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A 10 ml syringe with 2 mg/ml of methadone will be prepared and and study drug will be administered as intravenous bolus dose (0.15 mg/kg treatment weight (height (cm) - 100)). The study drug will be administered 1 hour prior to expected extubation.

A 10 ml syringe with 2 mg/ml of morphine will be prepared and and study drug will be administered as intravenous bolus dose (0.15 mg/kg treatment weight (height (cm) - 100)). The study drug will be administered 1 hour prior to expected extubation.

One intravenous administration of methadone (0.15 mg/kg treatment weight (height(cm)-100)) one hour prior to expected extubation.

One intravenous administration of morphine (0.15 mg/kg treatment weight (height(cm)-100)) one hour prior to expected extubation.

The role of a single-dose intraoperative methadone on postoperative pain and opioid consumption in patients undergoing Surgeon Accuracy Robot Assistant cystectomy. A prospective double-blind, randomized controlled trial investigating the effect of a single-dose of intraoperative methadone in patients undergoing robotassisted cystectomy.

During early recovery after surgery, intravenous opioids are typically administered to control the pain, either as intermittent bolus administration by nursing staff or by a patient-controlled analgesia device. Unfortunately, repeated doses or boluses of shorter-acting opioids, such as morphine, oxycodone and fentanyl, result in fluctuating blood concentrations, with the inherent risk of only relatively brief periods of adequate pain relief. Moreover, the use of shorter-acting opioids increases the risk of opioid-associated side effects, such as sedation, nausea and vomiting. An alternative approach to the postoperative use of shorter-acting opioids is therefore called for.

In this respect, methadone is an opioid with unique pharmalogical properties that may be advantageous when applied intraoperatively. A single-dose of this long acting opioid could provide a stable analgesia and potentially reduce the need for shorter-acting opioids

Method:

110 patients will be included in an investigator-initiated, prospective, randomised, double-blind, controlled trial with two arms: intervention arm (methadone 0.15 mg/kg ideal body weight). Control arm (morphine 0.15 mg/kg ideal body weight). The study will be GCP-monitored, and is approved by the Danish Health and Medicines Authority (2020041652) and the Central Denmark Region Committees on Health Research Ethics (1-10-72-275-19).

Hypothesis We hypothesize that a single-dose of intravenous intraoperative methadone is efficient and safe for the treatment of postoperative pain after cystectomy.

Objectives The primary objective is to determine whether a single-dose of intravenous methadone reduces postoperative opioid consumption when compared to morphine. The secondary objectives are to compare the effect and safety of intravenous methadone and morphine on postoperative pain, side effects, patient satisfaction and length of stay.

Randomization and medication will be handled by hospital pharmacy. Randomisation list will be concealed until all statistical analyses are made.

* plan for data analysis was decided upon at a meeting with a statistician on September 7th, 2023. The plan was made before A and B lists were obtained from the hospital pharmacy. This study will be undertaken as an equivalence trial with the application of intention to treat analysis. Missing data are assumed to be missing at random. Primary outcome will be analyzed paired or unpaired t-test for difference, depending on distribution. Analysis of secondary outcome NRS will be reported as median(interquartile range) and compared between groups at the various times using the Mann-Whitney U test. If normal distributed multilevel mixed effects linear regression will be carried out. Analysis of other secondary outcomes will be dichotomized and presented for 3 and 24 hours with X2 test.

Methadone in Cystectomy Patients

Clinical Effectiveness and Safety of Intraoperative Methadone in Patients

• Pain intensity (NRS, 0-10) at rest and coughing, questionnaires answered by nurse.

• Nausea and/or vomiting (PONV) on a 4-point Likert scale (none/mild/moderate/severe). Questionnaires answered by nurse.

Gastrointestinal function (flatus, stools) and laxatives ordained.

• Opioid consumption within the first 3 hours after extubation

• Opioid consumption within the first 24 hours after extubation

NRS (0-10) at rest and when coughing. Questionnaires answered by nurse.

• Opioid consumption within the first 72 hours after extubation

Level of sedation (Ramsey Sedation Score) assessed by PACU nurse.

Patient satisfaction with pain management (NRS 0-10) Questionnaires answered by nurse.

• Time from arrival to discharge from PACU and hospital (hours and minutes)

University of Aarhus

BCG Vaccine

Vaccines

Adjuvants, Immunologic

Immunologic Factors

Study Subjects randomized to the interventional arm will be assigned to BCG induction therapy once-weekly for 6 weeks and subsequent 1 year of maintenance (6+3x3) of which dwell-time during the first of the 6 induction instillations is 2 hours.

If side effects are registered before the second and all further instillations, Study Subject in the intervention arm will be reduced in dwell-time according to the grading of side effects as given by the study algorithm.

The Study Subjects will be treated according to guidelines with BCG instillation therapy once weekly for 6 weeks and subsequent 1 year of maintenance therapy (6+3x3) with 2 hours of dwelltime.

The same dose of the drug will be given in both arms but the dwell-time will be adjusted for the subjects in the intervention arm according to the grading of side effects given by the study algorithm.

Bacillus Calmette Guerin

Jørgen B. Jensen, Professor,DMSc

Lene Munk, MD

Knud Fabrin, MD

Gitte Lam, MD

Erik Hansen, MD

Ulla Nordström Joensen, MD, PhD Assoc. Professor

Lasse Bro, MD

Juan Luis Vásquez, MD

Sigurdur Gudjonsson

Viveka Ströck, MD

Tomas Thiel, MD

Tomas Jerlsström

Previous studies show that the majority NMIBC patients experience side effects to BCG and therefore terminate the instillations before completing all planned instillations. This will increase their risk of recurrence and potential cystectomy. The purpose of this study is to investigate if NMIBC patients who experience severe side effects to BCG instillations will experience fewer or less severe side effects if reducing dwell-time of BCG instillations.

The study will include patients from Denmark, Iceland, Norway and Sweden.

Approximately 8,000 patients are diagnosed with bladder cancer (BC) in the Nordic countries every year. The majority of BC patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). The majority of NMIBC are treated with Bacillus Calmette-Guérin vaccine (BCG) as adjuvant treatment but for carcinoma in situ it is the primary treatment. BCG is known to give a lot of side effects both local and systemic, the severity of these can lead to premature termination of the treatment.

The object of this PhD project is to investigate if reduced dwell time, the time the BCG is in the bladder, will decrease the severity of side effects due to BCG instillations.

This will be investigated in a Nordic setting and the project will be done as a two-armed randomized clinical trial.

By decreasing the severity of side effects, we hypothesize the number of patients completing all planned instillations will increase and thereby decrease the risk of the BC evolving into a more aggressive type.

multi-center, multi-national, two-armed, randomized, open-label, investigator-initiated clinical controlled - phase IV trial.

NORTH-REG Dwell-Time Study

Nordic Urothelial Cancer Research Group Study on Reduced BCG Dwell-Time in High Risk NMIBC

Number of Study Subjects completing all 6 induction instillations and subsequent maintenance installations for 12 months (6 + 3 x 3)

Recurrence rate within 24 months in Study Subjects with initial complete response

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Methadone in Cystectomy Patients	NCT04475029	Pain, Postopera... Postoperative C... Pathologic Proc... Bladder Cancer Pain Signs and Sympt... Neurologic Mani... Neurologic Symp... Side Effect of ...	Methadone Morphine	18 Years - 110 Years	University of Aarhus
Methadone in Cystectomy Patients	NCT04475029	Pain, Postopera... Postoperative C... Pathologic Proc... Bladder Cancer Pain Signs and Sympt... Neurologic Mani... Neurologic Symp... Side Effect of ...	Methadone Morphine	18 Years - 110 Years	University of Aarhus
NORTH-REG Dwell-Time Study	NCT04701151	Side Effect of ...	Bacillus Calmet...	18 Years -	Aarhus University Hospital

Spots Global Cancer Trial Database for side effect of drug