Protocol Amendment 1, Version 2 (24-Aug-2012) The amendment was issued following objections raised to the submitted protocol version 1.1 (12-Jul-2012) by the Läkemedelsverket/Swedish Medical Products Agency (MPA). In addition, updates were made to improve the clarity of the protocol and the procedures to be used for some assessments.

Protocol Amendment 2, Version 3 (03-Oct-2012) The amendment was issued following objections raised to the submitted protocol version 2.0 (24-Aug-2012) by the MPA and to the submitted protocol version 1.1 (12-Jul-2012) by the Berlin State Ethics Committee (State Office of Health and Social Affairs). Changes that were made included the exclusion of patients with significant cardiovascular complications and patients who were taking potent inhibitors of CYP3A4 and CYP1A2. Furthermore, updates were made to improve the clarity of the protocol and the procedures to be used for some assessments.

Non-Substantial Protocol Amendment 3, Version 3.1 (31-Oct-2012) The amendment was issued to ensure consistency between both the protocol and the patient’s eDiary.

Protocol Amendment 4, Version 4 (23-Oct-2013) The amendment was issued to adjust the eligibility criteria for patients entering the study in order to aid recruitment, as it was proving more challenging than anticipated for the study investigators to find patients that met the entry criteria of the protocol. In addition, there had been a higher frequency of anticipated AEs, which had resulted in early discontinuations. For better tolerability to the study drug, the therapeutic dose was reduced from 75 mg b.i.d to 50 mg b.i.d. Specifically, the following changes were made: For a better tolerability to the study drug, AMAP102 dosage was reduced from 75 mg b.i.d to 50 mg b.i.d AMAP102 50 mg b.i.d was selected following the results obtained from the Phase I study that showed 50 mg b.i.d was safe and well tolerated and the observations from the initial blinded safety review on the patients receiving AMAP102 75 mg or placebo b.i.d A titration step was introduced to allow the patient to become accustomed to the study drug prior to administering the proposed therapeutic dose of AMAP102. The brief physical examination on Day 7 was amended to complete physical examination prior to the up-titration of the study drug. The brief physical examination on Day 28 was amended to complete physical examination as this is the Early Discontinuation Visit and in case patients do not return to the follow-up visit on Day 35. The complete physical examination on Day 35 was amended to brief physical examination. The introduction of a blinded interim analysis and a safety review, to be performed in parallel, after the first 60 randomised patients. The blinded interim analysis was to determine the need for a sample size increase and the safety review involved reviewing all reported AEs, SAEs and patient withdrawals due to an AE. The inclusion and exclusion criteria were amended in order to remove the requirement for OA The requirement for the X-rays at screening were clarified.