NCT04101721: BUTTERFLEYE

Study to Assess the Efficacy, Safety, and Tolerability of Intravitreal Aflibercept Compared to Laser Photocoagulation in Patients With Retinopathy of Prematurity

Completed Phase 3 Results posted Last updated 20 July 2023

What this trial tests

Phase 3 trial testing aflibercept in Retinopathy of Prematurity in 127 participants. Completed in 18 August 2022.

Timeline

30 October 2019

Primary endpoint
18 August 2022

18 August 2022

Quick facts

Lead sponsor	Regeneron Pharmaceuticals
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	127
Start date	30 October 2019
Primary completion	18 August 2022
Estimated completion	18 August 2022
Sites	52 locations across Colombia, Slovakia, Russia, Taiwan, Vietnam, Hungary, South Korea, Romania

Drugs / interventions tested

• aflibercept (AFLIBERCEPT) — full drug profile →
• laser photocoagulation

Conditions studied

• Retinopathy of Prematurity — all drugs for Retinopathy of Prematurity →

Sponsor

Regeneron Pharmaceuticals — full company profile →

Who can join

Eligibility, any sex, with Retinopathy of Prematurity. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With Absence of Active Retinopathy of Prematurity (ROP) and Unfavorable Structural Outcomes From Baseline to Week 52 of Chronological Age Primary · Baseline to week 52 of chronological age

Active ROP was ROP requiring treatment and unfavorable structural outcome was defined as retinal detachment, macular dragging, macular fold, or retrolental opacity. For participants with both eyes enrolled in the study, both eyes must have met the endpoint. Participants with only one study eye enrolled were responders if the respective eye responded.

Group	Value	95% CI
Laser Photocoagulation	77.8
Aflibercept 0.4 mg	79.6

Percentage of Participants Requiring Intervention With a Second Treatment Modality From Baseline to Week 52 of Chronological Age Secondary · Baseline to to week 52 of chronological age

Second treatment modality includes any treatment in addition to that assigned to the participant at baseline. This includes per-protocol rescue treatment (laser for aflibercept group, aflibercept for laser group), anti-VEGF agents not part of study protocol (e.g., bevacizumab, ranibizumab, commercially-available aflibercept not provided as study medication), or any ocular surgery for the management of any retinal pathology secondary to ROP (e.g., victrectomy, scleral buckle for retinal detachments).

Group	Value	95% CI
Laser Photocoagulation	18.5
Aflibercept 0.4 mg	15.1

Percentage of Participants With Recurrence of ROP Through Week 52 of Chronological Age Secondary · Baseline to week 52 of chronological age

Recurrence of disease is defined as the reappearance of the disease requiring further treatment (including retreatment or rescue), where both "presence of ROP" and "presence of active ROP requiring treatment" are marked as "Yes", after initial regression. Here, the initial regression is defined as, at a particular visit, absence of ROP or ROP treatment not required for active ROP, i.e., presence of ROP is marked as "No" or the presence of active ROP requiring treatment is marked as "No."

Group	Value	95% CI
Laser Photocoagulation	29.6
Aflibercept 0.4 mg	39.8

Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Secondary · Baseline to Week 52 of chronological age

% Ocular TEAEs

Group	Value	95% CI
Laser Photocoagulation	25.9
Aflibercept 0.4 mg	18.3

% Ocular TESAEs

Group	Value	95% CI
Laser Photocoagulation	11.1
Aflibercept 0.4 mg	6.5

Percentage of Participants With Systematic (Non-ocular) TEAEs and TESAEs Secondary · Baseline to Week 52 of chronological age

% Systematic TEAEs

Group	Value	95% CI
Laser Photocoagulation	51.9
Aflibercept 0.4 mg	47.3

% Systematic TESAEs

Group	Value	95% CI
Laser Photocoagulation	7.4
Aflibercept 0.4 mg	12.9

Adverse events — posted to ClinicalTrials.gov

Time frame: From signing of informed consent form (ICF) to end of study (week 52 of chronological age visit), an average of 42 weeks. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Laser Photocoagulation

Serious: 12/27 (44%)

Deaths: 0/27

Aflibercept 0.4 mg

Serious: 32/93 (34%)

Deaths: 1/93

Serious adverse events (46 terms)

Reaction	System	Laser Photocoagulation	Aflibercept 0.4 mg
Retinal detachment Study Eye	Eye disorders	—	—
Bronchiolitis	Infections and infestations	—	—
COVID-19	Infections and infestations	—	—
Gastroenteritis	Infections and infestations	—	—
Apnoea	Respiratory, thoracic and mediastinal disorders	—	—
Bronchopulmonary dysplasia	Respiratory, thoracic and mediastinal disorders	—	—
Inguinal hernia	Gastrointestinal disorders	—	—
Vitreous haemorrhage Study Eye	Eye disorders	—	—
Bronchitis viral	Infections and infestations	—	—
Device related infection	Infections and infestations	—	—
Medical device site infection	Infections and infestations	—	—
Neonatal infection	Infections and infestations	—	—
Pneumonia	Infections and infestations	—	—
Pneumonia aspiration	Infections and infestations	—	—
Pneumonia viral	Infections and infestations	—	—
Septic shock	Infections and infestations	—	—
Wound infection	Infections and infestations	—	—
Choking	Respiratory, thoracic and mediastinal disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Interstitial lung disease	Respiratory, thoracic and mediastinal disorders	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—
Respiratory distress	Respiratory, thoracic and mediastinal disorders	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Apnoeic attack	Respiratory, thoracic and mediastinal disorders	—	—
Aspiration	Respiratory, thoracic and mediastinal disorders	—	—

Other adverse events (16 terms — click to expand)

Reaction	System	Laser Photocoagulation	Aflibercept 0.4 mg
Bronchopulmonary dysplasia	Respiratory, thoracic and mediastinal disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Strabismus Study Eye	Eye disorders	—	—
Gastrooesophageal reflux disease	Gastrointestinal disorders	—	—
Umbilical hernia	Gastrointestinal disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Conjunctival haemorrhage Study Eye	Eye disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Inguinal hernia	Gastrointestinal disorders	—	—
Pyrexia	General disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Bacterial disease carrier	Infections and infestations	—	—
Osteopenia	Musculoskeletal and connective tissue disorders	—	—
Apnoea	Respiratory, thoracic and mediastinal disorders	—	—
Wheezing	Respiratory, thoracic and mediastinal disorders	—	—
Hypotension	Vascular disorders	—	—

Most-reported serious reactions: Retinal detachment Study Eye, Bronchiolitis, COVID-19, Gastroenteritis, Apnoea, Bronchopulmonary dysplasia, Inguinal hernia, Vitreous haemorrhage Study Eye.

Data from ClinicalTrials.gov NCT04101721 adverse events section.

Sponsor's own description

The primary objective of the study is to assess the efficacy of aflibercept compared to laser in patients diagnosed with retinopathy of prematurity (ROP). The secondary objectives of the study are to assess the need for a second treatment modality, to assess the recurrence of ROP in the study and to assess the safety and tolerability of aflibercept.

Publications & conference data

4 peer-reviewed publications reference this trial (live from Europe PMC):

1. 80 Years of vision: preventing blindness from retinopathy of prematurity.
   Wood EH, Chang EY, Beck K, Hadfield BR, et al · · 2021 · cited 51× · PMID 33674712 · DOI 10.1038/s41372-021-01015-8
2. Role of Anti-Vascular Endothelial Growth Factor (Anti-VEGF) in the Treatment of Retinopathy of Prematurity: A Narrative Review in the Context of Middle-Income Countries.
   Dogra MR, Vinekar A. · · 2023 · cited 29× · PMID 36814935 · DOI 10.2147/phmt.s391591
3. Systemic Cytokines in Retinopathy of Prematurity.
   Wu PY, Fu YK, Lien RI, Chiang MC, et al · · 2023 · cited 27× · PMID 36836525 · DOI 10.3390/jpm13020291
4. Three-Year Outcomes of Intravitreal Aflibercept versus Laser Therapy for Retinopathy of Prematurity: Interim Analysis of the Efficacy and Safety Outcomes in the FIREFLEYE next Trial.
   Stahl A, Nakanishi H, Lepore D, Wu WC, et al · · 2026 · cited 1× · PMID 41505377 · DOI 10.1159/000549717