Clinical Trial Results:
Efficacy, safety and tolerability of a bowel cleansing preparation (Eziclen®/Izinova®) in paediatric subjects undergoing colonoscopy: a Phase III, multicentre, randomised, comparative study versus Klean-Prep® (PEG-Electrolytes), administered on the day before colonoscopy, investigator-blinded, non-inferiority in adolescents of 12 to 17 years of age (inclusive) >40 kg
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Summary
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EudraCT number |
2016-002265-60 |
Trial protocol |
DE FR NL CZ PL IT |
Global end of trial date |
29 Jun 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
14 Feb 2021
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First version publication date |
14 Feb 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
F-FR-58800-003
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03008460 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Ipsen Pharma SAS
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Sponsor organisation address |
65 quai Georges Gorse, Boulogne-Billancourt, France, 92100
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Public contact |
Medical Director, Ipsen Pharma SAS, clinical.trials@ipsen.com
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Scientific contact |
Medical Director, Ipsen Consumer Healthcare, clinical.trials@ipsen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000816-PIP02-10 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
29 Jun 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
29 Jun 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate that Eziclen®/Izinova®, an osmotic sulphate-based laxative preparation given on the day before colonoscopy has non-inferior efficacy to Klean-Prep® (polyethylene glycol [PEG]-electrolytes) on colon cleansing in adolescents aged 12 to 17 years (inclusive) with a body weight > 40 kilograms (kg), scheduled to undergo a colonoscopy for a routinely accepted diagnostic indication.
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Protection of trial subjects |
The study was conducted under the provisions of the Declaration of Helsinki, in accordance with the International Conference on Harmonisation Consolidated Guideline on Good Clinical Practice, and in compliance with Independent Ethics Committee and informed consent regulations, and adhered to all local regulatory requirements. Written informed consent was obtained from the subject’s parent(s)/legal representative(s) and as a signed assent from the adolescent prior to the subject entering the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 Oct 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 40
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Country: Number of subjects enrolled |
Poland: 139
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Country: Number of subjects enrolled |
Czechia: 6
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Country: Number of subjects enrolled |
France: 18
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Country: Number of subjects enrolled |
Germany: 26
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Country: Number of subjects enrolled |
Italy: 21
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Worldwide total number of subjects |
250
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EEA total number of subjects |
250
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
250
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted in adolescents who were undergoing a colonoscopy for a routinely accepted indication. Subjects were randomised 1:1 to Eziclen®/Izinova® (¾ of adult dose; 750 millilitres [mL] of preparation plus 1500 mL of water) or Klean-Prep® (70 mL/kg; maximum of 4000 mL). Subjects were randomised at 22 study centres in 6 countries. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
The study consisted of a 1-day enrolment (Day 1, baseline) and investigator-blind label dosing period, a colonoscopy (Day 2) and a 30-day follow-up period (Day 32 [-5/+15, i.e. Day 27 to Day 47]). Subjects were expected to participate in the study for a minimum of 27 days and up to 47 days. | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Randomisation Through Start of Treatment
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Is this the baseline period? |
No | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind | ||||||||||||||||||||||||
Roles blinded |
Investigator [1] | ||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Eziclen®/Izinova® | ||||||||||||||||||||||||
Arm description |
Subjects randomised to the Eziclen®/Izinova® treatment group. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Eziclen®/Izinova®
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Investigational medicinal product code |
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Other name |
Eziclen®, Izinova®
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Pharmaceutical forms |
Concentrate for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Period is prior to the start of treatment; no study drug administered.
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Arm title
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Klean-Prep® | ||||||||||||||||||||||||
Arm description |
Subjects randomised to the Klean-Prep® treatment group. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Klean-Prep®
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Investigational medicinal product code |
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Other name |
Macrogol 3350 plus electrolytes
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Pharmaceutical forms |
Powder for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Period is prior to the start of treatment; no study drug administered.
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| Notes [1] - The roles blinded appear inconsistent with a simple blinded trial. Justification: This was a single-blinded study in which the investigator (i.e. colonoscopist) was blinded to ensure an unbiased evaluation of the study preparations. |
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Period 2
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Period 2 title |
Treatment Through End of Study
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Is this the baseline period? |
Yes [2] | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind | ||||||||||||||||||||||||
Roles blinded |
Investigator [3] | ||||||||||||||||||||||||
Blinding implementation details |
In this single-blinded (investigator-blinded) study, to ensure an unbiased evaluation of the study preparations, the colonoscopist was not allowed to perform any study treatment-related activities (drug dispensing, return and accountability, acceptability, tolerability, and review of subject’s leaflet/questionnaires). Subjects and caregivers/nurses did not discuss their study preparation with the colonoscopist or any staff member other than with the study nurse who collected the questionnaires.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Eziclen®/Izinova® | ||||||||||||||||||||||||
Arm description |
Subjects received Eziclen®/Izinova® oral sulphate salt solution, administered as ¾ of the adult dose, as a 1-day regimen on the evening of the day before colonoscopy (Day 1). The 750 mL preparation was administered in 2 half doses as follows: the first half of preparation (375 mL) was drunk slowly in 30 minutes to 1 hour, followed by 750 mL of water over the next hour. Approximately 2 hours after starting the first half of preparation, the second half (375 mL) was drunk slowly in 30 minutes to 1 hour, followed by 750 mL of water over the next hour. Overall total volume (preparation + water) was 2250 mL (1125 mL per dose). | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Eziclen®/Izinova®
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Investigational medicinal product code |
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Other name |
Eziclen®, Izinova®
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Pharmaceutical forms |
Concentrate for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Eziclen®/Izinova® is a concentrate for oral solution packaged in 2 bottles, each containing: sodium sulphate anhydrous: 17.510 grams (g), magnesium sulphate heptahydrate: 3.276 g and potassium sulphate: 3.130 g. The 2 bottles were diluted up to 1000 mL with water and 250 mL were discarded, with the remaining 750 mL preparation being given on the evening of the day before colonoscopy.
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Arm title
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Klean-Prep® | ||||||||||||||||||||||||
Arm description |
Subjects received Klean-Prep® oral solution, administered as a 70 mL/kg dose (calculated based on subject’s weight) as a 1-day regimen on the evening of the day before colonoscopy (Day 1). The whole solution was administered in 2 half doses (1 litre per hour), with a 1-hour pause between the 2 half doses. Approximately 2 hours after starting the first half of preparation, the second half was drunk. The maximum global volume administered was 4000 mL (2000 mL per dose). | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Klean-Prep®
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Investigational medicinal product code |
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Other name |
Macrogol 3350 plus electrolytes
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Pharmaceutical forms |
Powder for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Each sachet of Klean-prep® contains the following active ingredients: macrogol 3350: 59.000 g, anhydrous sodium sulphate: 5.685 g, sodium bicarbonate: 1.685 g, sodium chloride: 1.465 g, potassium chloride: 0.7425 g. Each treatment pack was composed of 4 sachets with a total of 69 g of the product included in each sachet. Each sachet was diluted in 1000 mL of water and dosage was 70 mL/kg (calculated based on subject’s weight). Klean-Prep® was given on the evening of the day before colonoscopy.
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| Notes [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: Period 1 presents data for all subjects randomised until the start of treatment and Period 2 presents data for all subjects who received study drug. Baseline characteristics are based on subjects who were randomised and who received even a partial dose of study drug; Period 2 is therefore the baseline period. [3] - The roles blinded appear inconsistent with a simple blinded trial. Justification: This was a single-blinded study in which the investigator (i.e. colonoscopist) was blinded to ensure an unbiased evaluation of the study preparations. |
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| Notes [4] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline characteristics are based on subjects who were randomised and who received even a partial dose of study drug. |
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Baseline characteristics reporting groups
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Reporting group title |
Eziclen®/Izinova®
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Reporting group description |
Subjects received Eziclen®/Izinova® oral sulphate salt solution, administered as ¾ of the adult dose, as a 1-day regimen on the evening of the day before colonoscopy (Day 1). The 750 mL preparation was administered in 2 half doses as follows: the first half of preparation (375 mL) was drunk slowly in 30 minutes to 1 hour, followed by 750 mL of water over the next hour. Approximately 2 hours after starting the first half of preparation, the second half (375 mL) was drunk slowly in 30 minutes to 1 hour, followed by 750 mL of water over the next hour. Overall total volume (preparation + water) was 2250 mL (1125 mL per dose). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Klean-Prep®
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Reporting group description |
Subjects received Klean-Prep® oral solution, administered as a 70 mL/kg dose (calculated based on subject’s weight) as a 1-day regimen on the evening of the day before colonoscopy (Day 1). The whole solution was administered in 2 half doses (1 litre per hour), with a 1-hour pause between the 2 half doses. Approximately 2 hours after starting the first half of preparation, the second half was drunk. The maximum global volume administered was 4000 mL (2000 mL per dose). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Eziclen®/Izinova®
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Reporting group description |
Subjects randomised to the Eziclen®/Izinova® treatment group. | ||
Reporting group title |
Klean-Prep®
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Reporting group description |
Subjects randomised to the Klean-Prep® treatment group. | ||
Reporting group title |
Eziclen®/Izinova®
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Reporting group description |
Subjects received Eziclen®/Izinova® oral sulphate salt solution, administered as ¾ of the adult dose, as a 1-day regimen on the evening of the day before colonoscopy (Day 1). The 750 mL preparation was administered in 2 half doses as follows: the first half of preparation (375 mL) was drunk slowly in 30 minutes to 1 hour, followed by 750 mL of water over the next hour. Approximately 2 hours after starting the first half of preparation, the second half (375 mL) was drunk slowly in 30 minutes to 1 hour, followed by 750 mL of water over the next hour. Overall total volume (preparation + water) was 2250 mL (1125 mL per dose). | ||
Reporting group title |
Klean-Prep®
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Reporting group description |
Subjects received Klean-Prep® oral solution, administered as a 70 mL/kg dose (calculated based on subject’s weight) as a 1-day regimen on the evening of the day before colonoscopy (Day 1). The whole solution was administered in 2 half doses (1 litre per hour), with a 1-hour pause between the 2 half doses. Approximately 2 hours after starting the first half of preparation, the second half was drunk. The maximum global volume administered was 4000 mL (2000 mL per dose). | ||
Subject analysis set title |
Eziclen®/Izinova®
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects received Eziclen®/Izinova® oral sulphate salt solution, administered as ¾ of the adult dose, as a 1-day regimen on the evening of the day before colonoscopy (Day 1). The 750 mL preparation was administered in 2 half doses as follows: the first half of preparation (375 mL) was drunk slowly in 30 minutes to 1 hour, followed by 750 mL of water over the next hour. Approximately 2 hours after starting the first half of preparation, the second half (375 mL) was drunk slowly in 30 minutes to 1 hour, followed by 750 mL of water over the next hour. Overall total volume (preparation + water) was 2250 mL (1125 mL per dose).
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Subject analysis set title |
Klean-Prep®
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects received Klean-Prep® oral solution, administered as a 70 mL/kg dose (calculated based on subject’s weight) as a 1-day regimen on the evening of the day before colonoscopy (Day 1). The whole solution was administered in 2 half doses (1 litre per hour), with a 1-hour pause between the 2 half doses. Approximately 2 hours after starting the first half of preparation, the second half was drunk. The maximum global volume administered was 4000 mL (2000 mL per dose).
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End point title |
Percentage of Subjects With Successful Overall Colon Preparation, Assessed With the Cleansing Score (4-point Scale) | ||||||||||||
End point description |
Blinded overall assessment of preparation efficacy (Cleansing Score) was determined by the colonoscopist upon completion of the examination, based on a 4-point scale as follows:
• 4 (Excellent) = No more than small bits of adherent faeces/fluid
• 3 (Good) = Small amounts of faeces or fluid not interfering with examination
• 2 (Fair) = Enough faeces or fluid to prevent a completely reliable examination
• 1 (Poor) = Large amounts of faecal residue, additional cleansing required.
Only perfect preparations graded as excellent (4) or good (3), which allowed full, reliable examination of the mucosa were considered as successful. The adjusted percentage of subjects with a successful preparation was determined using a logistic regression model, including treatment and country as covariates.
The modified intention-to-treat population included all randomised subjects who received even a partial dose of study drug and produced a primary efficacy assessment.
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End point type |
Primary
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End point timeframe |
At Day 2 (colonoscopy visit)
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Statistical analysis title |
Adjusted treatment difference | ||||||||||||
Statistical analysis description |
Analysis of the treatment difference (Eziclen®/Izinova® minus Klean-Prep®) was performed using a logistic regression model, including treatment and country as covariates.
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Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
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Number of subjects included in analysis |
241
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
P-value |
= 0.0907 [2] | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Adjusted treatment difference | ||||||||||||
Point estimate |
-7.61
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-18.45 | ||||||||||||
upper limit |
3.24 | ||||||||||||
| Notes [1] - Non-inferiority would be demonstrated if the lower limit of the 95% confidence interval of the adjusted treatment difference was higher than -15%. [2] - P-value for non-inferiority was estimated from the adjusted treatment difference. |
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End point title |
Mean Colon Cleansing Score (4-point Scale) | ||||||||||||
End point description |
The Cleansing Score was determined by the blinded colonoscopist, based on a 4-point scale as follows:
• 4 (Excellent) = No more than small bits of adherent faeces/fluid
• 3 (Good) = Small amounts of faeces or fluid not interfering with examination
• 2 (Fair) = Enough faeces or fluid to prevent a completely reliable examination
• 1 (Poor) = Large amounts of faecal residue, additional cleansing required.
The adjusted mean score was estimated using a 2-way analysis of variance (ANOVA), including treatment and country as covariates.
The intention-to-treat (ITT) population included all randomised subjects who received even a partial dose of study drug.
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End point type |
Secondary
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End point timeframe |
At Day 2 (colonoscopy visit)
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Statistical analysis title |
Adjusted treatment difference | ||||||||||||
Statistical analysis description |
Analysis of the treatment difference (Eziclen®/Izinova® minus Klean-Prep®) was performed using a 2-way ANOVA, including treatment and country as covariates.
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Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
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Number of subjects included in analysis |
241
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.0428 | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Adjusted treatment difference | ||||||||||||
Point estimate |
-0.18
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.36 | ||||||||||||
upper limit |
-0.01 | ||||||||||||
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End point title |
Mean Boston Bowel Preparation Scale (BBPS) Global Score and BBPS Scores by Colon Segment | ||||||||||||||||||||||||
End point description |
The BBPS score for each colon segment (left, transverse, right) was determined by the blinded colonoscopist as follows:
• 0 = Unprepared colon segment with mucosa not seen due to solid stool that cannot be cleared
• 1 = Portion of mucosa of the segment seen, but other areas of the colon segment not well seen due to staining, residual stool and/or opaque liquid
• 2 = Minor amount of residual staining, small fragments of stool and/or opaque liquid, but mucosa of segment seen well
• 3 = Entire mucosa of segment seen well with no residual staining, small fragments of stool and/or opaque liquid.
Each segment score ranged from 0-3. Global score was sum of the 3 segment scores and ranged from 0-9 (worst to best). Successful colon cleansing was defined as a global BBPS score ≥6. The adjusted mean score was estimated using a 2-way ANOVA, including treatment and country as covariates.
The ITT population included all randomised subjects who received even a partial dose of study drug.
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End point type |
Secondary
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End point timeframe |
At Day 2 (colonoscopy visit)
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Statistical analysis title |
Adjusted treatment difference: Left colon | ||||||||||||||||||||||||
Statistical analysis description |
Analysis of the treatment difference (Eziclen®/Izinova® minus Klean-Prep®) was performed using a 2-way ANOVA, including treatment and country as covariates.
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Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
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Number of subjects included in analysis |
241
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||||||
P-value |
= 0.4676 | ||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||
Parameter type |
Adjusted treatment difference | ||||||||||||||||||||||||
Point estimate |
-0.07
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.25 | ||||||||||||||||||||||||
upper limit |
0.12 | ||||||||||||||||||||||||
Statistical analysis title |
Adjusted treatment difference: Transverse colon | ||||||||||||||||||||||||
Statistical analysis description |
Analysis of the treatment difference (Eziclen®/Izinova® minus Klean-Prep®) was performed using a 2-way ANOVA, including treatment and country as covariates.
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Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
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Number of subjects included in analysis |
241
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||||||
P-value |
= 0.3076 | ||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||
Parameter type |
Adjusted treatment difference | ||||||||||||||||||||||||
Point estimate |
-0.09
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-0.25 | ||||||||||||||||||||||||
upper limit |
0.08 | ||||||||||||||||||||||||
Statistical analysis title |
Adjusted treatment difference: Right colon | ||||||||||||||||||||||||
Statistical analysis description |
Analysis of the treatment difference (Eziclen®/Izinova® minus Klean-Prep®) was performed using a 2-way ANOVA, including treatment and country as covariates.
|
||||||||||||||||||||||||
Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
|
||||||||||||||||||||||||
Number of subjects included in analysis |
241
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||
P-value |
= 0.0155 | ||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||
Parameter type |
Adjusted treatment difference | ||||||||||||||||||||||||
Point estimate |
-0.24
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-0.44 | ||||||||||||||||||||||||
upper limit |
-0.05 | ||||||||||||||||||||||||
Statistical analysis title |
Adjusted treatment difference: Global score | ||||||||||||||||||||||||
Statistical analysis description |
Analysis of the treatment difference (Eziclen®/Izinova® minus Klean-Prep®) was performed using a 2-way ANOVA, including treatment and country as covariates.
|
||||||||||||||||||||||||
Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
|
||||||||||||||||||||||||
Number of subjects included in analysis |
241
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||
P-value |
= 0.0975 | ||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||
Parameter type |
Adjusted treatment difference | ||||||||||||||||||||||||
Point estimate |
-0.36
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-0.79 | ||||||||||||||||||||||||
upper limit |
0.07 | ||||||||||||||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Need for Rescue Treatment | ||||||||||||
End point description |
The percentage of subjects who needed rescue treatment (saline enema) prior to colonoscopy because of inadequate preparation intake was assessed.
The ITT population included all randomised subjects who received even a partial dose of study drug.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At Day 2 (colonoscopy visit, before colonoscopy)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Adjusted treatment difference rate | ||||||||||||
Statistical analysis description |
Analysis was performed using Cochran-Mantel-Haenszel (CMH) chi-square method (using the general association statistic), stratified on country.
|
||||||||||||
Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
|
||||||||||||
Number of subjects included in analysis |
240
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.2428 | ||||||||||||
Method |
CMH chi-square | ||||||||||||
Parameter type |
Adjusted treatment difference rate | ||||||||||||
Point estimate |
1.3847
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.8 | ||||||||||||
upper limit |
2.4 | ||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Need for Nasogastric Tube To Complete Preparation | ||||||||||||
End point description |
The percentage of subjects who needed placement of a nasogastric tube to achieve administration of the complete preparation was assessed.
The ITT population included all randomised subjects who received even a partial dose of study drug.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At Day 1 (treatment visit)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Adjusted treatment difference rate | ||||||||||||
Statistical analysis description |
Analysis was performed using CMH chi-square method (using the general association statistic), stratified on country.
|
||||||||||||
Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
|
||||||||||||
Number of subjects included in analysis |
241
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
CMH chi-square | ||||||||||||
Parameter type |
Adjusted treatment difference rate | ||||||||||||
Point estimate |
24.0219
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
12.6 | ||||||||||||
upper limit |
45.9 | ||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Colonoscopy Procedure Documented as Completed | ||||||||||||
End point description |
The percentage of subjects with a complete colonoscopy, defined as a procedure that reached the caecum, was assessed.
The ITT population included all randomised subjects who received even a partial dose of study drug.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At Day 2 (colonoscopy visit)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Adjusted treatment difference rate | ||||||||||||
Statistical analysis description |
Analysis was performed using CMH chi-square method (using the general association statistic), stratified on country.
|
||||||||||||
Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
|
||||||||||||
Number of subjects included in analysis |
241
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.9257 | ||||||||||||
Method |
CMH chi-square | ||||||||||||
Parameter type |
Adjusted treatment difference rate | ||||||||||||
Point estimate |
1.0022
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
1 | ||||||||||||
upper limit |
1.1 | ||||||||||||
|
|||||||||||||
End point title |
Median Time to Caecal Intubation | ||||||||||||
End point description |
The time to caecal intubation was defined as the time from colonoscope introduction to caecal intubation, estimated using the Kaplan-Meier product limit method. In the event the procedure did not reach the caecum, the subject was censored at time of withdrawal of colonoscope.
The ITT population included all randomised subjects who received even a partial dose of study drug. Note: for 2 subjects in the Eziclen®/Izinova® group and 1 subject in the Klean-Prep® group, although the procedure reached the caecum, the time was not reported and consequently, these subjects could not be included in the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At Day 2 (colonoscopy visit)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Mean Duration of Examination | ||||||||||||
End point description |
The duration of examination for colonoscopy (in minutes) was measured by the difference between the time of caecum intubation and the time of withdrawal of the colonoscope. The adjusted mean duration of examination was estimated using a 2-way ANOVA, including treatment and country as covariates. Subjects for whom the caecum was not reached were excluded from the analysis.
The ITT population included all randomised subjects who received even a partial dose of study drug.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At Day 2 (colonoscopy visit)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Adjusted treatment difference | ||||||||||||
Statistical analysis description |
Analysis of the treatment difference (Eziclen®/Izinova® minus Klean-Prep®) was performed using 2-way ANOVA, including treatment and country as covariates.
|
||||||||||||
Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
|
||||||||||||
Number of subjects included in analysis |
230
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.4459 | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Adjusted treatment difference | ||||||||||||
Point estimate |
-0.93
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.32 | ||||||||||||
upper limit |
1.47 | ||||||||||||
|
|||||||||||||
End point title |
Mean Score for Overall Treatment Acceptability, Assessed Using Treatment Acceptability Questionnaire | ||||||||||||
End point description |
The Treatment Acceptability Questionnaire was completed by the caregiver or subject after the subject ended the intake of preparation. Subject acceptability was rated as follows:
• 1 = Very badly accepted/unacceptable
• 2 = Badly but accepted
• 3 = Neither good nor bad
• 4 = Well accepted
• 5 = Very well accepted.
Overall acceptability score is the average of scores from the 2 doses ranging from 1 - 5 (worst to best). The adjusted mean score was estimated using a 2-way ANOVA, including treatment and country as covariates.
The ITT population included all randomised subjects who received even a partial dose of study drug.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At Day 1 (treatment visit)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Adjusted treatment difference | ||||||||||||
Statistical analysis description |
Analysis of the treatment difference (Eziclen®/Izinova® minus Klean-Prep®) was performed using 2-way ANOVA, including treatment and country as covariates.
|
||||||||||||
Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
|
||||||||||||
Number of subjects included in analysis |
235
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Adjusted treatment difference | ||||||||||||
Point estimate |
0.71
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.4 | ||||||||||||
upper limit |
1.03 | ||||||||||||
|
||||||||||||||||||||||
End point title |
Mean Overall Treatment Compliance | |||||||||||||||||||||
End point description |
Treatment compliance according the instructions of use provided in the prescription was assessed as the percentage of volume of fluid taken relative to the planned volume of fluid to be taken (measured by the caregiver and reported in the treatment questionnaire of subject’s leaflet during treatment administration). Overall treatment compliance was derived from the total volumes of fluid (i.e. preparation + hydration for Eziclen®/Izinova® and preparation only for Klean-Prep®) and was assessed for dose 1, dose 2 and globally (accounting for both doses). The adjusted mean overall treatment compliance (%) was estimated using a 2-way ANOVA, including treatment and country as covariates.
The ITT population included all randomised subjects who received even a partial dose of study drug.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
At Day 1 (treatment visit)
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Adjusted treatment difference rate: Dose 1 | |||||||||||||||||||||
Statistical analysis description |
Analysis of the treatment difference (Eziclen®/Izinova® minus Klean-Prep®) was performed using 2-way ANOVA, including treatment and country as covariates.
|
|||||||||||||||||||||
Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
|
|||||||||||||||||||||
Number of subjects included in analysis |
241
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.3945 | |||||||||||||||||||||
Method |
ANOVA | |||||||||||||||||||||
Parameter type |
Adjusted treatment difference rate | |||||||||||||||||||||
Point estimate |
1.22
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.6 | |||||||||||||||||||||
upper limit |
4.05 | |||||||||||||||||||||
Statistical analysis title |
Adjusted treatment difference rate: Dose 2 | |||||||||||||||||||||
Statistical analysis description |
Analysis of the treatment difference (Eziclen®/Izinova® minus Klean-Prep®) was performed using 2-way ANOVA, including treatment and country as covariates.
|
|||||||||||||||||||||
Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
|
|||||||||||||||||||||
Number of subjects included in analysis |
241
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.0085 | |||||||||||||||||||||
Method |
ANOVA | |||||||||||||||||||||
Parameter type |
Adjusted treatment difference rate | |||||||||||||||||||||
Point estimate |
6.38
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
1.65 | |||||||||||||||||||||
upper limit |
11.12 | |||||||||||||||||||||
Statistical analysis title |
Adjusted treatment difference rate: Global | |||||||||||||||||||||
Statistical analysis description |
Analysis of the treatment difference (Eziclen®/Izinova® minus Klean-Prep®) was performed using 2-way ANOVA, including treatment and country as covariates.
|
|||||||||||||||||||||
Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
|
|||||||||||||||||||||
Number of subjects included in analysis |
241
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.0036 | |||||||||||||||||||||
Method |
ANOVA | |||||||||||||||||||||
Parameter type |
Adjusted treatment difference rate | |||||||||||||||||||||
Point estimate |
7.48
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
2.46 | |||||||||||||||||||||
upper limit |
12.5 | |||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Mean Subject Tolerability Total Score, Assessed using a Symptom Scale | ||||||||||||||||||
End point description |
Tolerability was assessed using a Symptom Scale after each dose of treatment for stomach cramping, stomach bloating and nausea on a paediatric 5-point scale as follows:
• 1 = No symptom
• 2 = Mild
• 3 = Bothersome
• 4 = Distressing
• 5 = Severely distressing symptoms.
The total tolerability score is the sum of the scores for the 3 symptoms ranging from 3 to 15 (best to worst). Mean total tolerability scores after dose 1 and dose 2 are presented.
The safety population included all randomised subjects who received even a partial dose of study drug. Subjects were assessed according to the treatment received (1 subject randomised to the Eziclen®/Izinova® group was mistakenly administered Klean-Prep®; this subject was therefore included in the Klean-Prep® safety population).
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
At Day 1 (treatment visit)
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||
End point title |
Median Time to Clear Effluent | ||||||||||||
End point description |
The time to clear effluent, as reported by the subject, was defined as the time between first intake of prescription and first clear watery stool, estimated using the Kaplan-Meier product limit method. In the event of no clear watery stools, subjects with colonoscopy were censored at the time of colonoscope introduction, and subjects without colonoscopy were censored at time of start of treatment + 12 hours. Although time to clear effluent was pre-specified as a secondary endpoint in the study protocol, in a change to the planned analysis, it was subsequently analysed and reported as an 'other' efficacy endpoint.
The ITT population included all randomised subjects who received even a partial dose of study drug.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
At Day 2 (colonoscopy visit)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Mean Time Between Last Intake of Fluids and Start of Colonoscopy Procedure | ||||||||||||
End point description |
The time between the end of treatment administration (on Day 1) and the start of colonoscopy (on Day 2) was determined. The adjusted mean time between the last intake of fluids and the start of colonoscopy procedure was estimated using a 2-way ANOVA, including treatment and country as covariates.
The ITT population included all randomised subjects who received even a partial dose of study drug.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Day 1 (treatment visit) and Day 2 (colonoscopy visit)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Adjusted treatment difference | ||||||||||||
Statistical analysis description |
Analysis of the treatment difference (Eziclen®/Izinova® minus Klean-Prep®) was performed using 2-way ANOVA, including treatment and country as covariates.
|
||||||||||||
Comparison groups |
Eziclen®/Izinova® v Klean-Prep®
|
||||||||||||
Number of subjects included in analysis |
241
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.0015 | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Adjusted treatment difference | ||||||||||||
Point estimate |
1.05
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.41 | ||||||||||||
upper limit |
1.69 | ||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Treatment-emergent adverse events (TEAEs) were collected from Day 1 up to Day 32 (30 days [-5+/15] after colonoscopy).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The safety population included all randomised subjects who received even a partial dose of study drug. Subjects were assessed according to the treatment received (1 subject randomised to the Eziclen®/Izinova® group was mistakenly administered Klean-Prep®; this subject was therefore included in the Klean-Prep® safety population).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Eziclen®/Izinova®
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received Eziclen®/Izinova® oral sulphate salt solution, administered as ¾ of the adult dose, as a 1-day regimen on the evening of the day before colonoscopy (Day 1). The 750 mL preparation was administered in 2 half doses as follows: the first half of preparation (375 mL) was drunk slowly in 30 minutes to 1 hour, followed by 750 mL of water over the next hour. Approximately 2 hours after starting the first half of preparation, the second half (375 mL) was drunk slowly in 30 minutes to 1 hour, followed by 750 mL of water over the next hour. Overall total volume (preparation + water) was 2250 mL (1125 mL per dose). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Klean-Prep®
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received Klean-Prep® oral solution, administered as a 70 mL/kg dose (calculated based on subject’s weight) as a 1-day regimen on the evening of the day before colonoscopy (Day 1). The whole solution was administered in 2 half doses (1 litre per hour), with a 1-hour pause between the 2 half doses. Approximately 2 hours after starting the first half of preparation, the second half was drunk. The maximum global volume administered was 4000 mL (2000 mL per dose). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
13 Jan 2017 |
• Modification of the minimum weight for inclusion, from ≥40 kg to >40 kg;
• Update of the pharmacovigilance/emergency contact address;
• Update of exclusion criterion 1 to include advanced carcinoma;
• Clarification of exclusion criterion 5;
• Update of exclusion criterion 6 to include ascites, congestive heart failure of all grades, and hyperuricemia;
• Update of exclusion criterion 10 to include asthma;
• Modification of urine pregnancy test in blood pregnancy test and specification that urine pregnancy test was performed only when blood tests including pregnancy test were performed prior to Visit 1;
• Clarification with regards to blood sampling (laboratory assessments performed within ≤10 days prior to inclusion could be used to determine eligibility upon investigator agreement) and addition of a footnote in the schedule of study procedures;
• Addition of an Expert Committee to review safety data;
• Addition of caution for subjects taking some types of medications;
• Addition of medical care in the follow-up of adverse events (AEs). |
||
16 Mar 2018 |
• Update of the department name of the sponsor’s medically responsible person;
• Update of the pharmacovigilance/emergency contact;
• Update of the sponsor signatory;
• Clarification of colonoscopy assessment and addition of the collection of colonoscopy diagnosis or diagnostic findings as part of safety and tolerability variables;
• Update of the AE definition with regards to colonoscopy diagnosis or diagnostic findings;
• Deletion from the safety and tolerability variables of the description and histological examination of any colonic biopsy specimens of mucosal lesions suspected by the investigator to have been caused by colonic lavage. |
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26 Jul 2018 |
• Deletion of the collection of colonoscopy diagnosis or diagnostic findings as part of safety and tolerability variables;
• Addition from the safety and tolerability variables of the description and histological examination of any colonic biopsy specimens of mucosal lesions suspected by the investigator to have been caused by colonic lavage;
• Deletion of International Normalised Ratio (INR) from the assessments of biochemistry parameters and addition of INR in the assessments of haematology parameters;
• Update of the AE definition with regards to colonoscopy diagnosis or diagnostic findings. |
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02 Mar 2020 |
• Redefinition of the end of study and update of overall study duration and planned study period;
• Removal of the investigator from the unblinded personnel who ensured of the proper investigational medicinal product storage, reconstitution, and dispensation;
• Update in case the investigator had to break the blind for an emergency: the monitor to be informed was not blind;
• Update with regards to the data review on unblinded data;
• Update with regards to the review of safety data by the Expert Committee: this review was to be performed on blind data. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
