The key changes that Amendment 1 (4 October 2013) made to the protocol included the following: added clarification of BMCA inclusion criteria; added text to clarify eligibility criteria based on SBMs; changed text to clarify the steps taken for rescue laxative therapy; and added text to allow for Investigator discretion on medication that may have had a significant impact on the GI system or bowel habits.

The key changes that Amendment 2 (11 June 2014) made to the protocol included the following: clarification of allowed laxatives during the Follow-up Period; redefined allowable use of tramadol and tapentadol for clarity; and revised time points for primary efficacy endpoint for more robust analysis.

The key changes that Amendment 3 (16 October 2014) made to the protocol included the following: revised secondary efficacy endpoints to provide a more thorough clinical efficacy summary of naldemedine including effects from baseline to endpoint, baseline to the first week, straining, and CSBMs; added an exploratory endpoint to further assess the effect on SBMs without straining over time; removed PK assessment as an exploratory endpoint; changed the definition of the mITT Population to produce a population that more accurately accounted for challenges encountered by subjects required to use an electronic data capture tool; modified the Safety Population to be more inclusive in order to obtain a larger population; and further clarified the definition of insufficient primary endpoint data and a “non-response” week.