Mayet 2021.

Study characteristics
Methods	Study design: parallel‐group randomized controlled trial Number randomized (in total and per group): 110 participants in total, 55 participants each group Unit of randomization (individual or eye): individual Number analyzed (in total and per group): 54 participants in the botulinum group arm and 47 participants in the surgery group Unit of analysis (individual or eye): individual Exclusions and losses to follow‐up (total and per group): 9 participants (1 in the botulinum toxin arm and 8 in the surgery arm) were not included in the analysis. (Authors' explanation: they were lost "prior to any intervention. Six in the surgery arm expressed subsequent reservations about the surgery"). How were missing data handled?: excluded from analysis Length of follow‐up: 24 weeks Reported power calculation (Y/N), if yes, sample size and power: a sample size of 98 (49 per arm) was calculated using a Pearson Chi‐squared test with the proportion of success set at 0.65 for the surgery arm and 0.37 for the BTX arm, at a power of 80% and an alpha level of 0.05.
Participants	Country: South Africa Setting: Paediatric Ophthalmology Clinic at St John Eye Hospital. University of the Witwatersrand Baseline characteristics 1. Botulinum toxin injections, n = 54 Age (mean ± SD, range): 24.7 ± 13.6 months Gender: 20 boys and 34 girls Esotropia angle in PD (mean ± SD): 60.93 ± 13.7 Esotropia angle in PD (median, IQR): 65 (50‐70) Esotropia 40‐60 PD: 26 (44%) Esotropia > 60 PD: 28 (51.9%) 2. Surgical intervention, n = 47 Age (mean ± SD, range): 29.4 ± 15.2 months Gender: 20 boys and 27 girls Esotropia angle in PD (mean ± SD): 62.55 ± 11.79 Esotropia angle in PD (median, IQR): 60 (55‐70) Esotropia 40‐60 PD: 24 (51.1%) Esotropia > 60 PD: 23 (48.9%) Overall, n = 101 Age (mean ± SD, range): 26.9 ± 14.5 months Gender: 40 boys and 61 girls Esotropia angle in PD (mean ± SD): 61.68 ± 12.81 Esotropia angle in PD (median, IQR): 60 (55‐70) Inclusion criteria: children with onset of esotropia before 6 months of age; with large‐angle IE, defined as esotropia of ≥ 40 PD, between the ages of 6 months and 6 years at baseline; informed written parental consent Exclusion criteria: children with significant pattern deviation, neurological impairment and hyperopia of > + 5.00 diopters. Children underwent a full examination including a cycloplegic refraction, fundus examination and orthoptic assessment. Those with a refractive error ≥ + 2.50 DS were initially given their prescription and if there was no change or minimal change in their esotropic angle, patients were classified as IE and enrolled in the study. Baseline equivalence: comparable
Interventions	Intervention‐botulinum toxin injections: "Botulinum toxin (BotoxTM Allergan) was injected in each medial rectus muscle, administered subconjunctively after the muscle was grasped using forceps as described by Benabent et al. (Benabent 2002). All children received an initial dose of 5 units (U) that was repeated, for a maximum of three injections if the esotropia was > 10 PD at visits at 3, 6, 12 or 24 weeks following the last injection. The dosage at subsequent visits depended on the degree of esotropia, 5 U for deviations ≥ 40 PD and 3 U for deviations < 40 PD." Comparator‐surgery: "In the surgical arm, children underwent standard bilateral medial rectus muscle recession surgery for esotropia ≤ 60 PD. The medial recti were recessed to a maximum of 7 mm with 3U of botulinum toxin given intraoperatively to each recessed muscle in cases > 60 PD to augment the recessions."
Outcomes	Outcomes reported: complete response defined as orthophoria or residual esotropia of ≤ 10 PD; partial response as residual esotropia of > 10 PD and ≤ 20 PD and deemed acceptable by the parents; failures or non‐response as > 20 PD. Adverse outcomes: "Complications in the botulinum toxin arm were; partial transient ptosis in 9 children (16.7%), which resolved within 6–8 weeks, transient vertical deviation in 3 children (5.6%) and consecutive exotropia in 13 children (24.1%). Seven of the children with exotropia were associated with complete response. There were no cases of globe perforation, infections or chemosis following botulinum toxin injections." "The two children with exotropia, received botulinum toxin to the lateral rectus muscles as initial therapy followed bimedial rectus muscle advancement and had final non‐response. In total, 45 children (95.7%) had a complete response or partial response in the surgery arm. There were no major complications of surgery such as slipped or lost muscles, globe perforation or anaesthetic‐related issues." Measurement time points: 3, 6, 12 and 24 weeks
Notes	Study period: from January 2015 to January 2018 Publication language: English Trial registration: not found (PACTR201508001241218 was listed as an ongoing study in the previous version of this review. However, the website was no longer accessible.) Conflicts of interest: "The authors declare that they have no conflict of interest. " Funding source: "the Anglo‐American Chairman’s Fund for grant in facilitating additional surgical lists for the study"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Random sequence was not truly random. "Within each age category, participants were randomized by an independent study assistant and assigned to either the botulinum toxin (odd numbers) or surgery (even numbers) arms."
Allocation concealment (selection bias)	High risk	Study personnel were able to foresee the upcoming assignment when the allocation was performed based on odd or even number of enrollment.
Blinding (performance bias and detection bias) Investigators	High risk	This study was an "unblinded" study. Study investigators could not be masked due to the nature of interventions.
Blinding (performance bias and detection bias) Participants	High risk	This study was an "unblinded" study.
Blinding (performance bias and detection bias) Personnel	Low risk	Although the outcome assessor was not masked the outcomes were objective, and it is unlikely that results were affected by the knowledge of the intervention that participants received.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	110 patients were randomized (55 in each arm) nine of them were excluded "one patient was lost in the botulinum toxin and 8 in the surgery arm". The study investigator described the losses in each arm: "nine children were lost (one in the toxin arm and eight in the surgery arm)", and that they were lost "prior to any intervention. Six in the surgery arm expressed subsequent reservations about the surgery. Not an uncommon occurrence ...". It was unclear about the remaining three participants.
Selective reporting (reporting bias)	Low risk	We do not have access to the trial protocol because the URL was no longer available, but the study investigator sent us the file of the approval of the University trial ethics committee. All the outcomes were stated.
Other bias	Unclear risk	In the surgery arm, 23 children with very‐large‐angle esotropia (i.e. > 60PD) had botulinum toxin augment plus surgery, not surgery alone. "The medial recti were recessed to a maximum of 7 mm with 3 U of BTX given intraoperatively to each recessed muscle in cases > 60 PD to augment the recessions."