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.

The age cut-offs for stratum 2 and 3 were changed based on the EMA PDCO opinion dated 29 Sep 2014 .A twice daily dosing regimen using actual calculated dosages (according to Hayton equation) was implemented. It was clarified that patients aged 6 months to <8 years and those who cannot take capsule at an age of 8 to <12 years were to receive pellets, and that patients aged 0 to <6 months and those who cannot take pellets at an age of 6 to <12 months were to receive OLF. In the benefit-risk section of the CTP, information on the Phase IIa trials was updated as these trials were a prerequisite for opening the second age group (2 to <12 years). 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 all patients who continued treatment for VTE, regardless of whether this was a switch from DE to SoC or from one SoC to another, are not considered early discontinued. A more detailed and age-specific description of the blood sample volumes collected during the trial was added.

The up-titration dosing nomograms for capsules and pellets were updated to correct calculation errors. It was stated that the OLF dosing nomograms will need to be updated as well in advance of opening the youngest age group (0 to <2 years).

The assessment of thrombus extension at Visit 5 was removed from the CTP, to better reflect the clinical routine for follow-up of patients with VTE and to eliminate potential unwarranted radiation exposure. A summary of Phase I bioavailability trial 1160.194 was added to provide background information for considering DE formulations to be used interchangeable, without the need for a conversion factor. It was clarified that patients requiring VTE therapy beyond 3 months have to be switched at Visit 8 (Day 84) to SoC treatment (if randomised to DE) or continue SoC treatment (if randomised to the SoC arm) and could be treated with SoC during the follow-up period. Randomisation in a 1:1 ratio to an OLF with either a flavoured or an unflavoured solvent for reconstitution was introduced. It was clarified that eGFR retesting was allowed once during the screening period. The criterion when to remove patients from the trial because of low eGFR was decreased to <50 mL/min/1.73m². The 150 mg DE capsule was introduced to reduce the number of capsules taken by patient at a single time point. It was explained that in case of gastrointestinal symptoms, DE was to be taken with a meal or concomitantly with a proton pump inhibitor. 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.

The sample size was reduced from a minimum of 240 to a minimum of 180 evaluable patients for the efficacy component of the co-primary endpoint. The duration of the follow-up period was reduced from 9 months to 1 month after the last intake of trial medication. It was clarified that freedom from thrombus progression at the end of therapy (Day 84 after randomisation or eEOT whichever comes first) will be assessed in comparison with baseline. It was clarified that pre-treatment with VKAs during the initial parenteral treatment was acceptable if the INR had not reached a therapeutic level (INR <2.0) at the time of randomisation. To facilitate an expedited evaluation of the risk of bleeding in patients <2 months of age, the first trough dabigatran concentration assessment (at Visit 3) was required to be supplemented by a local aPTT measurement for patients <2 months and a baseline aPTT was also required to be available for these patients. The final results of the completed Phase IIa PK/PD trials relevant for the patients to be included in second age group (2 to<12 years) and in youngest age group (0 to <2 years) were provided. The eGFR threshold for exclusion from the trial was changed to <60 mL/min/1.73m2 for patients aged 12 to <18 years. 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 SoC in accordance with local labelling recommendations. 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 analysis set for PK analyses was defined. It was clarified that interim analyses based on selected or partial clinical trial data may be conducted for regulatory purposes.

The sample size was further reduced from a minimum of 180 to a minimum of 141 evaluable patients for the efficacy primary endpoint, but it was clarified that the recruitment of further patients could be continued if required by regulatory authorities. Based on FDA advice, freedom from major bleeding events was changed from the coprimary safety endpoint to a secondary endpoint. Fondaparinux was added as allowed SoC treatment based on therapeutic guidelines and EMA advice. The flow chart was amended with several clarifications regarding visit windows, the collection of post-dose samples, and follow-up periods.

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. A preference for usage of OLF over pellets in patients <12 months of age, provided that OLF supplies are available to the site, was implemented. The time window from Visit 1 (screening) to Visit 2 (first administration of trial medication)was expanded to 21 days to facilitate screening procedures. It was clarified that the discontinuation from trial medication is required if a drug-related SAE occurred. It was added that the type of SoC may be changed during the treatment period in patients randomised to SoC. The wording of several secondary endpoints was modified to clarify the meaning

The eGFR threshold in exclusion criterion 2 was lowered to <50 mL/min/1.73 m² for all patients, irrespective of their age.