Amendment was made to reduce the number of clinic visits, to limit the number and type of assessments, and add clarifications on some of the prohibitions and restrictions based on feedback from the Investigators. These included: Pharmacogenomic consent, testing, and analysis was eliminated to reduce the visit time and total blood volume based on feedback from the Investigators. The number of clinic visits and assessments were reduced to reduce burden on subjects. Inclusion criteria and prohibitions and restrictions were clarified that subjects cannot donate blood or sperm from screening to 6 months after the last study drug injection. Exclusion criteria was added: Subjects enrolled in an investigational study for an analgesic need to be washed out for 4 weeks, not 8 weeks, or 5 half lives, whichever was longer.

Amendment allowed subjects at some European sites the option to use a paper diary in place of an e-diary for daily numerical rating scale (NRS) pain and opioid breakthrough pain medication entries. Subjects were to stay on the same type of diary throughout the course of the study. Site staff personnel were to transcribe data from paper diary to an electronic format approved by the sponsor.

Amendment was made to correct inconsistent statement at the request of an Institutional Review Board (IRB). The following text from safety evaluations, informed consent and privacy of personal data was removed because the inclusion criteria did not allow for subjects who could not make decisions on the own: “or a legally acceptable representative”. Also, the following text from Attachment 9 for Weeks 5 and 6 telephone visits was removed: “Please indicate the approximate time and dose amount of each dose of opioid breakthrough pain medication each time a dose is taken.”

Amendment was made to incorporate the changes of Amendment dated on 18-Jun-2010 into the protocol being used at European sites.

After clinical hold, the targeted population was changed to terminally ill cancer subjects as per the judgment of the investigator (example, subjects who were in or who were candidates for hospice/palliative care for end-of-life management). Prior to the clinical hold, the study enrolled cancer pain subjects on stable doses of baseline around-the-clock opioids (not including breakthrough medication doses) with a life expectancy of greater than 3 months. Based on the debilitated condition of subjects in the target population (that is, terminally ill subjects with cancer-related pain), the number of assessments and blood samples were reduced, the requirements for the injection-site evaluation performed by the subject and the Total Neuropathy Score-Nurse (TNSn) and Mini Mental State Examination (MMSE) performed before administration of each dose of study drug were deleted, the collection of pain assessment scores was simplified (by using paper diaries instead of electronic diaries) and allowing trained caregivers to assist subjects in completing the diaries, and flexibility was added for some safety assessments to reduce the burden to the subjects. The stopping rules for the study and the characterization of hepatic failure and acute renal failure as events of interest were revised. The inclusion and exclusion criteria, and prohibitions and restrictions were modified to reflect common therapies used and comorbidities observed in the terminally ill population. The requirement for a urine pregnancy test was deleted because pregnancy was unlikely to be a risk in this terminally-ill population.