Evaluation of Naldemedine on Opioid-Induced Bowel Dysfunction in Patients Receiving Tramadol: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the effect of **naldemedine** on **opioid-induced bowel dysfunction** (OIBD), specifically focusing on the dysfunction caused by **tramadol**. The study aims to assess the impact of naldemedine on gastrointestinal transit, motility patterns, secretion, and colonic volume. This is clinically relevant as OIBD is a common adverse effect of opioid therapy, which can significantly affect patient quality of life and adherence to pain management regimens. By investigating these parameters, the study seeks to provide insights into the potential therapeutic benefits of naldemedine in managing OIBD, thereby improving patient outcomes in those requiring opioid treatment.

The clinical trial focuses on **opioid induced bowel dysfunction** and involves a study population exclusively composed of healthy males, aged between 20 and 40 years, of Northern European descent. The participants are opioid naïve and have a State-Trait Anxiety Inventory (STAI) score ranging from 20 to 37, indicating no or low anxiety. The trial population was selected based on their ability to read and understand Danish, and their compliance and understanding of the study details as assessed by the researcher. The sponsor has not provided information regarding the total number of participants. The study does not include female subjects to avoid the influence of menstrual cycles, and it does not involve a vulnerable population. Participants are expected to maintain their usual lifestyle, with no specific dietary or physical activity requirements mentioned.

The clinical trial is designed to evaluate the effect of **naldemedine** on **opioid-induced bowel dysfunction** (OIBD) in a controlled setting. This is a Phase 4, randomized, double-blind, placebo-controlled trial. The trial will involve the administration of **Rizmoic 200 micrograms film-coated tablets** and **Tramadol HCl Retard Mylan 100 mg prolonged-release tablets**, with a matching placebo provided by Shionogi. The trial is expected to commence on October 2, 2023, and conclude by June 30, 2025. The total duration of participant involvement is anticipated to be 10 days, with the possibility of early termination if the participant does not adhere to the study protocol or experiences adverse effects.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, health status, and opioid naivety. The main inclusion criteria include being a healthy male of Northern European descent, aged between 20 and 40 years, with no or low anxiety as measured by the STAI score. Following the screening, participants will be randomized to receive either the active treatment or placebo. The primary endpoints of the study include total gastrointestinal transit time and colorectal transit time, assessed using MTS-2. Secondary endpoints involve subjective assessments of constipation, diagnostic evaluation of opioid-induced constipation, and detailed assessments of gastrointestinal motility and colonic volume using advanced imaging techniques.

Follow-up visits will be scheduled to monitor the participants' response to the treatment and to collect data on the primary and secondary endpoints. The end-of-study visit will involve a comprehensive evaluation of the participants' health status and the collection of final data points. Participants may be withdrawn from the study if they fail to comply with the study requirements or if the investigator deems it necessary for safety reasons. The trial aims to provide valuable insights into the management of OIBD, contributing to the optimization of therapeutic strategies for patients affected by this condition.

The clinical trial involves the administration of **Rizmoic** 200 micrograms film-coated tablets, which contain the active substance **naldemedine**. Naldemedine is a chemical compound used to address opioid-induced bowel dysfunction. The pharmaceutical form of the medication is a film-coated tablet, and it is administered orally. The dosage is set at 200 micrograms per day, with a maximum treatment period of 10 days. The medication is provided by SHIONOGI B.V., and it is authorized for use in the European Union under the marketing authorization number EU/1/18/1291/001. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental medication, the trial includes the use of **Tramadol HCl Retard Mylan** 100 mg, which is a prolonged-release tablet containing the active substance **tramadol hydrochloride**. This medication is also administered orally, with a maximum daily dose of 200 mg. The treatment period for tramadol is aligned with that of naldemedine, lasting up to 10 days. Tramadol is provided by MYLAN PHARMACEUTICALS LIMITED and is authorized in the Netherlands under the marketing authorization number RVG 109064. The use of tramadol in the study is to induce bowel dysfunction, which naldemedine aims to alleviate.

A matching film-coated placebo tablet is also included in the study, provided by Shionogi. The placebo is designed to match the appearance of the active medication to maintain blinding in the trial. The placebo is administered orally, following the same dosing schedule as the active treatments, to ensure consistency in the administration process. The inclusion of a placebo group allows for the assessment of the true efficacy of naldemedine in comparison to no active treatment.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoints include the measurement of total gastrointestinal (GI) transit time and colorectal transit time, both evaluated using the MTS-2 method. Secondary endpoints encompass a range of assessments, including subjective evaluations of constipation using validated scales such as PAC-SYM, BSFS, GSRS, and BFI, as well as the diagnostic evaluation of opioid-induced constipation according to the Rome IV C6 criteria. Additionally, subjective assessment of opiate withdrawal will be conducted using the SOWS scale.

Further secondary endpoints involve segmental transit time of the stomach, small intestine, and colonic segments, also assessed with MTS-2, and detailed colonic motility evaluated using the 3D-Transit system. MRI will be utilized to assess colon volume and water content in the colon. Rear-front pressures and defecation indices will be measured using Fecobionics. These assessments will provide a comprehensive evaluation of the effect of **naldemedine** on opioid-induced bowel dysfunction, specifically focusing on gastrointestinal transit, motility patterns, secretion, and colonic volume.