Trial Outcomes & Findings for Aflibercept for Retinopathy of Prematurity - Intravitreal Injection Versus Laser Therapy (NCT NCT04004208)

Last Updated: 2022-05-06

Results Overview

Active ROP was defined as ROP requiring treatment. Unfavorable structural outcomes included retinal detachment, macular dragging, macular fold, or retrolental opacity.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

113 participants

Primary outcome timeframe

At 24 weeks after starting study treatment

Results posted on

2022-05-06

Participant Flow

Study was conducted at 64 centers in 27 countries or regions, between 25-SEP-2019 (first participant first visit) and 12-Feb-2021 (last participant last visit).

121 participants were screened. 1 participant was a screen fail and 2 participants were withdrawn by parent/guardian. 118 participants were randomized, 75 participants were randomized to the aflibercept arm and 43 to the laser arm. 113 participants were treated, 5 participants randomized to the laser photocoagulation arm were withdrawn before receiving any study intervention.

Participant milestones

Participant milestones
Measure	Aflibercept 0.4 mg One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Overall Study STARTED	75	38
Overall Study SAF	75	38
Overall Study PKS	75	0
Overall Study AAS	75	0
Overall Study COMPLETED	68	36
Overall Study NOT COMPLETED	7	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Aflibercept 0.4 mg One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Overall Study Withdrawal by parent/guardian	1	1
Overall Study Death	3	0
Overall Study COVID-19 pandemic	1	0
Overall Study Physician Decision	1	0
Overall Study Adverse Event	1	1

Baseline Characteristics

Aflibercept for Retinopathy of Prematurity - Intravitreal Injection Versus Laser Therapy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation n=38 Participants Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.	Total n=113 Participants Total of all reporting groups
Age, Continuous	26.43 weeks STANDARD_DEVIATION 2.1 • n=5 Participants	26 weeks STANDARD_DEVIATION 1.6 • n=7 Participants	26.29 weeks STANDARD_DEVIATION 1.9 • n=5 Participants
Age, Customized In utero	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized Preterm newborn infants (gestational age < 37 wks)	75 Participants n=5 Participants	38 Participants n=7 Participants	113 Participants n=5 Participants
Age, Customized Newborns (0-27 days)	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized Infants and toddlers (28 days-23 months)	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized Children (2-11 years)	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized Adolescents (12-17 years)	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized Adults (18-64 years)	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized From 65-84 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized 85 years and over	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Female	34 Participants n=5 Participants	19 Participants n=7 Participants	53 Participants n=5 Participants
Sex: Female, Male Male	41 Participants n=5 Participants	19 Participants n=7 Participants	60 Participants n=5 Participants
Race/Ethnicity, Customized White	55 Participants n=5 Participants	28 Participants n=7 Participants	83 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Asian Indian	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Chinese	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Japanese	10 Participants n=5 Participants	6 Participants n=7 Participants	16 Participants n=5 Participants
Race/Ethnicity, Customized Korean	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Asian: Other	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Multiple	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
ROP classification by investigator Zone I excluding AP-ROP	15 Participants n=5 Participants	7 Participants n=7 Participants	22 Participants n=5 Participants
ROP classification by investigator Zone II excluding AP-ROP	46 Participants n=5 Participants	26 Participants n=7 Participants	72 Participants n=5 Participants
ROP classification by investigator AP-ROP: Zone I	12 Participants n=5 Participants	4 Participants n=7 Participants	16 Participants n=5 Participants
ROP classification by investigator AP-ROP: Zone II	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: At 24 weeks after starting study treatment

Active ROP was defined as ROP requiring treatment. Unfavorable structural outcomes included retinal detachment, macular dragging, macular fold, or retrolental opacity.

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation n=38 Participants Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Proportion of Participants With Absence of Active ROP and Unfavorable Structural Outcomes	0.855 Proportion of participants	0.821 Proportion of participants

SECONDARY outcome

Timeframe: From baseline (treatment) up to week 24.

A second treatment modality for ROP was either rescue treatment or any other surgical or nonsurgical treatment for ROP (e.g. IVT anti-VEGF injection, ablative laser therapy, cryotherapy, or vitrectomy) captured as concomitant medication or surgery after study start.

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation n=38 Participants Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Proportion of Participants Requiring Intervention With a Second Treatment Modality	0.072 Proportion of participants	0.096 Proportion of participants

SECONDARY outcome

Timeframe: From baseline (treatment) up to week 24.

Participants with recurrence of ROP were defined as subjects requiring re-treatment or rescue treatment after in the past the absence of treatment-requiring active ROP had been confirmed by the investigator.

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation n=38 Participants Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Proportion of Participants With Recurrence of ROP	0.161 Proportion of participants	0.063 Proportion of participants

SECONDARY outcome

Timeframe: From baseline (treatment) up to week 24.

Eyes were evaluated for change in ROP activity scale proposed by the International Neonatal Consortium (2018). ROP Activity Scale value range is from 0 to 22. Value 0 to 7 are considered mild, 8 to 12 are moderate, and 13 to 22 are severe. Value 0 means the best and value 22 means the worst. Eyes evaluation was done at baseline and each visit.

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation n=38 Participants Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Exploration of ROP Activity Scale Proposed by the International Neonatal Consortium Baseline	16.20 Scores on a scale Standard Deviation 2.81 • Interval 2.81 to	15.63 Scores on a scale Standard Deviation 3.53 • Interval 3.53 to
Exploration of ROP Activity Scale Proposed by the International Neonatal Consortium Change from baseline to Week 24	-15.42 Scores on a scale Standard Deviation 4.46 • Interval 4.46 to	-14.77 Scores on a scale Standard Deviation 4.19 • Interval 4.19 to

SECONDARY outcome

Timeframe: From baseline (treatment) up to week 24

A treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that was observed or reported after the first and not later than 30 days after the last administration of study treatment. Participants treated after week 21 were followed-up for adverse events up to week 28. Ocular TEAEs in treated eyes only were reported

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation n=38 Participants Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs)	38.7 Percentage of participants	36.8 Percentage of participants

SECONDARY outcome

Timeframe: From baseline (treatment) up to week 24

Participants treated after week 21 were followed-up for adverse events up to week 28. Ocular SAEs in treated eyes only were reported.

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation n=38 Participants Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Percentage of Participants With Ocular Serious Adverse Events (SAEs)	13.3 Percentage of participants	7.9 Percentage of participants

SECONDARY outcome

Timeframe: From baseline (treatment) up to week 24

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation n=38 Participants Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Percentage of Participants With Systemic TEAEs	52.0 Percentage of participants	63.2 Percentage of participants

SECONDARY outcome

Timeframe: From baseline (treatment) up to week 24

Participants treated after week 21 were followed-up for adverse events up to week 28. Systemic SAEs only were reported.

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation n=38 Participants Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Percentage of Participants With Systemic SAEs	24.0 Percentage of participants	36.8 Percentage of participants

SECONDARY outcome

Timeframe: From Day 1 up to week 24.

Population: The outcome measure was analyzed based on pharmacokinetic analysis set (PKS). The PKS included all participants who received aflibercept treatment at the baseline visit and who had at least one nonmissing PK assessment following the first dose of study drug.

Blood samples for determination of aflibercept concentrations in plasma were collected in the aflibercept 0.4 mg arm at Day 1 (within 24 hours after injection), and at weeks 2 and 4, and if feasible also at weeks 8, 12 and 24. Statistics for week 8, 12, 24 not calculated as \> 1/3 of the concentrations were below the lower limit of quantification. Free Aflibercept Concentrations in Plasma were only measured in the Aflibercept 0.4 mg treatment arm.

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Concentrations of Free Aflibercept in Plasma WEEK 0, DAY 1	480.607 ng/mL Standard Deviation 884.724	—
Concentrations of Free Aflibercept in Plasma WEEK 2	218.965 ng/mL Standard Deviation 358.933	—
Concentrations of Free Aflibercept in Plasma WEEK 4	133.093 ng/mL Standard Deviation 205.052	—

SECONDARY outcome

Timeframe: Baseline (treatment) and 12 weeks after aflibercept injection

Immunogenicity was characterized by anti-drug antibody (ADA) responses in patients in the aflibercept 0.4 mg arm. Serum samples were taken at baseline prior to the injection and at 12 weeks after injection. ADA titers were summarized for 3 categories: Low (titer \<1,000); Moderate (1,000 ≤ titer ≤ 10,000); High (titer \>10,000). ADA in serum were only measured in the Aflibercept 0.4 mg treatment arm.

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Number of Participants With Anti-drug Antibodies (ADA) Baseline · ADA positive response	0 Participants	—
Number of Participants With Anti-drug Antibodies (ADA) Baseline · ADA negative response	75 Participants	—
Number of Participants With Anti-drug Antibodies (ADA) Week 12 · ADA positive response	1 Participants	—
Number of Participants With Anti-drug Antibodies (ADA) Week 12 · ADA negative response	74 Participants	—

SECONDARY outcome

Timeframe: At 12 weeks after aflibercept injection

NAb status was evaluated for the samples that were positive in the ADA assay and had sufficient volume to analyze. NAb were only measured in participants with positive ADA in the Aflibercept 0.4 mg treatment arm

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=1 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Number of Participants With Potential Neutralizing Antibodies (NAb)	0 Participants	—

SECONDARY outcome

Timeframe: From baseline (treatment) up to week 24.

Total number of injections in both eyes.

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation n=38 Participants Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Number of Aflibercept Administrations 0 aflibercept administration	0 Participants	34 Participants
Number of Aflibercept Administrations 1 aflibercept administration	4 Participants	0 Participants
Number of Aflibercept Administrations 2 aflibercept administrations	55 Participants	3 Participants
Number of Aflibercept Administrations 3 aflibercept administrations	6 Participants	1 Participants
Number of Aflibercept Administrations 4 aflibercept administrations	10 Participants	0 Participants

SECONDARY outcome

Timeframe: From baseline (treatment) up to week 24.

Total number of laser treatment in both eyes. If multiple sessions of laser treatment were necessary within 1 week from baseline, they were counted as a single treatment.

Outcome measures

Outcome measures
Measure	Aflibercept 0.4 mg n=75 Participants One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation n=38 Participants Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Number of Laser Treatments 4 laser treatments	0 Participants	2 Participants
Number of Laser Treatments 0 laser treatment	70 Participants	0 Participants
Number of Laser Treatments 1 laser treatment	3 Participants	4 Participants
Number of Laser Treatments 2 laser treatments	2 Participants	30 Participants
Number of Laser Treatments 3 laser treatments	0 Participants	1 Participants
Number of Laser Treatments 6 laser treatments	0 Participants	1 Participants

Adverse Events

Aflibercept 0.4 mg

Serious events: 9 serious events

Other events: 53 other events

Deaths: 3 deaths

Laser Photocoagulation

Serious events: 10 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Therapeutic Area Head

Bayer

Phone: (+) 1-888-8422937

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The disclosure restriction is that the PI has to ensure that the sponsor can review results communications at least 60 days prior to the planned public release.
Publication restrictions are in place

Restriction type: OTHER

Measure	Aflibercept 0.4 mg n=75 participants at risk One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.	Laser Photocoagulation n=38 participants at risk Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
Cardiac disorders Pulmonary valve stenosis	0.00% 0/75 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	2.6% 1/38 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Eye disorders Corneal oedema	1.3% 1/75 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	0.00% 0/38 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Eye disorders Retinal detachment	4.0% 3/75 • Number of events 3 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	5.3% 2/38 • Number of events 2 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Eye disorders Retinal haemorrhage	2.7% 2/75 • Number of events 2 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	0.00% 0/38 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Eye disorders Retinopathy of prematurity	1.3% 1/75 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	0.00% 0/38 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Eye disorders Vitreous haemorrhage	1.3% 1/75 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	0.00% 0/38 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Gastrointestinal disorders Necrotising colitis	0.00% 0/75 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	2.6% 1/38 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Infections and infestations Bronchiolitis	2.7% 2/75 • Number of events 2 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	2.6% 1/38 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Infections and infestations Conjunctivitis	0.00% 0/75 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	2.6% 1/38 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Infections and infestations Pneumonia	1.3% 1/75 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	0.00% 0/38 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Infections and infestations Rhinitis	0.00% 0/75 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	2.6% 1/38 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Infections and infestations Upper respiratory tract infection	1.3% 1/75 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	0.00% 0/38 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Infections and infestations COVID-19	1.3% 1/75 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	0.00% 0/38 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Injury, poisoning and procedural complications Overdose	1.3% 1/75 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	0.00% 0/38 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Investigations C-reactive protein increased	0.00% 0/75 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	2.6% 1/38 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Investigations Intraocular pressure increased	1.3% 1/75 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	0.00% 0/38 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Respiratory, thoracic and mediastinal disorders Apnoea	0.00% 0/75 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	2.6% 1/38 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Respiratory, thoracic and mediastinal disorders Bronchopulmonary dysplasia	1.3% 1/75 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	0.00% 0/38 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	1.3% 1/75 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	0.00% 0/38 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Respiratory, thoracic and mediastinal disorders Respiratory arrest	0.00% 0/75 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	2.6% 1/38 • Number of events 1 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.
Respiratory, thoracic and mediastinal disorders Infantile apnoea	0.00% 0/75 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.	5.3% 2/38 • Number of events 2 • After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study.