne muscular dystrophy, Dystrophinopathy, Nonsense mutation, Premature stop codon, Becker muscular dystrophy, DMD/BMD, PTC124, Ataluren

Brief summary

The primary objective of this study is to obtain long term safety data of ataluren in male participants with nonsense mutation dystrophinopathy (who participated and completed a previous Phase 3 study of ataluren \[PTC124-GD-020-DMD {NCT01826487}\]) to augment the overall safety database. Screening and baseline procedures are structured to avoid a gap in treatment between the double-blind study (PTC124-GD-020-DMD) and this extension study. This study may be further extended by amendment until either ataluren becomes commercially available or the clinical development of ataluren in duchenne muscular dystrophy (DMD) is discontinued.

Interventions

DRUGAtaluren

Ataluren will be administered per the dose and schedule specified in the arm.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

MALE

Age

7 Years to 15 Years

Healthy volunteers

Inclusion criteria

* Completion of study treatment in the previous Phase 3, double-blind study (PTC124-GD-020-DMD). * Evidence of signed and dated informed consent/assent document(s) indicating that the participant (and/or his parent/legal guardian) has been informed of all pertinent aspects of the trial. 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 Ethic 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. * In participants who are sexually active, willingness to abstain from sexual intercourse or employ a barrier or medical method of contraception during the period of study drug administration and 6-week follow-up period. * Willingness and ability to comply with scheduled visits, ataluren administration plan, study procedures, laboratory tests, and study restrictions.

Exclusion criteria

* Known hypersensitivity to any of the ingredients or excipients of the study drug (Litesse® UltraTM \[refined polydextrose\], polyethylene glycol 3350, Lutrol® micro F127 \[poloxamer 407\], mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, vanilla, Cab-O-Sil® M5P \[colloidal silica\], and magnesium stearate). * Ongoing participation in any other therapeutic clinical trial. * Prior or ongoing medical condition (for example, concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings, electrocardiogram (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.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Baseline (Day 1) up to 6 weeks post-treatment (Week 150)	An adverse event (AE): any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of AEs: graded per Common Terminology Criteria for AEs (CTCAE), Version 3.0 as Grade 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Drug-related AEs: AEs with possible, probable, unlikely relationship, or unrelated to study drug. Serious AEs (SAEs): death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention. TEAE: an AE that occurred or worsened in the period extending from first dose of study drug in this study to 6 weeks after last dose of study drug in this study. A summary of other non-serious AEs and all SAEs, regardless of causality is located in Reported AE section.
Number of Participants With Abnormalities in Clinical Laboratory Parameters	Baseline (Day 1) up to 6 weeks post-treatment (Week 150)	Abnormalities in laboratory variables as pre-defined in protocol for safety-monitoring were: Hepatic (Serum alanine aminotransferase \[ALT\]: increase of greater than \[\>\] 150 units/liter \[U/L\] with stable or decrease of creatinine kinese \[CK\]; Serum glutamyl amino transferase \[GGT\] \[U/L\]: Grade 2 \[\>2.5 - 5.0 \* upper limit of normal {ULN}\]), renal (Serum cystatin C miiligrams/liter \[mg/L\] \>1.33 - 2.00 mg/L; Serum blood urea nitrogen \[UREAN\] \[millimoles/liter {mmol/L}\] greater than or equal to \[≥\]1.5 - 3.0 \* ULN; Urine occult blood: 2+ \[Small\], 3+ \[Moderate\], 4+ \[Large\]), and electrolytes (Serum sodium: low \[mmol/L\], Grade 3-4 \[less than {\<}130 mmol/L\]; serum potassium: high \[mmol/L\], Grade 3-4 \[\>6.0 mmol/L\]; and Serum bicarbonate \[mmol/L\]: Grade 2 \[\<16 - 11 mmol/L\]).

Secondary

Measure	Time frame	Description
Change From Baseline in Time to Stand From Supine Position at Week 144	Baseline, Week 144	If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used.
Change From Baseline in Time to Walk/Run 10 Meters at Week 144	Baseline, Week 144	If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used.
Change From Baseline in Time to Climb 4 Stairs at Week 144	Baseline, Week 144	If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used.
Change From Baseline in Time to Descend 4 Stairs at Week 144	Baseline, Week 144	If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used.
Change From Baseline in Physical Function Total Score as Measured by NSAA at Week 144	Baseline, Week 144	Physical function was assessed via the NSAA, a functional scale specifically designed for ambulant Duchenne muscular dystrophy (DMD) participants. The assessment comprised tests for 17 abilities of a participant, such as ability to stand, rise from the floor, get from lying to sitting, get from sitting to standing, raise one's head, stand on one's heels, hop, jump, and run. For each activity, a score of 0, 1, or 2 was recorded, with 0 = unable to achieve independently, 1 = modified method but achieves goal independent of physical assistance from another, or 2 = normal- achieves goal without any assistance. The sum of these scores (except for 'raise one's head' activity score) was reported as the ordinal total score, which was transformed to a linear total score ranging from 0 (worst) to 100 (best). Participants with confirmed loss of ambulation at a particular visit were assigned a score of 0.
Change From Baseline in PUL Total Score at Week 144	Baseline, Week 144	The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into shoulder level (4 items), elbow level (9 items), and distal level (8 items) dimensions. Scoring options per item may not be uniform and may vary from 0-1 and 0-6, according to the performance, with higher values corresponding to better performance. Each dimension was scored separately with a maximum score of 16 for shoulder level, 34 for elbow level, and 24 for distal level. Total score was calculated by adding the 3 level scores, with a maximum global score of 74 (total score range = 0-74). Higher score = better outcome.
Change From Baseline in Percent Predicted FVC as Measured by Spirometry at Week 144	Baseline, Week 144	FVC is a standard pulmonary function test. FVC was defined as the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Percent predicted FVC (in %) = \[(observed FVC)/(predicted FVC)\]\*100.
Change From Baseline in PODCI Transfers/Basic Mobility Score at Week 144	Baseline, Week 144	Changes in health-related quality of life (HRQL) were measured via the PODCI questionnaire that has been shown to correlate with disease progression and clinical outcome measures in DMD. PODCI includes a Global Functioning Scale and 5 core scales: Upper Extremity and Physical Function,Transfer/Basic Mobility, Sports/Physical Functioning, Pain/Comfort,and Happiness. The following PODCI domain was prespecified in the protocol for analysis:Transfers/Basic Mobility domain assesses difficulty experienced in performing routine motor activities in daily life. Each domain was scored from 0 to 100, with 0 representing a poor outcome/worse health, while 100 representing the highest level of functioning and least pain.
Change From Baseline in PEF as Measured by Spirometry at Week 144	Baseline, Week 144	PEF was defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated.
Change From Baseline in PCF as Measured by Spirometry at Week 144	Baseline, Week 144	PCF measures an individual's maximum speed of expiration during cough.
Number of Participants With Change From Baseline in Activities of Daily Living and Disease Status at Week 144, as Assessed by a Standardized Survey Administered by Site Personnel	Baseline, Week 144	Changes in activities of daily living and disease symptoms were captured via a DMD-specific survey administered by Site personnel. At screening or baseline, the participant and/or parent/caregiver were asked to identify any activities of daily living (for example, ambulation, balance, personal hygiene/grooming, dressing and undressing, self-feeding, using the bathroom, handwriting, school performance, behavior or energy level) or symptoms that were affected by the participant's DMD. At post-baseline visit (Week 144), the same participant and/or parent/caregiver was asked to describe any changes from baseline in those activities of daily living/symptoms, within the following categories: physical functioning; general energy level; cognition/school function; emotional/social functioning; and sleep. Changes from baseline were reported on a 5-point Likert scale: 1 (much better), 2 (slightly better), 3 (unchanged), 4 (slightly worse), or 5 (much worse).
Ataluren Plasma Concentration	Pre-dose at Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 144	Pre-dose ataluren plasma concentrations prior to morning ataluren administration at each clinic visit was assessed using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC/MS-MS) method.
Change From Baseline in Systolic and Diastolic Blood Pressure at Week 144	Baseline, Week 144	Blood pressure determination was performed with the participant in a sitting position after a 5-minute rest.
Change From Baseline in Pulse Rate at Week 144	Baseline, Week 144	Pulse rate determination was performed with the participant in a sitting position after a 5-minute rest.
Change From Baseline in Body Temperature at Week 144	Baseline, Week 144	—
Change From Baseline in Percent Predicted FEV1 as Measured by Spirometry at Week 144	Baseline, Week 144	FEV1 is a standard pulmonary function test. FEV1 was defined as the volume of air that can forcibly be blown out in 1 second, after full inspiration in the upright position, measured in liters. Percent predicted FEV1 (in %) = \[(observed FEV1)/(predicted FEV1)\]\*100.
Change From Baseline in 6MWD at Week 144	Baseline, Week 144	The 6MWD test was performed in a 30 meters long flat corridor, where the participant was instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Ambulation was assessed via the 6MWD test following standardized procedures by measuring the 6MWD in meters. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test.

Countries

Australia, Belgium, Brazil, Bulgaria, Canada, Chile, Czechia, France, Germany, Israel, Italy, Poland, South Korea, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States

Participant flow

Recruitment details

All participants who successfully completed the double-blind, placebo-controlled Phase 3 study (PTC124-GD-020-DMD \[NCT01826487\]) were screened for this open-label extension study.

Pre-assignment details

A total of 221 participants completed the double-blind Phase 3 Study PTC124-GD-020-DMD. Of the 221 participants who completed Study PTC124-GD-020-DMD, 219 participants were enrolled in this open-label extension study and 218 were treated.

Participants by arm

Arm	Count
Ataluren Participants received ataluren suspension orally TID, 10 mg/kg at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for up to 144 weeks.	218
Total	218

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	1
Overall Study	Enrolled but not treated	1
Overall Study	Entered in to other study	34
Overall Study	Investigator decision	2
Overall Study	Move to medical need program	3
Overall Study	Other than specified	2
Overall Study	Study termination	6
Overall Study	Switched to commercial supply	88
Overall Study	Transfer for compassionate use medicine	4
Overall Study	Withdrawal by Subject	10

Baseline characteristics

Characteristic	Ataluren
6 Minute Walk Distance (6MWD)	349.885 meters STANDARD_DEVIATION 105.7913
Age, Continuous	9.9 years STANDARD_DEVIATION 1.78
Blood Pressure Diastolic blood pressure	68.6 millimeters of mercury (mm Hg) STANDARD_DEVIATION 11.01
Blood Pressure Systolic blood pressure	106.3 millimeters of mercury (mm Hg) STANDARD_DEVIATION 10.72
Body Temperature	36.47 degrees centigrade STANDARD_DEVIATION 0.453
North Star Ambulatory Assessment (NSAA) Total Score	20.73 units on a scale STANDARD_DEVIATION 8.513
Peak Cough Flow (PCF)	3.30 L/sec STANDARD_DEVIATION 1.139
Peak Expiratory Flow (PEF)	3.36 liters/second (L/sec) STANDARD_DEVIATION 1.055
Pediatric Outcomes Data Collection Instrument (PODCI) Transfers/Basic Mobility Score	74.6 units on a scale STANDARD_DEVIATION 23.66
Percent Predicted Forced Expiratory Volume in 1 Second (FEV1)	53.76 percent predicted FEV1 STANDARD_DEVIATION 12.87
Percent Predicted Forced Vital Capacity (FVC)	59.42 percent predicted FVC STANDARD_DEVIATION 13.843
Performance Upper Limb (PUL) Total Score	68.7 units on a scale STANDARD_DEVIATION 4.61
Pulse Rate	97.0 beats/minute STANDARD_DEVIATION 13.31
Race/Ethnicity, Customized Asian	13 Participants
Race/Ethnicity, Customized Black	2 Participants
Race/Ethnicity, Customized Hispanic	12 Participants
Race/Ethnicity, Customized Missing	14 Participants
Race/Ethnicity, Customized Other	8 Participants
Race/Ethnicity, Customized White	169 Participants
Sex: Female, Male Female	0 Participants
Sex: Female, Male Male	218 Participants
Time to Climb 4 Stairs	9.03 seconds STANDARD_DEVIATION 8.939
Time to Descend 4 Stairs	7.52 seconds STANDARD_DEVIATION 8.401
Time to Stand From Supine Position	13.0 seconds STANDARD_DEVIATION 10.34
Time to Walk/Run 10 Meters	9.31 seconds STANDARD_DEVIATION 7.388

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 218
other Total, other adverse events	201 / 218
serious Total, serious adverse events	24 / 218

Outcome results

Primary

Number of Participants With Abnormalities in Clinical Laboratory Parameters

Abnormalities in laboratory variables as pre-defined in protocol for safety-monitoring were: Hepatic (Serum alanine aminotransferase \[ALT\]: increase of greater than \[\>\] 150 units/liter \[U/L\] with stable or decrease of creatinine kinese \[CK\]; Serum glutamyl amino transferase \[GGT\] \[U/L\]: Grade 2 \[\>2.5 - 5.0 \* upper limit of normal {ULN}\]), renal (Serum cystatin C miiligrams/liter \[mg/L\] \>1.33 - 2.00 mg/L; Serum blood urea nitrogen \[UREAN\] \[millimoles/liter {mmol/L}\] greater than or equal to \[≥\]1.5 - 3.0 \* ULN; Urine occult blood: 2+ \[Small\], 3+ \[Moderate\], 4+ \[Large\]), and electrolytes (Serum sodium: low \[mmol/L\], Grade 3-4 \[less than {\<}130 mmol/L\]; serum potassium: high \[mmol/L\], Grade 3-4 \[\>6.0 mmol/L\]; and Serum bicarbonate \[mmol/L\]: Grade 2 \[\<16 - 11 mmol/L\]).

Time frame: Baseline (Day 1) up to 6 weeks post-treatment (Week 150)

Population: AT population included all participants who received at least 1 dose of ataluren treatment in this extension study.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Ataluren	Number of Participants With Abnormalities in Clinical Laboratory Parameters	29 Participants

Primary

Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

An adverse event (AE): any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of AEs: graded per Common Terminology Criteria for AEs (CTCAE), Version 3.0 as Grade 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Drug-related AEs: AEs with possible, probable, unlikely relationship, or unrelated to study drug. Serious AEs (SAEs): death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention. TEAE: an AE that occurred or worsened in the period extending from first dose of study drug in this study to 6 weeks after last dose of study drug in this study. A summary of other non-serious AEs and all SAEs, regardless of causality is located in Reported AE section.

Time frame: Baseline (Day 1) up to 6 weeks post-treatment (Week 150)

Population: AT population included all participants who received at least 1 dose of ataluren treatment in this extension study.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Ataluren	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Any AEs	202 Participants
Ataluren	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	SAEs	24 Participants
Ataluren	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Drug-Related AEs	44 Participants
Ataluren	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	AEs Leading to Withdrawal From Study	1 Participants
Ataluren	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Mild AEs	87 Participants
Ataluren	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Moderate AEs	71 Participants
Ataluren	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Severe AEs	42 Participants
Ataluren	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Life-threatening AEs	2 Participants

Secondary

Ataluren Plasma Concentration

Pre-dose ataluren plasma concentrations prior to morning ataluren administration at each clinic visit was assessed using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC/MS-MS) method.

Time frame: Pre-dose at Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 144

Population: AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Ataluren	Ataluren Plasma Concentration	Week 12	4.5231 micrograms/milliliter (μg/mL)	Standard Deviation 5.08583
Ataluren	Ataluren Plasma Concentration	Week 24	4.4817 micrograms/milliliter (μg/mL)	Standard Deviation 5.65883
Ataluren	Ataluren Plasma Concentration	Week 36	5.1551 micrograms/milliliter (μg/mL)	Standard Deviation 5.67555
Ataluren	Ataluren Plasma Concentration	Week 48	5.2221 micrograms/milliliter (μg/mL)	Standard Deviation 5.32846
Ataluren	Ataluren Plasma Concentration	Week 60	5.0396 micrograms/milliliter (μg/mL)	Standard Deviation 5.07812
Ataluren	Ataluren Plasma Concentration	Week 72	6.0677 micrograms/milliliter (μg/mL)	Standard Deviation 6.05912
Ataluren	Ataluren Plasma Concentration	Week 84	5.4673 micrograms/milliliter (μg/mL)	Standard Deviation 5.15083
Ataluren	Ataluren Plasma Concentration	Week 96	5.8870 micrograms/milliliter (μg/mL)	Standard Deviation 5.90954
Ataluren	Ataluren Plasma Concentration	Week 108	5.5905 micrograms/milliliter (μg/mL)	Standard Deviation 6.48016
Ataluren	Ataluren Plasma Concentration	Week 120	5.2406 micrograms/milliliter (μg/mL)	Standard Deviation 5.69648
Ataluren	Ataluren Plasma Concentration	Week 132	6.6729 micrograms/milliliter (μg/mL)	Standard Deviation 7.03882
Ataluren	Ataluren Plasma Concentration	Week 144	5.3898 micrograms/milliliter (μg/mL)	Standard Deviation 6.28487

Secondary

Change From Baseline in 6MWD at Week 144

The 6MWD test was performed in a 30 meters long flat corridor, where the participant was instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Ambulation was assessed via the 6MWD test following standardized procedures by measuring the 6MWD in meters. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test.