During the feasibility assessment and set-up of the study, some changes to the evaluations specified in the protocol were agreed to ensure the study could be run in line with local practice and in line with the published quality of life (QoL) tools. These comprised the following: 1) Urinalysis added to the safety laboratory tests. 2) Clarified that pregnancy tests should be conducted on a urine sample. 3) Timing of QoL assessments amended to specify when the questionnaires should be completed in relation to waking in the morning. 4) AddiQoL questionnaire changed from weekly assessment to every 4 weeks. 5) Clarification added for what should happen if a participant receives a coronavirus disease 2019 (COVID-19) vaccine. 6) Example VAS updated with specific VASs for each treatment period. 7) Requirement for a blood sample for plasma renin activity or plasma renin concentration removed. 8) The requirement for adverse event of special interests (AESIs) to be reported and followed up in the same way as serious adverse events (SAEs) removed. 9) Clarified that SAE reporting was to be conducted using a paper SAE form not an electronic data collection tool.

Provisions for remote monitoring were added in the case of continued pandemic procedures. 1) Number of sites increased to 6 sites in 2 countries. 2) Clarified that participants with type 2 diabetes receiving regular insulin were excluded. 3) Clarified that participants receiving daily inhaled, topical, nasal, or oral steroids for any indication other than adrenal insufficiency were excluded. 4) Participants taking sleeping medication added to the exclusion criteria. 5) Requirement for SAEs on Plenadren to be reported to the Marketing Authorisation Holder was removed. 6) New section added on remote monitoring visits.

Changes to the protocol were made following review of the protocol by the regulatory authorities. Updates to the blood volume were also made following recalculation in the laboratory manual. 1) Non-high-density lipoprotein (HDL) cholesterol was removed from the assessments since this test was not performed by the central laboratory. 2) Added that any visit (home or on-site) should be delayed if the participant was stress dosing. 3) Clarified that only treatment-related SAEs occurring after the 30-day follow-up period needed to be reported and followed up. 4) Windows added for blood and saliva sampling. 5) Clarified that if the Day 29 or 57 visits were delayed, the collection of saliva and urine samples, the completion of QoL questionnaires (except the daily PROMIS 7b) were delayed until the day before the rescheduled visit. 6) Details of approval of Chronocort in the European Union (EU) added, along with the tradename of Efmody. 7) New criterion added to exclude participants with a known hypersensitivity to any of the components of the Chronocort capsules, the Plenadren tablets, the Chronocort placebo, or the Plenadren placebo. 8) Requirement for participants to fast before the 07:00 hour blood sampling point removed. 8) Added that hydrocortisone can interact with cytochrome P3A4 (CYP3A4) inhibitors and inducers so since dose adjustment was not allowed, inclusion of participants taking these medications was to be discussed with the Medical Monitor. 9) Blood volumes required updated in line with updates to the laboratory manual. 10) Clarified that all SAEs had to be reported immediately rather than within 24 hours. 11) Timepoints for the serum cortisol assessments corrected.

The following changes were made to the protocol: 1) A window of +3 days was added around the Day 29 and Day 57 visits to allow flexibility of visits around weekends etc. 2) Clarified that scheduling delays due to stress dosing were not limited to the window of 3 days noted above, and in these cases the visit should be scheduled at the soonest date feasible for the participant after 48 hours free from any stress doses. 3) Early morning pre-dose serum sample amended to specify collection time of 07:00 hours (±15 minutes). 4) Clarified that osteocalcin, Apo A-I, Apo-B and Lp(a) were not required at the Screening Visit. 5) Added that on Days 20, 21, 27, and 28 of Treatment Period 1 and Days 48, 49, 55 and 56 of Treatment Period 2, the morning dose of study drug was to be taken at 07:00 hours and the evening dose of study drug taken at 23:00 hours to ensure accurate pharmacokinetic (PK) measurements could be taken. 6) Added that if the Day 29 and Day 57 study visits were delayed, then the completion of QoL questionnaires (with the exception of the daily PROMIS 7b which was to continue to be completed daily), were also to be delayed until the day before the rescheduled visit. These assessments were then also moved out accordingly at subsequent visits. 7) Added that participants took their last dose of standard of care in the afternoon of Day 1, and the first dose of their allocated Treatment Period 1 investigational medicinal product (IMP) in the evening of Day 1. 8) Added that participants were to take their last dose of Treatment Period 1 IMP in the morning of Day 29, and the first dose of their allocated Treatment Period 2 IMP in the morning of Day 29, and the first dose of their allocated Treatment Period 2 IMP in the evening of Day 29.