The protocol amendments include several key updates. Firstly, the eligibility criteria were refined to specify that participants must be children aged 12 to <18 years at the time of consent, with a note that an approved amended protocol will be implemented before enrolling each subsequent age group. In Section 2.2, the examples of Index VTE status were corrected from "progression, regression, or resolution" to "unchanged, regression, or resolution." Section 7.1 was updated to include targeted physical examinations for evidence of bleeding at Day 14, Day 42, and Day 84 (End of Treatment, EOT) visits, as well as when clinically indicated. Additionally, visits on Days 28 and 63 were added, which can be conducted either by telephone or on-site. Lastly, the statement regarding radiologic images was revised to include "Day 84 (EOT)" and "if not medically necessary," now reading: "Radiologic images that require sedation or radiation at the Day 42 or Day 84 (EOT) visits are not required and may be omitted, if not medically necessary." These updates ensure clarity and compliance with the amended guidelines.

The protocol amendments include several significant updates. Appendix 2 was added to provide the dose selection rationale for Amendment 3, detailing eliquis (apixaban) dose recommendations for subjects aged 2 to 18 years, both those who are ≥35 kg and those who are <35 kg. Section 12, which covers the background and rationale for dose selection, was updated to include the revised eliquis (apixaban) doses for Age Groups 1 and 2 in Table 1. The follow-up period was changed from "30±5 days post End of Treatment" to "35±5 days post End of Treatment" to comply with current Pfizer and BMS SOPs. Inclusion criterion 1 was updated to allow for the enrollment of children aged 2 to 18 years at the time of consent, covering both age groups 1 and 2. Inclusion criterion 6 was corrected to ensure consistency across the protocol, requiring contraception use for at least 33 days (5 half-lives plus 30 days) after the last dose of the assigned treatment for women of childbearing potential. Additional instructions were added for subjects on eliquis (apixaban) treatment who required the medication beyond Day 84. Section 9.1 on Sample Size Determination was updated to specify that the study team, in conjunction with regulators, will evaluate exposure duration, imaging results, and other trial aspects to determine if the data from the subjects are sufficient to address the study objectives. Throughout the trial, the sponsor will monitor the number of subjects who do not complete 12 weeks of eliquis (apixaban) treatment and will determine if additional subjects need to be recruited to supplement the safety database. These updates ensure the protocol remains clear, consistent, and compliant with current guidelines.

Appendix 3 was added to provide the dose selection rationale for Amendment 4, detailing dose recommendations for subjects aged ≥3 months and weighing ≥6 kg. The Schedule of Activities in Section 6.4 was updated to include a 6-week or 12-week Extension Phase for subjects continuing on eliquis (apixaban). A footnote "p" was added to clarify that sites should continue the mg/kg dosing regimen for subjects randomized and dosed using the eliquis (apixaban) oral solution when Protocol Amendment 3 was effective, as depicted in Table 1. Section 12, covering the background and rationale for dose selection, was updated to reflect both the mg/kg dosing under Protocol Amendment 3 for subjects already dosed and the fixed-dose body weight-tiered regimen for subjects randomized or switched to the 0.5 mg tablet under Protocol Amendment 4. Inclusion criterion 1 was updated to allow the enrollment of children aged 3 months to 18 years with a minimum weight of 6 kg at the time of consent. Inclusion criterion 6 was updated per the Portugal Competent Authority's request to include abstinence from heterosexual intercourse as acceptable contraception for women of childbearing potential. Neonates were defined throughout the protocol as ≥34 weeks gestational or ≥37 weeks post-conceptual but not more than 27 days of age.

The protocol amendments include adding language in Section 5 to specify that only Vitamin K Antagonist formulations are to be administered to pediatric subjects in Germany, per local regulations. Section 7.2 and Table 4 were added to provide an overview and summary of the maximum potential blood volume collected in pediatric subjects during the study, based on a regulatory request.

The protocol amendments include several key updates. Appendix 4 was added to provide the dose selection rationale for Amendment 6, detailing dose recommendations for age group 3 subjects aged ≥28 days to 2 years and weighing ≥4 kg. The Schedule of Activities was updated to allow SOC administration up to 14 days prior to randomization and to permit local labs to replace central labs to minimize blood volume collected in younger subjects. Section 12 was updated with PK data to inform updated dosing. Section 3 added the definition of the index event and specified that midpoint imaging for subjects aged 2 years is only required at the investigator's discretion, but an EOT image should be collected. Inclusion criterion 1 was updated to allow enrollment of children aged 28 days to 18 years with a minimum weight of 4 kg. Inclusion criterion 3 was updated to include children aged 2 years with the intent to treat for 6 to 12 weeks. Exclusion criterion 1 was updated to extend the unacceptable length of time for anticoagulation treatment for the index VTE prior to randomization from 7 to 14 days. Additional inclusion and exclusion criteria were added for safety and program consistency, including criteria for oral, nasogastric, or gastric feeding tolerance, exclusion of subjects using aggressive lifesaving therapies, and exclusion of subjects with certain medical conditions. Section 5 was updated to include a 0.1 mg eliquis (apixaban) formulation and limit SOC to heparin (UFH or LMWH) for subjects aged 2 years. Section 7.6 was added to include details on the adjudication of safety and efficacy endpoints. Section 8.5 was added to define medication errors for eliquis (apixaban). Section 9.1 updated the sample size determination from 150 to 250 with rationale. These updates ensure the protocol remains clear, consistent, and compliant with current guidelines.

Appendix 5 was added to provide the dose selection rationale for Age Group 4 (≤27 days of age) in Amendment 7, including dose recommendations for neonates. Section 12.4 updated Table 2 to include starting doses for neonates in both PK and post-PK cohorts and explained dosing adjustments when a subject reaches 28 days or older. Section 2.2 clarified that endpoints would include "other thrombotic events" as a component of the primary endpoint, given the prevalence of catheter-related thrombosis in neonates. This change was reflected throughout the protocol for consistency, and other thrombotic events were also added as a secondary endpoint. The description of PE was updated to include both symptomatic and asymptomatic cases. Inclusion criterion 1 was updated to define neonates and clarify that neonates could be enrolled if they achieved a minimum weight of 2.6 kg, with relevant updates made elsewhere in the protocol. Inclusion criterion 2 was updated to include central venous catheter-related thrombosis as an example of index VTE. Exclusion criterion 1 was updated to describe pretreatment SOC requirements for both PK and post-PK cohorts. Exclusion criterion 12 was updated to include allergies to other ingredients in the eliquis (apixaban) formulation or hypersensitivity to any components of the comparators. Section 6.2.4 added language for physical examination, allowing the investigator to contact the study sponsor to discuss a possible change in dosing regimen if there is a 20% change in weight for subjects aged 2 years or older. Section 6.4 clarified that the Extension Phase is only applicable to subjects in age groups 1 through 3.