Non-Inferiority Study of Mannitol Versus Macrogol Combination in Bowel Preparation for Elective Colonoscopy

The primary objective of this study is to demonstrate the **non-inferiority** of Mannitol compared to the standard Plenvu® same-day dosing regimen in bowel cleansing for elective colonoscopy. This is clinically relevant as effective bowel preparation is crucial for the success of colonoscopy, impacting the detection of colonic lesions and overall procedural outcomes.

Secondary objectives include:

• Evaluating indicators of quality in performed colonoscopies, which is important for ensuring high standards in endoscopic procedures.
• Assessing adherence and acceptability of bowel preparation with Mannitol and Plenvu®, as patient compliance and satisfaction can influence the effectiveness of the preparation.
• Evaluating the safety and tolerability of Mannitol and Plenvu®, which is essential for patient safety and minimizing adverse effects.
• Conducting a pharmacokinetic (PK) sub-study to evaluate the PK profile of 100 g Mannitol powder dissolved in 1,000 ml of water in patients with and without factors that can influence pharmacokinetic parameters, such as inflammatory bowel disease (IBD) and mild-to-moderate renal failure. This is significant for understanding the drug's behavior in different patient populations.

The clinical trial involves **subjects** scheduled for elective colonoscopy performed according to ESGE (European Society of Gastrointestinal Endoscopy) guidelines. The study population includes both **males and females** aged 18 years and older. Participants are required to have the ability to consent and provide signed written informed consent, and they must be willing and able to complete the entire study and comply with instructions. The trial population was selected based on these criteria, ensuring that all participants are scheduled for the specified medical procedure. The sponsor has not provided information regarding the total number of participants. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that special considerations may be necessary for certain participants.

The clinical trial is designed as a **randomized**, parallel-group, endoscopist-blinded, non-inferiority study to evaluate the efficacy, safety, and patient acceptance of **mannitol** versus a standard bowel preparation regimen for elective colonoscopy. The trial aims to demonstrate the non-inferiority of mannitol compared to the standard Plenvu® same-day dosing regimen in bowel cleansing. The study will involve adult participants scheduled for elective colonoscopy according to the European Society of Gastrointestinal Endoscopy (ESGE) guidelines. The trial is expected to commence recruitment on July 1, 2025, and conclude by March 31, 2026.

Participants will be involved in the study for a maximum of one day, corresponding to the duration of the bowel preparation regimen. The trial will include several key visits: an initial **screening** visit to assess eligibility based on inclusion criteria such as age (≥18 years), ability to provide informed consent, and willingness to comply with study procedures. Follow-up visits will be conducted to monitor the primary endpoint, which is the proportion of patients achieving adequate bowel cleansing, defined by a Boston Bowel Preparation Scale (BBPS) total score of ≥6. Secondary endpoints include adenoma detection rate, caecal intubation rate, and incidence of adverse events.

The study will employ a double-blind methodology, ensuring that neither the participants nor the endoscopists are aware of the treatment allocation. Participants will be randomly assigned to receive either the test product, mannitol, or the comparator, Plenvu®. The trial will be conducted under controlled conditions, with oral administration of the study drugs. Participants may be withdrawn from the study if they experience significant adverse events or if they are unable to adhere to the study protocol. The trial will also include a pharmacokinetic sub-study to assess parameters such as maximum observed concentration and terminal elimination half-life.

The clinical trial involves the administration of two treatments: **MACROGOL, COMBINATIONS** and **Mannitol**. The experimental medication, MACROGOL, COMBINATIONS, is an osmotically acting laxative formulated for **oral use**. It is composed of several active substances, including **simeticone**, **sodium hydrogen carbonate**, **potassium chloride**, **sodium chloride**, **sodium sulfate anhydrous**, and **macrogol 4000**. The pharmaceutical form is identified as PHF00169MIG. The maximum daily dose is 212.05 grams, with the same amount being the maximum total dose, administered over a treatment period of one day. The administration schedule is designed to ensure compliance, with monitoring mechanisms in place to track participant adherence to the dosing regimen.

The comparator treatment in the study is **Mannitol**, an osmotic laxative also intended for **oral use**. Mannitol is provided in the form of an **oral solution**. The maximum daily and total dose for Mannitol is 100 grams, administered over a single day. As with the experimental treatment, participant compliance is monitored to ensure adherence to the dosing schedule. The trial aims to demonstrate the non-inferiority of Mannitol compared to the standard Plenvu® same-day dosing regimen in bowel cleansing for colonoscopy.

Efficacy in this clinical trial will be assessed primarily through the proportion of patients achieving adequate bowel cleansing. This is defined by a **Boston Bowel Preparation Scale (BBPS)** total score of 6 or higher, with each of the three colon segments (right, transverse including flexures, and left including sigmoid and rectum) scoring at least 2 after standard washing and air or CO2 insufflation for luminal distension. Secondary endpoints include the adenoma detection rate, caecal intubation rate, and the proportion of patients needing to repeat the procedure due to inadequate intestinal cleansing. Additional secondary measures involve the presence of colonic bubbles assessed through the Colon Endoscopic Bubble Scale (CEBuS), and the evaluation of neoplastic and inflammatory colorectal lesions in terms of number, appearance, size, location, and histological examination.

Patient adherence to the study drug, ease of use, taste, willingness to reuse the preparation, and satisfaction with bowel preparation compared to previous agents will also be evaluated. These will be measured using a numeric rating scale (NRS) for ease of use and taste, and a yes/no response for willingness to reuse. Safety assessments will include the incidence of adverse events and drug-related adverse events from the start of study drug administration. Clinically significant changes from baseline in haematological and chemical parameters, heart rate, blood pressure, and oxygen saturation will be monitored. Pharmacokinetic parameters such as maximum observed concentration (Cmax), time to maximum observed concentration (tmax), area under the concentration-time curve (AUC), and terminal elimination half-life (t1/2) will be evaluated in a PK sub-study.