Trial Outcomes & Findings for A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy (NCT NCT02193074)

NCT ID: NCT02193074

Last Updated: 2021-02-17

Results Overview

The definition of a motor milestones responder was based on improvement in the motor milestones categories in Section 2 of the Hammersmith Infant Neurological Examination (HINE), with the exclusion of voluntary grasp, as follows: (i) subject demonstrates ≥ 2-point increase in the motor milestones category of ability to kick or achievement of maximal score on that category (touching toes), or a 1-point increase in the motor milestones category of head control, rolling, sitting, crawling, standing, or walking, and (ii) among the motor milestone categories, with the exclusion of voluntary grasp, there are more categories where there is improvement as defined in (i) than worsening. (For the category of ability to kick, worsening is defined as ≥ 2-point decrease or decrease to the lowest possible score of no kicking. For the other categories, worsening is defined as ≥ 1-point decrease.) The lowest possible score for the HINE is 0 (zero), and the highest possible score for the HINE is 28.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

122 participants

Primary outcome timeframe

assessed at the later of the Day 183, Day 302, or Day 394 study visits

Results posted on

2021-02-17

Participant Flow

Of the 149 participants screened, 27 were screening failures. A total of 122 participants enrolled and were randomized; 1 participant withdrew prior to receiving treatment.

Participant milestones

Participant milestones
Measure	Control Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen Nusinersen (2.4 mg/mL) administered as an intrathecal (IT) lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Study STARTED	41	80
Overall Study Completed During Follow-Up Period	11	26
Overall Study Completed Due to Early Study Termination	13	39
Overall Study COMPLETED	24	65
Overall Study NOT COMPLETED	17	15

Reasons for withdrawal

Reasons for withdrawal
Measure	Control Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen Nusinersen (2.4 mg/mL) administered as an intrathecal (IT) lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Overall Study Withdrawal by Subject	1	2
Overall Study Adverse Event	16	13

Baseline Characteristics

A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Control n=41 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=80 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.	Total n=121 Participants Total of all reporting groups
Age, Continuous Age at Screening	164.7 days STANDARD_DEVIATION 48.54 • n=93 Participants	147.2 days STANDARD_DEVIATION 46.85 • n=4 Participants	153.1 days STANDARD_DEVIATION 47.95 • n=27 Participants
Age, Continuous Age at First Dose	180.5 days STANDARD_DEVIATION 50.92 • n=93 Participants	163.4 days STANDARD_DEVIATION 49.57 • n=4 Participants	169.2 days STANDARD_DEVIATION 50.48 • n=27 Participants
Sex: Female, Male Female	24 Participants n=93 Participants	43 Participants n=4 Participants	67 Participants n=27 Participants
Sex: Female, Male Male	17 Participants n=93 Participants	37 Participants n=4 Participants	54 Participants n=27 Participants

PRIMARY outcome

Timeframe: assessed at the later of the Day 183, Day 302, or Day 394 study visits

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure with Day 183, Day 302, or Day 394 data; the last available assessment was used. (Participants who died or withdrew from the study were counted as non-responders and were included in the denominator for the calculation of the percentages.)

Outcome measures

Outcome measures
Measure	Control n=37 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=73 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Percentage of Motor Milestones Responders	0 percentage of participants	51 percentage of participants

PRIMARY outcome

Timeframe: Day 91, Day 182, Day 273, Day 364, Day 394

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure and who died or required permanent ventilation.

Estimated proportion of participants who died or required permanent ventilation by a given study day, based on the Kaplan-Meier product-limit method. Time to death or permanent ventilation was defined as either tracheostomy or ≥ 16 hours ventilation/day continuously for \> 21 days in the absence of an acute reversible event. This endpoint was adjudicated by a blinded, independent group of experienced clinicians, the Event Adjudication Committee (EAC), based on review of clinical study data and supporting information. Results are based on all available data.

Outcome measures

Outcome measures
Measure	Control n=28 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=31 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Time to Death or Permanent Ventilation By Day 91 (13 weeks/3 months)	0.268 proportion of participants	0.240 proportion of participants
Time to Death or Permanent Ventilation By Day 182 (26 weeks/6 months)	0.605 proportion of participants	0.294 proportion of participants
Time to Death or Permanent Ventilation By Day 273 (39 weeks/9 months)	0.702 proportion of participants	0.404 proportion of participants
Time to Death or Permanent Ventilation By Day 364 (52 weeks/12 months)	0.735 proportion of participants	0.447 proportion of participants
Time to Death or Permanent Ventilation By Day 394 (13 months)	0.735 proportion of participants	0.447 proportion of participants

SECONDARY outcome

Timeframe: assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits

A participants was considered a CHOP-INTEND responder if the change from baseline in CHOP-INTEND total score is ≥ 4 points based on assessment at the later of the Day 183, Day 302, or Day 394 study visits. CHOP-INTEND tests includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). Total scores range from 0 to 64, with higher scores indicating better movement functioning. Results are based on all available data.

Outcome measures

Outcome measures
Measure	Control n=37 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=73 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Percentage of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders	3 percentage of participants	71 percentage of participants

SECONDARY outcome

Timeframe: Day 91, Day 182, Day 273, Day 364, Day 394

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure and who died. Results are based on all available data.

Estimated proportion of participants who died by given duration thresholds, based on the Kaplan-Meier product-limit method.

Outcome measures

Outcome measures
Measure	Control n=16 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=13 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Summary of Time to Death by Day 273	0.382 proportion of particiants	0.173 proportion of particiants
Summary of Time to Death by Day 91	0.195 proportion of particiants	0.101 proportion of particiants
Summary of Time to Death by Day 182	0.348 proportion of particiants	0.141 proportion of particiants
Summary of Time to Death by Day 364	0.419 proportion of particiants	0.173 proportion of particiants
Summary of Time to Death by Day 394	0.419 proportion of particiants	0.173 proportion of particiants

SECONDARY outcome

Timeframe: Up to Day 394

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure.

Outcome measures

Outcome measures
Measure	Control n=41 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=80 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Percentage of Participants Not Requiring Permanent Ventilation	68 percentage of participants	77 percentage of participants

SECONDARY outcome

Timeframe: assessed at the later of the Day 183, Day 302, or Day 394 study visits

CMAP is an electrophysiological technique that can be used to determine the approximate number of motor neurons in a muscle or group of muscles. A participant was defined as a CMAP responder if the CMAP amplitude at the peroneal nerve was increasing to or maintained at ≥ 1 mV (comparing to the baseline) based on assessment at the later of the Day 183, Day 302, or Day 394 study visits. Results are based on all available data.

Outcome measures

Outcome measures
Measure	Control n=37 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=73 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Percentage of Compound Muscular Action Potential (CMAP) Responders	5 percentage of participants	36 percentage of participants

SECONDARY outcome

Timeframe: Day 91, Day 182, Day 273, Day 364, Day 394

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure and were below the study median disease duration.

Estimated proportion of participants who died or required permanent ventilation (EAC-adjudicated events) among participants below the study median disease duration (13.1 weeks), by given duration thresholds, based on the Kaplan-Meier product-limit method.

Outcome measures

Outcome measures
Measure	Control n=21 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=39 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration by Day 394	0.773 proportion of participants	0.271 proportion of participants
Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration by Day 91	0.238 proportion of participants	0.128 proportion of participants
Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration by Day 182	0.546 proportion of participants	0.128 proportion of participants
Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration by Day 273	0.697 proportion of participants	0.228 proportion of participants
Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration by Day 364	0.773 proportion of participants	0.271 proportion of participants

SECONDARY outcome

Timeframe: Day 91, Day 182, Day 273, Day 364, Day 394

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure and were above the study median disease duration.

Estimated proportion of participants who died or required permanent ventilation (EAC-adjudicated events) among participants above the study median disease duration (13.1 weeks), by given duration thresholds, based on the Kaplan-Meier product-limit method.

Outcome measures

Outcome measures
Measure	Control n=20 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=41 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration by Day 91	0.300 proportion of participants	0.350 proportion of participants
Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration by Day 182	0.670 proportion of participants	0.462 proportion of participants
Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration by Day 273	0.725 proportion of participants	0.584 proportion of participants
Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration by Day 364	0.725 proportion of participants	0.625 proportion of participants
Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration by Day 394	0.725 proportion of participants	0.625 proportion of participants

SECONDARY outcome

Timeframe: Screening through Day 394 (± 7 days) or early termination

Population: Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure.

AE: any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. SAE: any AE that in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening: that is, poses an immediate risk of death at the time of the event; requires in-patient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect in the offspring of the participant (whether male or female); is an important medical event in the opinion of the Investigator or Sponsor.

Outcome measures

Outcome measures
Measure	Control n=41 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=80 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs Any event	40 participants	77 participants
Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs Moderate or severe event	39 participants	70 participants
Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs Severe event	33 participants	45 participants
Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs Possibly related or related event	6 participants	9 participants
Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs Related event	0 participants	0 participants
Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs Serious event	39 participants	61 participants
Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs Related serious event	0 participants	0 participants
Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs Treatment discontinuation due to an event	16 participants	13 participants

SECONDARY outcome

Timeframe: up to Day 394 (± 7 days) or early termination

Population: Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure.

Outcome measures

Outcome measures
Measure	Control n=41 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=80 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Number of Participants With AEs Corresponding to Changes in Hematology Values Anemia	1 participants	1 participants
Number of Participants With AEs Corresponding to Changes in Hematology Values Neutrophil count increased	0 participants	1 participants
Number of Participants With AEs Corresponding to Changes in Hematology Values Leukocytosis	1 participants	0 participants

SECONDARY outcome

Timeframe: up to Day 394 (± 7 days) or early termination

Population: Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure.

Outcome measures

Outcome measures
Measure	Control n=41 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=80 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values Blood potassium decreased	0 participants	2 participants
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values Liver function test abnormal	0 participants	1 participants
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values Alanine aminotransferase increased	0 participants	1 participants
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values Aspartate aminotransferase increased	0 participants	1 participants
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values Blood chloride decreased	0 participants	1 participants
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values Blood iron decreased	0 participants	1 participants
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values Blood sodium decreased	0 participants	1 participants
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values C-reactive protein increased	1 participants	2 participants
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values Hypokalemia	3 participants	2 participants
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values Hypoglycemia	2 participants	0 participants
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values Hyperglycemia	1 participants	0 participants
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values Transaminases increased	1 participants	0 participants

SECONDARY outcome

Timeframe: up to Day 394 (± 7 days) or early termination

Population: Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure and had an assessment.

Outcome measures

Outcome measures
Measure	Control n=41 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=80 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Systolic blood pressure >160 mmHg	0 participants	0 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Diastolic blood pressure <50 mmHg	26 participants	71 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Diastolic blood pressure >90 mmHg	13 participants	12 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Diastolic blood pressure >100 mmHg	3 participants	0 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Pulse rate <60 bpm	0 participants	0 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Pulse rate >100 bpm	41 participants	80 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Temperature >38.0 C	7 participants	6 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Temperature <36.0 C	21 participants	45 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Respiratory rate <12 breaths/min	0 participants	0 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Respiratory rate >20 breaths/min	41 participants	80 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Body weight ≥7% decrease from BL	1 participants	4 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Body weight ≥7% increase from BL	33 participants	67 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Systolic blood pressure <90 mmHg	36 participants	74 participants
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Systolic blood pressure >140 mmHg	4 participants	4 participants

SECONDARY outcome

Timeframe: up to Day 394 (± 7 days) or early termination

Population: Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure and whose baseline value was not abnormal and who had at least one post-baseline value.

Shift to 'abnormal, not clinically significant' includes 'unknown' or 'normal' to 'abnormal, not clinically significant'. Shift to 'abnormal, clinically significant' includes 'unknown' or 'normal' to 'abnormal, clinically significant'.

Outcome measures

Outcome measures
Measure	Control n=34 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=65 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Summary of Shifts in 12-lead Electrocardiogram (ECG) Results Shift to abnormal, not clinically significant	5 participants	17 participants
Summary of Shifts in 12-lead Electrocardiogram (ECG) Results Shift to abnormal, clinically significant	0 participants	8 participants
Summary of Shifts in 12-lead Electrocardiogram (ECG) Results From unknown to abnormal, clinically significant	0 participants	0 participants

SECONDARY outcome

Timeframe: up to Day 394 (± 7 days) or early termination

Population: Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure.

Outcome measures

Outcome measures
Measure	Control n=41 Participants Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=80 Participants Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values	0 participants	0 participants

Adverse Events

Control

Serious events: 39 serious events

Other events: 35 other events

Deaths: 0 deaths

Nusinersen

Serious events: 61 serious events

Other events: 70 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Biogen Study Medical Director

Biogen

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	Control n=41 participants at risk Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.	Nusinersen n=80 participants at risk Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
Cardiac disorders Bradycardia	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	5.0% 4/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Cardiac disorders Tachycardia	12.2% 5/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	8.8% 7/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Gastrointestinal disorders Constipation	22.0% 9/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	35.0% 28/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Gastrointestinal disorders Diarrhoea	17.1% 7/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	13.8% 11/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Gastrointestinal disorders Dysphagia	22.0% 9/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	8.8% 7/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Gastrointestinal disorders Flatulence	2.4% 1/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	5.0% 4/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Gastrointestinal disorders Gastrooesophageal reflux disease	19.5% 8/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	12.5% 10/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Gastrointestinal disorders Salivary hypersecretion	2.4% 1/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	7.5% 6/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Gastrointestinal disorders Teething	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	17.5% 14/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Gastrointestinal disorders Vomiting	17.1% 7/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	13.8% 11/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
General disorders Oedema	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	0.00% 0/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
General disorders Pyrexia	58.5% 24/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	53.8% 43/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Bacterial tracheitis	9.8% 4/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	1.2% 1/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Bronchiolitis	4.9% 2/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	5.0% 4/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Candida infection	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	0.00% 0/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Conjunctivitis	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	6.2% 5/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Ear infection	2.4% 1/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	6.2% 5/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Influenza	0.00% 0/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	6.2% 5/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Nasopharyngitis	9.8% 4/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	17.5% 14/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Oral candidiasis	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	8.8% 7/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Pneumonia	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	8.8% 7/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Respiratory tract infection	4.9% 2/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	5.0% 4/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Rhinitis	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	2.5% 2/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Rhinovirus infection	9.8% 4/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	5.0% 4/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Stoma site infection	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	1.2% 1/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Upper respiratory tract infection	22.0% 9/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	27.5% 22/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Urinary tract infection	0.00% 0/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	7.5% 6/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Viral infection	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	5.0% 4/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Infections and infestations Viral upper respiratory tract infection	2.4% 1/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	7.5% 6/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Injury, poisoning and procedural complications Feeding tube complication	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	1.2% 1/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Investigations Oxygen saturation decreased	22.0% 9/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	11.2% 9/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Investigations Weight decreased	2.4% 1/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	5.0% 4/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Metabolism and nutrition disorders Hypokalaemia	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	0.00% 0/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Musculoskeletal and connective tissue disorders Scoliosis	4.9% 2/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	5.0% 4/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Respiratory, thoracic and mediastinal disorders Atelectasis	22.0% 9/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	11.2% 9/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Respiratory, thoracic and mediastinal disorders Bronchial secretion retention	4.9% 2/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	5.0% 4/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Respiratory, thoracic and mediastinal disorders Cough	19.5% 8/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	11.2% 9/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Respiratory, thoracic and mediastinal disorders Dyspnoea	9.8% 4/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	3.8% 3/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Respiratory, thoracic and mediastinal disorders Hypoxia	4.9% 2/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	5.0% 4/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Respiratory, thoracic and mediastinal disorders Nasal congestion	12.2% 5/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	10.0% 8/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	3.8% 3/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Respiratory, thoracic and mediastinal disorders Respiratory distress	14.6% 6/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	5.0% 4/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Respiratory, thoracic and mediastinal disorders Respiratory failure	14.6% 6/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	0.00% 0/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	7.5% 6/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	9.8% 4/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	0.00% 0/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Respiratory, thoracic and mediastinal disorders Upper respiratory tract congestion	2.4% 1/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	7.5% 6/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Skin and subcutaneous tissue disorders Decubitus ulcer	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	0.00% 0/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Skin and subcutaneous tissue disorders Dermatitis contact	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	2.5% 2/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Skin and subcutaneous tissue disorders Dermatitis diaper	9.8% 4/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	7.5% 6/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Skin and subcutaneous tissue disorders Erythema	7.3% 3/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	1.2% 1/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.
Skin and subcutaneous tissue disorders Rash	9.8% 4/41 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.	11.2% 9/80 • Screening through Day 394 (± 7 days) or early termination Treatment-emergent events are presented.