With Global Amendment 1, recruitment of patients with a body weight >40 kg was temporarily suspended. It was projected that, because of the performed capping of the maximum single starting dose at 220 mg, a considerable proportion of patients with a body weight >40 kg will have dabigatran plasma levels falling below 50 ng/mL. Of note, with Global Amendment 2 (see below) a two times daily regimen using actual calculated dosages (according to Hayton equation) was implemented instead of capped dosages.

A twice daily dosing regimen using actual calculated dosages (according to Hayton equation) was implemented. This dosing regimen also included the additional safeguard of up- or down-titration to achieve a trough plasma level of 50 to <250 ng/mL. The temporary suspension of recruitment of patients with a body weight >40 kg was terminated. It was explained that the maximal daily dose level does neither exceed a daily dose level of 22.2 mg/kg nor a single dose of 330 mg, resulting in a maximal daily dose of 660 mg in the higher age/body weight group. With this amendment, only one dose adjustment was allowed. Consequently, patients not reaching the target trough plasma concentrations after one dose adjustment were to discontinue DE and were to receive subsequently SoC at the investigator’s discretion. The extent of up-titration was modified from initially 85 - 100% to 15 -100% to not exceed maximum daily dosages based on acceptable toxicology limits. Dosing and dose adjustment nomograms were incorporated in Appendix 10.4 of the CTP. It was clarified that patients aged 6 months to <8 years and those who cannot take capsule were to receive pellets while patients aged 0 to <6 months and those who cannot take pellets at an age of 6 to <12 months were to receive OLF. For clarification, it was added to inclusion criterion 2 that patients who were switched from DE to the SoC arm during the treatment phase of trial 1160.106 for any reason were not eligible for this trial. An additional exclusion criterion was introduced: Patients in age group 0 to <2 years with gestational age at birth <37 weeks or with a body weight lower than the 3rd percentile (according to the WHO Child growth standards) were not to be entered in the trial. It was clarified that use of a specific reversal agent to counteract the antithrombotic activity of DE is allowed as soon as available in a framework of clinical investigation.

The up-titration dosing nomograms for capsules and pellets were updated. It was stated that the dosing nomograms for the OLF will be revised as well in light of the errors identified for the capsule and pellet nomograms and to reflect the acceptable daily intake of tartaric acid. It was defined that this revision will be done before opening the youngest age group (0 to <2 years).

The assessment of acceptability of all age-appropriate formulations (capsules, pellets, OLF) was added. Randomisation in a 1:1 ratio to an OLF with either a flavoured or an unflavoured solvent for reconstitution was introduced. A summary of the Phase I bioavailability trial 1160.194 was added to provide background information on the interchangeability of the different DE formulations. Information on the Phase IIa trial 1160.89 was updated. In the inclusion criteria, it was added that a temporary interruption of the anticoagulant therapy for the index VTE event or prior to the start of secondary VTE prophylaxis was acceptable, if one of the defined pre-requisites was met. In the exclusion criteria, it was clarified that central venous line insertion is not considered a major surgery and that patients with a history of asymptomatic petechial or microbleeds are eligible for the trial. The threshold when to remove patients from the trial because of low eGFR was decreased to <50 mL/min/1.73 m^2. The threshold for inclusion into the trial remained at ≥80 mL/min/1.73 m^2. A precise definition of the eGFR Schwarz formula was added. The 150 mg DE capsule was introduced to reduce the number of capsules taken by a patient at a single time point. The derived DE target doses based on Hayton calculations for newborns aged <1 month and with a body weight <3 kg were added. Dose adjustment step ranges for up-titration were corrected to 10-100% and for downtitration to 25-50% to reflect the respective dosing nomograms. The dosing nomograms for the OLF were updated. It was explained that as soon as a clinical trial with a specific reversal agent in paediatric patients is initiated, eligible patients from trial 1160.108 can be entered in this trial and receive the reversal agent. Cross reporting of laboratory results between trials is then allowed to limit the blood volume required for analysis.

In the section on sample size, it was clarified that recruitment can be kept open after 100 patients have been recruited. The final results of the completed Phase IIa PK/PD trials 1160.89 and 1160.105, which were relevant for the patients to be included in second age group (2 to<12 years) and in the youngest age group (0 to <2 years), were provided. To reflect the sequential introduction of age-appropriate formulations (and OLF in particular), it was clarified that patients in age group 2 to <12 years are to be entered and treated considering the availability of the age-appropriate DE formulations. The 60 mg and 70 mg strengths, which were not planned to be used in the trial, were removed from the dosing nomograms for DE pellets. The eGFR threshold for exclusion from the trial was changed to <60 mL/min/1.73m^2 for patients aged 12 to <18 years. For patients aged 0 to <12 years, the eGFR threshold for exclusion from the trial remained unchanged at <80 mL/min/1.73m^2. It was clarified that patients with a heart valve prosthesis requiring anticoagulation are not to be included in the trial. The analysis set for PK analyses was defined; it was specified that this analysis set will also be used for PK/PD analyses. It was defined that multiple PK/PD and safety interim analyses for any of the age groups may be considered. It was clarified that interim analyses based on selected or partial clinical trial data may be conducted for regulatory purposes. It was added that all deaths are to be considered as non-events for occurrence of PTS and therefore are to be censored. The recommendation to use a proton pump inhibitor such as pantoprazole in case of development of gastrointestinal symptoms was replaced by the recommendation to use a proton pump inhibitor according to the local standard of care in accordance with local labelling recommendations.

Active meningitis, encephalitis, and intracranial abscess at Visit 2 were added as exclusion criteria. Furthermore, patients who developed active meningitis, encephalitis, or intracranial abscess were to be discontinued from the trial medication.

The option to administer pellets was expanded to patients <6 months of age. It was explained that the use of OLF is preferred over pellets in patients <12 months of age, provided that OLF supplies are available to the site. The time window from Visit 1 (screening) to Visit 2 (first administration of trial medication) was expanded to 14 days to facilitate screening procedures. It was clarified that the discontinuation from trial medication is required if a drug-related SAE occurred. Accordingly, the option to re-start DE after a major bleeding event was deleted. Reaching steady state of the currently assigned DE formulation (i.e. at least 6 consecutive DE doses taken) was introduced as a prerequisite for considering a switch to another formulation. It was deleted that the primary analysis can only be conducted after all patients have completed the 12-month evaluation or otherwise dropped out from the trial. The requirement not to publish any trial data prior to the finalisation of CTRs was deleted. The definition of the PD endpoints was modified: PD assessments at Visit 3 (after at least 6 consecutive DE doses) and after at least 3 days following any DE dose adjustment were to be considered instead of PD assessments at Visit 4. It was clarified that the PD sample Aliquot 1, if not needed for DE concentration measurement guiding dose adjustment, can be used for the central analysis of PD and PK based on dTT (Anti-Factor IIa activity), aPTT and/or ECT. An explanation was added that the secondary endpoint of ‘number of DE dose adjustments during the treatment period’ is equivalent to the number of patients with DE adjustments during the treatment period since only one dose adjustment was allowed per patient.

The eGFR threshold in exclusion criterion 2 was lowered to <50 mL/min/1.73m^2 for all patients, irrespective of their age.