• Added a serum pregnancy test at Visit 2 (Day 1) prior to dosing for all females of childbearing potential • Added directions for collecting data for laxative use during the Treatment Period at study site visits and recording the data on the CRF • Added directions for recording all opioid pain medication(s) dosing daily in the eDiary during the Screening Period and for the first 2 weeks of the Treatment Period • Added directions that opioid therapy was then to be captured on the CRF throughout the entire duration of the study • Added list of prohibited medications that were not to be taken by subjects at any time during the study; specified that the Visit 8 (Week 24) safety data would be analyzed by the DSMB

• Added text to the synopsis and inclusion criteria stating that subjects must meet the following criteria based on an eDiary to be completed over a 14-consecutive-day qualifying period during the 28-day Screening Period: no more than 4 SBMs total over the 14-consecutive-day qualifying period. In addition, no more than 3 SBMs in a given week of the qualifying period. • Added text to specify that subjects might use laxatives during the Screening Period. • Added text to specify that tramadol and tapentadol would not be used in the calculations for either inclusion criterion No. 3, calculation of the stable opioid regimen at a total average daily dose of ≥ 30 mg equivalents of oral morphine sulfate, or for stratification by average daily dose of 30 to 100 mg equivalents of oral morphine sulfate versus > 100 mg equivalents of oral morphine sulfate. Specified that use of tramadol and tapentadol was allowed in the trial but only in conjunction with other opioid agonists • Added subheading stating that the change in frequency of BMs from baseline to selected timepoints in the Treatment Period was to be assessed as an efficacy endpoint. Subjects were to monitor BMs during the 52-week Treatment Period and were to be asked to complete the Bowel Habits paper diary. Also that during the Treatment Period, subjects were to record BM data on the paper diary during the week prior to each of the selected study visits (ie, Bowel Habits paper diary should have been filled out during Weeks 11, 23, 35, and 51, corresponding to the week prior to Study Visits 6, 8, 10 and 13, respectively).

• Change wording primary objective to “Assess the overall safety and tolerability of naldemedine in subjects with non-malignant chronic pain receiving a stable opioid therapy regimen for ≥ 1 month and having OIC.” • Change sample size per alignment with ICHE1. • Modifications made to Overall Study Design and Plan: separation of Treatment Period into Core Period Data Set and Supplemental Period Data Set (Study visits and Schedule of Events remained as presented). • Precisions made regarding blinding and unblinding. • (Efficacy) Assessments changed to Secondary (Efficacy) Assessments. • Early Termination changed: subjects who terminated early should also have Follow-up Period Visit, 2 weeks after last dose of study drug. • Addition made to General Considerations: “The Core Period Data Set will consist of all subjects with at least 24 weeks of treatment (up to and including Visit 8 at minimum). The Core Period Data Set is considered a complete and “stand alone” data set that will be used for Global Registration purposes. The Supplemental Period Data Set will consist of all remaining data (study visits not completed at the time of the Core Period data lock). For Statistical purposes, a Combined data set will also be compiled that will consist of the Core Period and the Supplemental Period.” • Primary endpoint changed from number of MACEs during 52-week Treatment Period to “Safety: The incidence of TEAEs, serious TEAEs, and AEs leading to discontinuation”. TEAEs will be used for safety analyses. The definition of TEAE is an AE which occurs from first dose of study drug until 14 days after last study dose.” • Addition AEs of Special Interest: MACEs and Assessment of Opioid Withdrawal.