Clinical Trial Results:
Double-blind, double-dummy, randomised, multi-centre, comparative phase III clinical study on the efficacy and tolerability of an 8-week oral treatment with three times daily 1000 mg mesalazine versus three times daily 2x500 mg mesalazine in patients with active ulcerative colitis.
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Summary
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EudraCT number |
2012-001830-32 |
Trial protocol |
DE HU LV LT PL |
Global end of trial date |
06 Oct 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Jul 2016
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First version publication date |
20 Jul 2016
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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 |
SAT-25/UCA
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01745770 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Dr. Falk Pharma GmbH
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Sponsor organisation address |
Leinenweberstraße 5, Freiburg, Germany, 79108
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Public contact |
Department of Medical Science, Dr. Falk Pharma GmbH, 0049 7611514-0,
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Scientific contact |
Department of Medical Science, Dr. Falk Pharma GmbH, 0049 7611514-0,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 Jun 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 Sep 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Oct 2014
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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 |
The main objective of the trial is to proof the non-inferiority of an 8-week treatment with three times daily 1000mg mesalazine versus three times daily 2x500 mg mesalazine in patients with active ulcerative colitis.
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Protection of trial subjects |
Prior to recruitment of patients, all relevant documents of the clinical study were submitted and proved by the Independent Ethics Committees (IECs) responsible for the participating investigators. Written consent documents embodied the elements of informed consent as described in the Declaration of Helsinki, the ICH Guidelines for Good Clinical Practice (GCP) and were in accordance with all applicable laws and regulations. The informed consent form and patient information sheet described the planned and permitted uses, transfers and disclosures of the patient's personal data and personal health information for purposes of conducting the study. The informed consent form and the patient information sheet further explained the nature of the study, its objectives and potential risks and benefits as well as the date informed consent was given. Before being enrolled in the clinical trial, every patient was informed that participation in this trial was voluntary and that he/she could withdraw from the study at any time without giving a reason and without having to fear any loss in his/her medical care. The patient’s consent was obtained in writing before the start of the study. By signing the informed consent, the patient declared that he/she was participating voluntarily and intended to follow the study protocol instructions and the instructions of the investigator and to answer the questions asked during the course of the trial.
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Background therapy |
No concomitant background therapy was allowed during the trial. | ||
Evidence for comparator |
Eudragit-L-coated 500 mg mesalazine tablets (Salofalk® 500 mg tablets) were selected as comparator because this galenical principle was demonstrated to be effective in mildly to moderately active UC in several trials and are approved for the treatment of mildly to moderately active UC. | ||
Actual start date of recruitment |
03 Jan 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Poland: 10
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Country: Number of subjects enrolled |
Germany: 6
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Country: Number of subjects enrolled |
Hungary: 32
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Country: Number of subjects enrolled |
Latvia: 34
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Country: Number of subjects enrolled |
Lithuania: 29
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Country: Number of subjects enrolled |
Russian Federation: 122
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Country: Number of subjects enrolled |
Ukraine: 73
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Worldwide total number of subjects |
306
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EEA total number of subjects |
111
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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) |
1
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Adults (18-64 years) |
282
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From 65 to 84 years |
23
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85 years and over |
0
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Recruitment
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Recruitment details |
This clinical trial was conducted in 42 sites in 7 countries in Europe. The first patient was enrolled on 03 January 2013. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A screening period up to 7 days prior to randomisation was implemented to evaluate eligibility of patients. A total of 374 patients were screened for enrolment into the study. Sixty-eight patients could not be randomised, mainly due to violation of in-/exclusion criteria (41 patients). 306 patients were randomised to either of both treatments. | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Treatment Phase (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||
Blinding implementation details |
The study was to be conducted using the double-dummy technique to guarantee the double-blinding.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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M1000 | ||||||||||||||||||||||||
Arm description |
8-week treatment with three times daily 1000 mg mesalazine | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Mesalazine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Three times daily 1000 mg mesalazine
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Arm title
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M2x500 | ||||||||||||||||||||||||
Arm description |
8-week treatment with three times daily 2x500 mg mesalazine | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Mesalazine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Three times daily 2x500 mg mesalazine
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Baseline characteristics reporting groups
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Reporting group title |
M1000
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Reporting group description |
8-week treatment with three times daily 1000 mg mesalazine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
M2x500
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Reporting group description |
8-week treatment with three times daily 2x500 mg mesalazine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
M1000
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Reporting group description |
8-week treatment with three times daily 1000 mg mesalazine | ||
Reporting group title |
M2x500
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Reporting group description |
8-week treatment with three times daily 2x500 mg mesalazine | ||
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End point title |
Clinical remission at week 8 / EOT (PP interim) | |||||||||
End point description |
Percentage of patients being in clinical remission at week 8 / EOT. Clinical remission was defined as clinical activity index (CAI) ≤ 4 with stool frequency subscore of 0 (i.e. < 18 stools/week [CAI subscore 1]) and rectal bleeding subscore of 0 (i.e. 0-1 stools with blood in or on the stool [CAI subscore 2]). This is the primary analysis, as non-inferiority was proven already for the first interim analysis. The analysis set is the per-protocol analysis set for the first interim analysis (N = 217).
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End point type |
Primary
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End point timeframe |
After 8-week treatment: week 8 / EOT
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Statistical analysis title |
Non-inferiority test | |||||||||
Statistical analysis description |
For statistical testing a non-inferiority margin of 15% was defined. Hence, non-inferiority is shown if the lower bound of the 95% repeated confidence interval for the treatment difference with respect to clinical remission (πM1000 – πM2x500) is above -15%. This corresponds to a local significance level of 0.0043 for the first interim analysis. This is the primary analysis, as non-inferiority was proven already at stage 1 of the 3 stage adaptive study design.
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Comparison groups |
M1000 v M2x500
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Number of subjects included in analysis |
217
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
P-value |
= 0.0003 [1] | |||||||||
Method |
Normal approximation test | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
8
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-9.6 | |||||||||
upper limit |
25.2 | |||||||||
| Notes [1] - As the p-value is lower than the local significance level of 0.0043 for interim analysis 1, non-inferiority has been proven for the PP analysis set for interim analysis I. |
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End point title |
Clinical remission at week 8 / EOT (PP final) | |||||||||
End point description |
Percentage of patients being in clinical remission at week 8 / EOT. Clinical remission was defined as clinical activity index (CAI) ≤ 4 with stool frequency subscore of 0 (i.e. < 18 stools/week [CAI subscore 1]) and rectal bleeding subscore of 0 (i.e. 0-1 stools with blood in or on the stool [CAI subscore 2]). This is a sensitivity analysis. The analysis set is the per-protocol analysis set for the final analysis (N = 278), taking into account the 68 overrunning patients who have been included into the study during interim analysis I.
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End point type |
Primary
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End point timeframe |
After 8-week treatment: week 8 / EOT
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Statistical analysis title |
Non-inferiority test | |||||||||
Statistical analysis description |
For statistical testing a non-inferiority margin of 15% was defined. Hence, non-inferiority is shown if the lower bound of the 95% repeated CI for the treatment difference with respect to clinical remission (πM1000 – πM2x500) is above -15%. This corresponds to a local significance level of 0.0043 for the first interim analysis. This is a sensitivity analysis, taking into account the 68 overrunning patients who have been included into the study during interim analysis I.
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Comparison groups |
M1000 v M2x500
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Number of subjects included in analysis |
278
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
P-value |
= 0.0003 [2] | |||||||||
Method |
Normal approximation test | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
5.4
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-10.2 | |||||||||
upper limit |
20.8 | |||||||||
| Notes [2] - As the p-value is lower than the local significance level of 0.0043, non-inferiority has been proven for the PP analysis set inlcuding overrunning patients. |
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End point title |
Clinical remission at week 8 / EOT (FAS final) | |||||||||
End point description |
Percentage of patients being in clinical remission at week 8 / EOT. Clinical remission was defined as clinical activity index (CAI) ≤ 4 with stool frequency subscore of 0 (i.e. < 18 stools/week [CAI subscore 1]) and rectal bleeding subscore of 0 (i.e. 0-1 stools with blood in or on the stool [CAI subscore 2]). This is a sensitivity analysis. The analysis set is the full analysis set for the final analysis (N = 306).
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End point type |
Primary
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End point timeframe |
After 8-week treatment: week 8 / EOT
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Statistical analysis title |
Non-inferiority test | |||||||||
Statistical analysis description |
For statistical testing a non-inferiority margin of 15% was defined. Hence, non-inferiority is shown if the lower bound of the 95% repeated CI for the treatment difference with respect to clinical remission (πM1000 – πM2x500) is above -15%. This corresponds to a local significance level of 0.0043 for the first interim analysis. This is a sensitivity analysis for the full analysis set, taking into account the 68 overrunning patients who were included into the study during interim analysis I.
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Comparison groups |
M2x500 v M1000
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Number of subjects included in analysis |
306
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
P-value |
= 0.0006 [3] | |||||||||
Method |
Normal approximation test | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
3.1
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-11.7 | |||||||||
upper limit |
17.8 | |||||||||
| Notes [3] - As the p-value is lower than the local significance level of 0.0043, non-inferiority has been proven for the full analysis set including overrunning patients. |
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End point title |
Clinical improvement in CAI | |||||||||
End point description |
Percentage of patients with clincal improvement, defined as increase of clinical activity index (CAI) by ≥ 3 points from baseline to week 8 / EOT. The analysis set is the full analysis set for the final analysis (N = 306).
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End point type |
Secondary
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End point timeframe |
From baseline to week 8 / EOT
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Statistical analysis title |
Confidence interval for risk difference | |||||||||
Comparison groups |
M1000 v M2x500
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Number of subjects included in analysis |
306
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
Method |
Wald 95% confidence interval | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
-2.53
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-11.8 | |||||||||
upper limit |
6.73 | |||||||||
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End point title |
Endoscopic remission (mucosal healing) | |||||||||
End point description |
Percentage of patients being in endoscopic remission at week 8 / EOT, defined as endoscopic index (EI) < 4. The analysis set is the full analysis set for the final analysis (N = 306).
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End point type |
Secondary
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End point timeframe |
After 8-week treatment: week 8 / EOT
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Statistical analysis title |
Confidence interval for risk difference | |||||||||
Statistical analysis description |
The Wald 95% confidence interval is calculated for the difference in remission rates between M1000 and M2x500.
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Comparison groups |
M1000 v M2x500
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Number of subjects included in analysis |
306
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
Method |
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Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
0.49
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-9.91 | |||||||||
upper limit |
10.89 | |||||||||
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End point title |
Endoscopic improvement | |||||||||
End point description |
Percentage of patients with endoscopic improvement, defined as decrease of endoscopic index (EI) by ≥ 1 point from baseline to week 8 / EOT. The analysis set is the full analysis set for the final analysis (N = 306).
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End point type |
Secondary
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End point timeframe |
After 8-week treatment: week 8 / EOT
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Statistical analysis title |
Confidence interval for risk difference | |||||||||
Statistical analysis description |
The Wald 95% confidence interval is calculated for the difference in improvement rates between M1000 and M2x500.
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Comparison groups |
M1000 v M2x500
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Number of subjects included in analysis |
306
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
Method |
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Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
-3.76
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-12.48 | |||||||||
upper limit |
4.97 | |||||||||
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End point title |
Histological improvement | |||||||||
End point description |
Percentage of patients with histological improvment, defined as decrease of histological index (HI) by ≥ 1 point from baseline to week 8 / EOT. The analysis set is the full analysis set for the final analysis (N = 306).
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End point type |
Secondary
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End point timeframe |
After 8-week treatment: week 8 / EOT
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Statistical analysis title |
Confidence interval for risk difference | |||||||||
Comparison groups |
M1000 v M2x500
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Number of subjects included in analysis |
306
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [4] | |||||||||
Method |
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Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
-4.52
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-15.71 | |||||||||
upper limit |
6.66 | |||||||||
| Notes [4] - The Wald 95% confidence interval is calculated for the difference in improvement rates between M1000 and M2x500. |
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End point title |
Tablet preference | |||||||||||||||||||||
End point description |
Patients had to assess their tablet preference: one big mesalazine tablet or two smaller mesalazine tablets.
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End point type |
Secondary
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End point timeframe |
After 8-week treatment: week 8 / EOT
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| No statistical analyses for this end point | ||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From baseline to week 8 / EOT
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Adverse event reporting additional description |
All treatment emergent adverse events which occurred from the first drug administration to week 8 / EOT.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
M1000
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Reporting group description |
8-week treatment with three times daily 1000 mg masalazine | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
M2x500
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Reporting group description |
8-week treatment with three times daily 2x500 mg mesalazine | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 2% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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08 Apr 2013 |
Clinical study protocol amendment 1, version 1.0 of 08 Apr 2013, became necessary in order to incorporate changes due to the update of the Investigator's Brochure for Salofalk® (oral formulations) and Summary of Product Characteristics for Salofalk® 500 mg tablets. This amendment was also used to increase clarity of the study protocol. |
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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 | |||
