Trial Outcomes & Findings for Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy (NCT NCT03179631)

The study consisted of a 72-week double-blind (DB) treatment period followed by a 72-week open-label (OL) treatment period.

Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy

The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is 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. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Participants with confirmed loss of ambulation at a particular visit were assigned a 6MWD result of 0. Baseline was defined as the maximum measurement of valid Day 1 and Day 2 6MWD values. Least square (LS) mean and standard error (SE) was calculated using the mixed-model repeated measures (MMRM).

The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is 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. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Participants with confirmed loss of ambulation at a particular visit were assigned a 6MWD result of 0. Baseline was defined as the maximum measurement of valid Day 1 and Day 2 6MWD values. LS mean and SE was calculated using the MMRM.

The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is 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. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Participants with confirmed loss of ambulation at a particular visit were assigned a 6MWD result of 0. Baseline was defined as the maximum measurement of valid Day 1 and Day 2 6MWD values. LS mean and SE was calculated using the MMRM.

The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is 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. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Participants with confirmed loss of ambulation at a particular visit were assigned a 6MWD result of 0. Baseline was defined as the maximum measurement of valid Day 1 and Day 2 6MWD values. LS mean and SE was calculated using the MMRM.

During the test for walking/running 10 meters, the method of walk/run used by the participant was categorized as follows: 1. Unable to walk independently; 2. Unable to walk independently but can walk with support from a person or with assistive device (full leg calipers \[knee-ankle-foot orthoses\] or walker); 3. Highly adapted gait, wide-based lordotic gait, cannot increase walking speed; 4. Moderately adapted gait, can pick up speed but cannot run; 5. Able to pick up speed but runs with a double stance phase (that is, cannot achieve both feet off the ground); 6. Runs and gets both feet off the ground (with no double stance phase). Participants who could not perform a timed function test (TFT) within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

During the test for walking/running 10 meters, the method of walk/run used by the participant was categorized as follows: 1. Unable to walk independently; 2. Unable to walk independently but can walk with support from a person or with assistive device (full leg calipers \[knee-ankle-foot orthoses \] or walker); 3. Highly adapted gait, wide-based lordotic gait, cannot increase walking speed; 4. Moderately adapted gait, can pick up speed but cannot run; 5. Able to pick up speed but runs with a double stance phase (that is, cannot achieve both feet off the ground); 6. Runs and gets both feet off the ground (with no double stance phase). Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

During the test for stair-climbing, the method of climbing used by the participant was categorized as follows: 1. Unable to up climb 4 standard stairs; 2. Climbs 4 standard stairs "marking time" (climbs one foot at a time, with both feet on a step before moving to next step), using both arms on one or both handrails; 3. Climbs 4 standard stairs "marking time", using one arm on one handrail; 4. Climbs 4 standard stairs "marking time", not needing handrail; 5. Climbs 4 standard stairs alternating feet, needs handrail for support; 6. Climbs 4 standard stairs alternating feet, not needing handrail support. Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

During the test for stair-climbing, the method of climbing used by the participant was categorized as follows: 1. Unable to up climb 4 standard stairs; 2. Climbs 4 standard stairs "marking time" (climbs one foot at a time, with both feet on a step before moving to next step), using both arms on one or both handrails; 3. Climbs 4 standard stairs "marking time", using one arm on one handrail; 4. Climbs 4 standard stairs "marking time", not needing handrail; 5. Climbs 4 standard stairs alternating feet, needs handrail for support; 6. Climbs 4 standard stairs alternating feet, not needing handrail support. Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

During the test for stair-descending, the method of descending used by the participant was categorized as follows: 1. Unable to descend 4 standard stairs; 2. Descends 4 standard stairs "marking time" (climbs one foot at a time, with both feet on a step before moving to next step), using both arms on one or both handrails; 3. Descends 4 standard stairs "marking time", using one arm on one handrail; 4. Descends 4 standard stairs "marking time", not needing handrail; 5. Descends 4 standard stairs alternating feet, needs handrail for support; 6. Descends 4 standard stairs alternating feet, not needing handrail support. Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

During the test for stair-descending, the method of descending used by the participant was categorized as follows: 1. Unable to descend 4 standard stairs; 2. Descends 4 standard stairs "marking time" (climbs one foot at a time, with both feet on a step before moving to next step), using both arms on one or both handrails; 3. Descends 4 standard stairs "marking time", using one arm on one handrail; 4. Descends 4 standard stairs "marking time", not needing handrail; 5. Descends 4 standard stairs alternating feet, needs handrail for support; 6. Descends 4 standard stairs alternating feet, not needing handrail support. Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

The composite TFT was defined as the average in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs. Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement (average in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs) on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

The composite TFT was defined as the average in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs. Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement (average in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs) on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

The composite TFT was defined as the average in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs. Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement (average in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs) on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

The composite TFT was defined as the average in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs. Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement (average in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs) on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is 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. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Time to 10% persistent worsening in 6MWD was defined as the last time that 6MWD was not 10% worse compared with baseline. Participants who did not have 10% 6MWD worsening were censored at the time of the last 6-minute walk test during the DB period.

6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where participant is instructed to walk as far as possible, back and forth around two cones, with permission to slow down, rest, or stop if needed. Ambulation was assessed via 6MWD test following standardized procedures. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during 6MWD test. Time to 10% persistent worsening in 6MWD was defined as the last time that 6MWD was not 10% worse compared with baseline. Participants who did not have 10% 6MWD worsening were censored at the time of last 6-minute walk test during DB period. Due to COVID, there were many participants who participated in the protocol-defined Week 72 visit late. Due to this reason, the calculated median for the time to event for the Ataluren arm in the DB period were greater than Week 72.

The NSAA total score in the original scale is the sum of scores from 16 activities (excluding head lift). Each activity was scored as 0 (activity couldn't be performed), 1 (modified method, achieved goal without assistance), or 2 (normal, achieved goal without assistance). The total score ranges from 0 to 32, where higher scores indicate better functioning. If fewer than 13 of the 16 activities were performed, the total score was considered missing. If from 13 to 16 activities were performed, the total score was standardized by (observed total score / number of non-missing activities) x 16. If an activity could not be performed due to disease progression, a score of 0 was assigned. Baseline was defined as the last observed measurement on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

The NSAA total score in the original scale is the sum of scores from 16 activities (excluding head lift). Each activity was scored as 0 (activity couldn't be performed), 1 (modified method, achieved goal without assistance), or 2 (normal, achieved goal without assistance). The total score ranges from 0 to 32, where higher scores indicate better functioning. If fewer than 13 of the 16 activities were performed, the total score was considered missing. If from 13 to 16 activities were performed, the total score was standardized by (observed total score / number of non-missing activities) x 16. If an activity could not be performed due to disease progression, a score of 0 was assigned. Baseline was defined as the last observed measurement on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

Time to loss of ambulation was defined as persistent inability to perform the 10-meter run/walk test within 30 seconds at any post-baseline visit and for all remaining visits. Due to COVID, there were many participants who participated in the protocol-defined Week 72 visit late. Due to this reason, the calculated median and 95% CI for the time to event for the Ataluren arm in the DB period were greater than Week 72.

Time to loss of ambulation was defined as persistent inability to perform the 10-meter run/walk test within 30 seconds at any post-baseline visit and for all remaining visits.

Time to loss of stair-climbing was defined as persistent inability to perform the 4-stair climb test within 30 seconds at any post-baseline visit and for all remaining visits. Due to COVID, there were many participants who participated in the protocol-defined Week 72 visit late. Due to this reason, the calculated median and 95% CI for the time to event for the Ataluren arm in the DB period were greater than Week 72.

Time to loss of stair-climbing was defined as persistent inability to perform the 4-stair climb test within 30 seconds at any post-baseline visit and for all remaining visits. Due to COVID, there were many participants who participated in the protocol-defined Week 72 visit late. Due to this reason, the calculated median and 95% CI for the time to event for the Ataluren arm in the DB period were greater than Week 72.

Time to loss of stair-descending was defined as persistent inability to perform the 4-stair descend test within 30 seconds at any post-baseline visit and for all remaining visits. Due to COVID, there were many participants who participated in the protocol-defined Week 72 visit late. Due to this reason, the calculated median and 95% CI for the time to event for the Ataluren arm in the DB period were greater than Week 72.

Time to loss of stair-descending was defined as persistent inability to perform the 4-stair descend test within 30 seconds at any post-baseline visit and for all remaining visits. Due to COVID, there were many participants who participated in the protocol-defined Week 72 visit late. Due to this reason, the calculated median and 95% CI for the time to event for the Ataluren arm in the DB period were greater than Week 72.

Function loss was defined as a drop of score from 1 or 2 at baseline to a score of 0 at the specified post-baseline of NSAA items. The missing assessments at post baseline visits were imputed using last observation carried forward (LOCF).

Function loss was defined as a drop of score from 1 or 2 at baseline to a score of 0 at the specified post-baseline of NSAA items. The missing assessments at post baseline visits were imputed using LOCF.

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A TEAE was defined as an AE that occurred or worsened on or after the first dose of study drug and up to 4 weeks after the last dose of double-blind study drug and prior to the first dose of open-label treatment. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.

The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is 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. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Participants with confirmed loss of ambulation at a particular visit were assigned a 6MWD result of 0. Baseline was defined as the maximum measurement of valid Day 1 and Day 2 6MWD values. LS mean and SE was calculated using the MMRM.

The composite TFT was defined as the average in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs. Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement (average in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs) on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

During the test for walking/running 10 meters, the method of walk/run used by the participant was categorized as follows: 1. Unable to walk independently; 2. Unable to walk independently but can walk with support from a person or with assistive device (full leg calipers \[knee-ankle-foot orthoses \] or walker); 3. Highly adapted gait, wide-based lordotic gait, cannot increase walking speed; 4. Moderately adapted gait, can pick up speed but cannot run; 5. Able to pick up speed but runs with a double stance phase (that is, cannot achieve both feet off the ground); 6. Runs and gets both feet off the ground (with no double stance phase). Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

During the test for stair-climbing, the method of climbing used by the participant was categorized as follows: 1. Unable to up climb 4 standard stairs; 2. Climbs 4 standard stairs "marking time" (climbs one foot at a time, with both feet on a step before moving to next step), using both arms on one or both handrails; 3. Climbs 4 standard stairs "marking time", using one arm on one handrail; 4. Climbs 4 standard stairs "marking time", not needing handrail; 5. Climbs 4 standard stairs alternating feet, needs handrail for support; 6. Climbs 4 standard stairs alternating feet, not needing handrail support. Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

During the test for stair-descending, the method of descending used by the participant was categorized as follows: 1. Unable to descend 4 standard stairs; 2. Descends 4 standard stairs "marking time" (climbs one foot at a time, with both feet on a step before moving to next step), using both arms on one or both handrails; 3. Descends 4 standard stairs "marking time", using one arm on one handrail; 4. Descends 4 standard stairs "marking time", not needing handrail; 5. Descends 4 standard stairs alternating feet, needs handrail for support; 6. Descends 4 standard stairs alternating feet, not needing handrail support. Participants who could not perform a TFT within 30 seconds, including those who loss of ambulation or the TFT was above 30 seconds, a value of 30 seconds was used. Baseline was defined as the last observed measurement on or prior to the first dose of study drug. LS mean and SE was calculated using the MMRM.

The NSAA total score in the original scale is the sum of scores from 16 activities (excluding head lift). Each activity was scored as 0 (activity couldn't be performed), 1 (modified method, achieved goal without assistance), or 2 (normal, achieved goal without assistance). The total score ranges from 0 to 32, where higher scores indicate better functioning. If fewer than 13 of the 16 activities were performed, the total score was considered missing. If from 13 to 16 activities were performed, the total score was standardized by (observed total score / number of non-missing activities) x 16. If an activity could not be performed due to disease progression, a score of 0 was assigned. Baseline was defined as the last observed measurement on or prior to the first dose of study drug. LS mean and SE was calculated using analysis of covariation (ANCOVA) with multiple imputation.

Time to loss of ambulation was defined as persistent inability to perform the 10-meter run/walk test within 30 seconds at any post-baseline visit and for all remaining visits.

Time to loss of stair-climbing was defined as persistent inability to perform the 4-stair climb test within 30 seconds at any post-baseline visit and for all remaining visits.

Time to loss of stair-descending was defined as persistent inability to perform the 4-stair descend test within 30 seconds at any post-baseline visit and for all remaining visits.

Function loss was defined as a drop of score from 1 or 2 at baseline to a score of 0 at the specified post-baseline in NSAA items. The missing assessments at post baseline visits were imputed using LOCF.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A TEAE was defined as an AE that occurs or worsens on or after the first dose of ataluren (regardless of double-blind or open-label) and up to 4 weeks after the last dose of ataluren. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.