Protocol amendment 1 - the following changes to the protocol were included in this amendment: Interim data analyses were expected to be required for regulatory review as part of any Marketing Authorisation Applications. As such a statement to this effect was added to the statistical methods section of the synopsis and in Section 13. In addition to the Infacort granules being administered directly onto the top, and towards the back, of the child’s tongue, it was added that the granules could also be sprinkled onto yoghurt, fruit purees (e.g. apple sauce) or fruit mousses immediately before being administered to the child. The granules could also be washed down with water, breast milk, formula milk or whole milk following administration. This information was added to Section 10.2.1 of the protocol. In Section 8.5 (Previous and Concomitant Medication/Treatment) the protocol incorrectly stated that the trade names of the medications should be provided. This was amended to specify that generic names should be stated. The timing of the blood spot samples was clarified to state that these should be taken in the morning wherever possible, since this is usually the time of poor control. The statistical analysis section was updated to confirm that the change from baseline at each visit for continuous and categorical data would only be conducted if appropriate. Section 10.2.2 of the protocol (Packaging and Labelling) was updated to state that Infacort capsules would be supplied in either blister packs or bottles.

Protocol amendment 2 - the following changes to the protocol were included in this amendment: It was confirmed that AEs, whether or not they are considered serious, leading to the application of sick day rules and use of sick day medication and which lead to any medical intervention either sought or required, such as at a hospital/clinic, are to be considered to be AEs of special interest. In addition, any occurrence of adrenal crisis must be recorded as an AE of special interest. In some cases, whilst the subject is cared for at the study site for the purposes of the study, it may be necessary for the Investigator to visit the subject at their local hospital. A detailed procedure for this scenario has been added as an appendix to the protocol. The wording around administration of the granules was amended to say that the granules can be sprinkled onto a spoonful of yoghurt, fruit purees (e.g. apple sauce) or fruit mousses rather than using the term 'mixed'. A footnote was added stating that at the time of submission of this amendment (protocol version 4.0), Infacort is the subject of an ongoing Marketing Authorisation Application procedure and that for clarity, the end of study visits for each subject will occur after Infacort is commercially available locally. It was added that if a visit needs to be postponed for more than 10 days, then the subject should attend for the visit before the period of absence for safety and drug supply reasons. Subsequent visits will then be scheduled at regular intervals from the revised early visit date. Testing of hydrocortisone acetate in the blood spot analyses was removed since this is no longer analysed. It was decided that the secondary endpoint of growth velocity would not be used, but instead the standard deviation score for height and weight would be calculated for each subject using an age- and gender-matched healthy German reference cohort. This change was implemented throughout the protocol.