This amendment was made to change all text pertaining to the use of 15 mg morphine tablets as rescue therapy. Due to the unavailability of the 15 mg dose in some of the participating countries, 10 mg tablets were used to ensure that all countries were adhering to the same rescue medication regimen. Additionally, this amendment clarified the timings for the evaluation of home readiness via Post-Anaesthetic Discharge Scoring System.

In addition to the correction of some administrative errors, this amendment detailed, added, or clarified: the addition of the long-term safety visit, that the participant’s evaluability would be decided at the Blinded Data Review Meeting, the allowance of intravenous morphine administration post-operatively to optimise the participant’s pain treatment, the recording of background treatment (in the electronic case report form, not the electronic Diary [eDiary]), flexibility regarding the taking of PK blood samples, the use of alternative anaesthesia during surgery, the causality statement for adverse events, the definition of “at rest”, the recording of concomitant illness (not past illness) and additional information regarding the safety of benzyl alcohol was added. Additionally, exclusion criterion number 16 was added to the protocol in this amendment. The schedule of assessments was updated in accordance with the changes. Twenty-three (23) participants were randomised at the time of this amendment.

In addition to a clarification of some text, this amendment detailed that paracetamol should only be taken on Days 0 to 2 (72 hours) instead of Days 0 to 7. The paracetamol background treatment was not limited to orally administered paracetamol and was administered immediately after surgery to ensure that there was sufficient pain relief from background medication and subsequent adherence to the protocol. The amendment also detailed the removal of the baseline blood-draw as it was identical to the screening blood-draw and that alternative syringes were packed with the Investigational Medicinal Product (IMP) to avoid application of the incorrect volume of IMP following surgery. Additionally, anti-emetic use was clarified. Ninety -three (93) participants were randomised at the time of this amendment.

The number of sites planned was updated to 20. The procedures for the collection of PK samples were clarified, which included decreasing the number of participants having blood samples taken for PK being reduced and clarifying that for participants not selected for PK profiling, a blood sample for PK analysis should be taken in case of any cardiac or central nervous system events. One hundred seven (107) participants were randomised at the time of this amendment.

The wording of the amended protocol concerning paracetamol (that is, stopping use of paracetamol after 3 days [Amendment 3]) unintentionally resulted in not allowing for other analgesics other than rescue morphine from Days 3 to 7. The issue of as a high number of participants had mild pain, manageable with a weak analgesic. It was not considered acceptable in the light of standard practice and the World Health Organization analgesics ladder to allow only morphine during this part of the trial. Therefore the use of paracetamol was reinstated on an as-needed basis for the period from 72 hours to 7 days post-surgery. Morphine could still be used by those participants requiring a stronger analgesic or rescue medication. A file note from the Sponsor, Nycomed (03 March 2010) also clarified this decision. Clarification of the use of ondansetron as antiemetic treatment, even though listed in the Appendix 1 of the protocol, was included. During routine monitoring visits, a number of discrepancies in the recording of oral morphine rescue medication in the eDiary, as compared to the medication dispensed, were identified through discussions with the site personnel and the source data verification process. Due to an inconsistency in the process for resolving queries on eDiary data, one eDiary entry for a participant was overlooked when cleaning the data in accordance with the procedure described above. As a consequence an additional analysis of the total morphine equivalent dosage was performed with morphine equivalent dosage for this participant set to 0. There was 1 change to the planned analysis. The pair-wise comparison of placebo versus standard bupivacaine HCl for opioid consumption was excluded. One hundred twenty-six (126) participants were randomised at the time of this amendment.