Amendment 1 - Repeatability Extension This amendment implements a suggestion from a Scientific Advice Procedure with EMA (Procedure No. EMEA/H/SA/FU1/2015/SME/III) on the planned Phase III Trial of macimorelin. In the Final Advice Letter (EMA/CHMP/SAWP/295316/2015, dated 21 May 2015), the Scientific Advice Working Party (SAWP) suggested to assess the reproducibility of the macimorelin GHST, and a “three-way cross-over with two repeat macimorelin tests and one ITT per participant” was suggested, leaving open the choice of other trial design option. The amendment describes the performance of a second macimorelin GHST in subjects that have completed the trial procedures according to the core protocol AEZS-130-052 (furtheron referred to as “core trial”) and was implemented at selected trial sites in Europe. A subset of 30 participants who have completed the core trial, 10 subjects each from Group A, B, and C (subjects with high, intermediate, and low AGHD likelihood, respectively) was planned to be retested with macimorelin. No healthy control subjects (Group D) were retested, as a sufficient number of “true test-negative” subjects was included in the retested Group B and C subjects to assess the repeatability of the macimorelin GHST in subjects without AGHD. The additional macimorelin GHST was performed at or after the End-of-trial visit of the core trial to minimize the impact of the amendment on the analysis and reporting of the core trial.

Amendment 2 was implemented in a Protocol Version 2. The main reason for this Amendment 2 was a refinement of the rules for the inclusion of GHST results in the primary analysis and an extension in the scope of the Data Review Committee (DRC). Like the new task of verifying an investigator’s Group assignment of a trial subject, the adjudication of the GHST performance by the DRC had to be done before GH concentration data were available to prevent bias in the qualification of a GHST as “evaluable” or “not evaluable”. However, if potentially critical deviations in a GHST procedure would lead to the conservative adjudication of a GHST as “not evaluable”, subsequently available GH concentration data would re-qualify a GHST as “evaluable”. Under specific conditions, missing values would reasonably be imputed and also allow to re-qualify a GHST as “evaluable”, so that the repetition of that GHST would finally not be needed and justifiable. Additional changes related to clarifications of DRC-related procedures, IMP dosage, and three exclusion criteria, as well as the affiliation of the coordinating investigator. Amendment 2 was based on clinical trial protocol version 1.0 and CTP version 2.0 was applicable for all sites participating in the trial. Amendment 2 did not affect Amendment 1 (‘Exploratory evaluation of the repeatability of the macimorelin GHST’) that remained in place unchanged at all sites participating in that trial extension. For trial sites in France, Amendment 2 replaced the local amendment 1 (19-Nov-2015) which covered Change 4 of Amendment 2. For trial sites in Germany, Amendment 2 replaced a note to file (17-Dec-2015) which covered the clarification provided in Change 7 of Amendment 2.