Efficacy and Safety of mAnnitol in Bowel Preparation During Elective Colonoscopy and Comparison With Moviprep®

Study Overview
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Brief Summary
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The purpose of this dose finding/comparative efficacy study is to first single out the most appropriate dose of mannitol for bowel preparation (phase II) and, subsequently, demonstrate the non-inferiority of the efficacy of single dose mannitol vs standard split 2L PEG ASC (Moviprep®) (phase III) in bowel preparation for colonoscopy .

Detailed Description
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Study Start and Study Completion dates relative to the Phase II/III are reported here: Phase II (Patients n. 183) Date of first enrolment: 22 June 2020 Date LPLV: 12 November 2020 Phase III (Patients n. 703) Date of first enrolment: 2 March 2021 Date LPLV: 16 July 2021 Date on which the study was entered in the EudraCT database: 13 October 2020

Official Title
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Efficacy and Safety of mAnniTol in Bowel Preparation: Assessment of Adequacy and Presence of Intestinal levelS of Hydrogen and Methane During Elective Colonoscopy aFter mAnnitol or Standard Split 2-liter Polyethylene Glycol Solution Plus asCorbaTe - a Phase II/III, International, Multicentre, Randomized, Parallel-group, endoscOpist-bliNded, Dose-finding/Non-inferiority Study - SATISFACTION

Conditions
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Elective Colonoscopy

Intervention / Treatment
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* Drug: Phase II: NTC015 low dose
* Drug: Phase II: NTC015 medium dose
* Drug: Phase II: NTC015 high dose
* Drug: Phase III: NTC015 selected dose
* Drug: Phase III: Polyethylene glycol plus ascorbate solution (2L PEG ASC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability of patient to consent and provide signed written informed consent Age ≥ 18 years Males and females scheduled for elective (screening, surveillance or diagnostic) colonoscopy to be prepared and performed according to the European Society of Gastrointestinal Endoscopy (ESGE) Guideline Patients willing and able to complete the entire study and to comply with instructions Exclusion Criteria: Pregnancy or breastfeeding. Females of childbearing potential must have a negative pregnancy test at Visit 2 and must practice one of the following methods of birth control throughout the study period (unless postmenopausal or surgically sterile, or whose sole sexual partner has had a successful vasectomy): oral, implantable, or injectable contraceptives (for a minimum of three months before study entry) in combination with a condom; intrauterine device in combination with a condom; double barrier method (condom and occlusive cap with spermicidal foam/gel/film/cream/suppository). Severe renal failure: glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 estimated by means of simplified MDRD equation. Severe heart failure: NYHA Class III-IV. Severe anaemia (Hb ≤ 8 g/dl). Severe acute and chronically active Inflammatory Bowel Disease; patients in clinical remission (Crohn's Disease Activity Index - CDAI < 150 for Crohn Disease and Partial Mayo Score ≤ 2 for Ulcerative Colitis) are allowed. Chronic liver disease Child-Pugh class B or C. Electrolyte disturbances (Na, Cl, K, Ca or P out of normal ranges). Recent (< 6 months) symptomatic acute ischemic heart disease. History of significant gastrointestinal surgeries, including colon resection, sub-total colectomy, abdominoperineal resection, de-functioning colostomy or ileostomy, Hartmann's procedure and other surgeries involving the structure and function of the colon. Use of laxatives, colon motility altering drugs and/or other substances (e.g. simethicone) that can affect bowel cleansing or visibility during colonoscopy within 24 hours prior to colonoscopy. Suspected bowel obstruction or perforation. Indication for partial colonoscopy. Patients who have received an investigational drug or therapy within 5 half-lives of the first visit. Patients previously screened for participation in this study. Hypersensitivity to the active ingredients or to any of the excipients of the study drugs. Contraindication to Moviprep® (only for phase III).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized, parallel-group study.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase II: NTC015 low dose (Mannitol 50 g)<br>One day single dose preparation same day of colonoscopy | Drug: Phase II: NTC015 low dose<br>* Participants should self administer the preparation within 30 minutes and drink clear liquid according to local practice at the centre to prevent dehydration<br>|
| Experimental: Phase II: NTC015 medium dose (Mannitol 100 g)<br>One day single dose preparation same day of colonoscopy | Drug: Phase II: NTC015 medium dose<br>* Participants should self administer the preparation within 30 minutes and drink clear liquid according to local practice at the centre to prevent dehydration<br>|
| Experimental: Phase II: NTC015 high dose (Mannitol 150 g)<br>One day single dose preparation same day of colonoscopy | Drug: Phase II: NTC015 high dose<br>* Participants should self administer the preparation within 60 minutes and drink clear liquid according to local practice at the centre to prevent dehydration<br>|
| Experimental: Phase III: NTC015 selected dose<br>One day single dose preparation same day of colonoscopy | Drug: Phase III: NTC015 selected dose<br>* Participants should self administer the preparation within 30 minutes and drink clear liquid according to local practice at the centre to prevent dehydration<br>|
| Active Comparator: Phase III: Polyethylene glycol plus ascorbate solution (2L PEG ASC) (Moviprep®)<br>Two litres of Moviprep® taken according to split-dose regimen (to commence in the evening before colonoscopy) | Drug: Phase III: Polyethylene glycol plus ascorbate solution (2L PEG ASC)<br>* The instructions for product administration are followed according to the Summary of Product Characteristics. One treatment consists of two litres of Moviprep® taken according to split-dose regimen. The first litre of Moviprep® is prepared by dissolving one sachet A and one sachet B together in water to make one litre of solution. The reconstituted solution must be drunk over a period of one to two hours the evening before colonoscopy. About half a litre of clear liquid should be drunk in the next hour to prevent dehydration according to local practice at the centre. This process should be repeated with a second litre of Moviprep® prepared by dissolving one sachet A and one sachet B together in water to make one litre of solution in the early morning of the day of the procedure.<br>* Other names: Moviprep®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II - Dose finding: Proportion of patients with adequate bowel cleansing | Proportion of patients with adequate bowel cleansing, defined as BBPS total score ≥ 6, with a score for each of the three colon segments (right; transverse, including flexures; and left, including sigmoid and rectum) ≥ 2 during colonoscopy after standard washing and air insufflation for luminal distension. | During colonoscopy (Visit 4) | 
| Phase III - Non-inferiority: Proportion of patients with adequate bowel cleansing | Proportion of patients with adequate bowel cleansing, defined as BBPS total score ≥ 6, with a score for each of the three colon segments (right; transverse, including flexures; and left, including sigmoid and rectum) ≥ 2 during colonoscopy after standard washing and air insufflation for luminal distension. | During colonoscopy (Visit 4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II - Dose finding: Caecal intubation rate | The percentage of patients with appendiceal orifice visible to the endoscopist. | During colonoscopy at Visit 4 | 
| Phase II - Dose finding: Adherence to bowel preparation | Proportion of patient that completely taken, partially taken or not taken assigned mannitol dose. | During visit 4, 4 hours after the end of study drug self-administration, before colonoscopy | 
| Phase II - Dose finding: ease of use | Descriptive statistics (Mean) of Numeric Rating Scale (NRS) values ranging from 0 (very difficult) to 10 (very easy). | During visit 4, 4 hours after the end of study drug self-administration, before colonoscopy | 
| Phase II - Dose finding: Willingness to reuse the preparation | Proportion of patient who confirmed that they would like to reuse the preparation for other colonoscopies. | During visit 4, 4 hours after the end of study drug self-administration, before colonoscopy | 
| Phase II - Dose finding: Treatment acceptability | Descriptive statistics (Mean) of Numeric Rating Scale (NRS) values ranging from 0 (terrible) to 10 (very good). | During visit 4 (day of colonoscopy), 4 hours after the end of study drug self-administration, before colonoscopy | 
| Phase II - Pharmacokinetic Parameter: Peak Plasma Concentration | descriptive statistics (mean) of peak plasma concentration (Cmax) as pharmacokinetic parameter. | During vist 4 (day of colonoscopy), before mannitol self-administration (T0 - baseline),1 hour (T1), 2 hours (T2), 4 hours (T4) and 8 hours (T8) after completion of mannitol self-administration | 
| Phase II - Pharmacokinetic Parameter: Time to Maximum Concentration | Descriptive statistics (Median) of time to maximum concentration (tmax) as pharmacokinetic parameter. | During vist 4 (day of colonoscopy), before mannitol self-administration (T0 - baseline),1 hour (T1), 2 hours (T2), 4 hours (T4) and 8 hours (T8) after completion of mannitol self-administration | 
| Phase II - Pharmacokinetic Parameter: Area Under the Curve | Descriptive statistics (Mean) of area under the curve from t0 to the last blood sampling time point (AUC 0-t8), as pharmacokinetic parameter. | During vist 4 (day of colonoscopy), before mannitol self-administration (T0 - baseline),1 hour (T1), 2 hours (T2), 4 hours (T4) and 8 hours (T8) after completion of mannitol self-administration | 
| Phase II - Pharmacokinetic Parameter: Elimination Half Life | Descriptive statistics (Mean) of elimination half life (t1/2), as pharmacokinetic parameter. | During vist 4 (day of colonoscopy), before mannitol self-administration (T0 - baseline),1 hour (T1), 2 hours (T2), 4 hours (T4) and 8 hours (T8) after completion of mannitol self-administration | 
| Phase III - Non-inferiority: Adenoma detection rate | The percentage of patients with at least one lesion detected. | During the colonoscopy at Visit 4 | 
| Phase III - Non-inferiority: Ottawa Bowel Preparation Scale (OBPS) | Ottawa scale is used to measure the quality of the preparation in three different parts of the colon before washing and insufflation. descriptive statistics (Mean) of the total score (from 0 excellent to 14 inadequate). | During the colonoscopy at Visit 4 | 
| Phase III - Non-inferiority: Caecal intubation rate | The percentage of patients with appendiceal orifice visible to the endoscopist. | During the colonoscopy at Visit 4 | 
| Phase III - Non-inferiority: Bowel Cleansing Impact Review (BOCLIR) (Italian sites only) | The BOCLIR is a questionnaire filled in by patients to measure the acceptability and tolerability of bowel cleansers consisting of three unidimensional scales (satisfaction, symptoms and activity limitations) with good psychometric and scaling properties. Item responses are summed to provide a score for each scale and a total score. The satisfaction scale contains eight items and the score ranges from 0 (highly satisfied) to 32 (highly dissatisfied). The symptoms scale includes 14 items and the score ranges from 0 (no symptoms) to 42 (severe symptoms). The activity limitations scale is made up of 12 items and the score ranges from 0 (no effect on activities) to 36 (activities greatly affected). The total score is the sum of the three scales and ranges from 0 to 110. Patients who report a worse experience in terms of the three factors score higher on the BOCLIR scale. | Visit 4 after the end of study drug self-administration, before colonoscopy | 
| Phase III - Non-inferiority: Adherence to bowel preparation with mannitol and with Moviprep®. | Proportion of patients that completely taken, partially taken or not taken assigned mannitol dose | During visit 4, 4 hours after the end of study drug self-administration, before colonoscopy | 
| Phase III - Non-inferiority: ease of use | Descriptive statistics (Mean) of Numeric Rating Scale (NRS) values ranging from 0 (very difficult) to 10 (very easy). | During visit 4, 4 hours after the end of study drug self-administration, before colonoscopy | 
| Phase III - Non-inferiority: Willingness to reuse the preparation | Proportion of patient who confirmed that they would like to reuse the preparation for other colonoscopies. | During visit 4, 4 hours after the end of study drug self-administration, before colonoscopy | 
| Phase III - Non-inferiority: Treatment acceptability | Descriptive statistics (Mean) of Numeric Rating Scale (NRS) values ranging from 0 (terrible) to 10 (very good). | During visit 4, 4 hours after the end of study drug self-administration, before colonoscopy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colonoscopy preparation, Bowel cleansing, Gas, Mannitol