Provides guidance with respect to the number of days the subjects need to remain as inpatients. All subjects need to remain as inpatients until patch removal (Day 8). From Day 8 to Day 12, subjects do not need to be inpatients as long as they return daily for assessments. PCO2 and oxygen saturation monitoring will be continuous up until Day 8. Provides further guidance that blood samples can now be taken from a central line as well as an indwelling cannula. Clarifies that hospitals can use their own internal protocol with respect to the use of Naloxone Hydrochloride.

Addresses the fact that after discussions with the Medicines for Children Research Network (MCRN), it was decided that recruitment would only be open to subjects weighing ≥15kg. The study will now be conducted in two phases with subjects weighing ≥25kg being recruited in the first phase of the study. The data obtained from these subjects will then be reviewed by an Independent Data and Safety Monitoring Committee (IDSMC). If the IDSMC is satisfied that there are no significant safety concerns, subjects weighing ≥15kg and <25kg will then be included in the second phase of the study. This approach also leads to slight changes in dose being administered for safety purposes. As this study will now be only conducted in children weighing ≥15kg, this leads to a change in study title. The study title now is: BUP1501: A multi-centre, open-label, single therapy, dose ranging study to characterise the pharmacokinetics and tolerability of BTDS 5-20 μg/h in children who require opioid analgesia for severe mouth pain secondary to chemotherapy induced mucositis Also addresses the fact that the original protocol was not clear that the capnography was mandatory and continuous for the whole time that the subject had the patch applied, so this has been re-worded. Recommends that the patch is positioned on/near the subject’s shoulder blade and that the patch can be removed if it is felt the subject has achieved adequate pain control

Addresses the fact that 7-day buprenorphine transdermal system has a changed therapeutic indication in adults and is now indicated for the treatment of non-malignant pain of moderate intensity when an opioid is necessary for obtaining adequate analgesia. After extensive discussions with Dr Richard Hain (Principal Investigator) and the Danish Regulatory Authorities (DKMA) who act as the reference Member State for BuTrans, it was felt that this study would benefit from assessing whether any children entering the study had moderate to severe pain. There would be no change in the study design; the FLACC or FPS (R) pain scales will be utilised in the same manner and the pain score on entry will be used as a baseline pain score. These pain scores would be reviewed to see if some children classified their pain as moderate rather than severe. Although we expect the majority of children suffering oral mucositis to experience severe pain we know that pain is very subjective and some may report moderate pain and this would give us the opportunity to characterise the pharmacokinetics in moderate to severe pain. As this study will now be conducted in children with moderate to severe pain, this leads to a change in study title. The study title now is: BUP1501: A multi-centre, open-label, single therapy, dose ranging study to characterise the pharmacokinetics and tolerability of BTDS 5-20 μg/h in children who require opioid analgesia for moderate to severe mouth pain secondary to chemotherapy induced mucositis Also addresses some omissions from amendment number 2. In amendment number 2, all references to “age group” should have been changed to “weight group”, however some of these were omitted erroneously.

Instigated after a meeting with Dr Richard Hain (Chief Investigator), Dr Richard Howard (Principal Investigator, Great Ormond Street Hospital, UK) and representatives from the Medicines for Children Research Network, UK. It was discussed and agreed that subjects weighing ≥10kg could safely be recruited into the study (current weight limit ≥15kg) and that subjects of any weight could be recruited initially (currently recruiting only subjects weighing ≥25kg). It was felt by all of the clinicians present that neither of these two changes would compromise subject safety. It was also decided that the measurement of PCO2 andoxygen saturation levels during the study would be discretionary as this intervention was not normally part of clinical practice in these subjects.

Instigated following the meeting of the Independent Data Monitoring Committee (IDSMC) on 01 July 2011. Following an interim whole statistics analysis, 2 out of 15 patients were identified as having buprenorphine AUCt values of 87.5 and 85.3 ng.h/mL, which are above the guideline limits set out in the protocol. Guidelines for the IDMC are to recommend stopping the study if any subject has an AUCt measure of buprenorphine greater than 82 ng.h/mL. It was therefore decided by the sponsor on the 20 April 2011 to put recruitment on hold until the IDSMC had convened to review the interim safety data and pharmacokinetic exposure profile and make a recommendation on whether the study should continue in its current design. The IDSMC suggested the following modifications to the protocol, which form the basis of this amendment: • Increase the lower age limit to 2 years • Increase the lower weight limit to 12 kg • Increase the AUCt safety threshold recommendation for the IDMC, based on data from more recent healthy volunteer studies (increased to greater than 156 ng.h/mL). • Recommend that when a patient is immobile such as in a high dependency unit or PICU that an alternative patch site (above the abdomen) could be considered • If the Investigator feels it is appropriate to use a different strength of patch from the recommended dose, then this is allowable (especially if the subject has a weight close to the lower limits of the dose) • A further meeting of the IDSMC to be convened after the next 15 patients have been recruited with the revised protocol The risk benefit document has been updated with the above information and there is considered to be no change to the risk benefit profile for the IMP.

Instigated following a recommendation from the UK Ethics Committee (letter dated 15 August 2011). Further guidance has been included in the protocol regarding how close to the lower weight limit a child should be in order to allow the clinician to exercise their discretion to change to a lower dose.