Clinical Trial Results:
Double-blind, randomised, placebo-controlled, multi-centre phase III clinical study comparing the combination of ursodeoxycholic acid capsules plus budesonide capsules to ursodeoxycholic acid capsules plus placebo in the treatment of primary biliary cirrhosis
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Summary
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EudraCT number |
2007-004040-70 |
Trial protocol |
DE SE FR AT NL FI ES HU GB LT DK IT PL |
Global end of trial date |
19 Oct 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Dec 2018
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First version publication date |
23 Dec 2018
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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 |
BUC-56/PBC
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00746486 | ||
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 |
Project Management, Dr. Falk Pharma GmbH
, +49 7611514199, markus.proels@drfalkpharma.de
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Scientific contact |
Project Management, Dr. Falk Pharma GmbH
, +49 7611514199, markus.proels@drfalkpharma.de
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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 |
20 Jul 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
19 Oct 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Oct 2015
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
- To compare the efficacy and tolerability of a combination therapy with ursodeoxycholic acid (12-16 mg/kg body weight/d) plus budesonide (9 mg/d) vs. ursodeoxycholic acid (12-16 mg/kg body weight/d) plus placebo in the treatment of PBC.
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Protection of trial subjects |
Close supervision of subjects by implementing interim visits every 14 days during the first 4 weeks of treatment, every 3 months up to Month 12 and every 6 months up to month 36 to guarantee their safety and wellbeing.
Prior to recruitment of patients all relevant documents of the clinical study were submitted and approved 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 |
None. | ||
Evidence for comparator |
Ursodeoxycholic acid (Ursofalk®250 mg capsules) is registered for the treatment of cholestatic liver diseases including PBC. | ||
Actual start date of recruitment |
21 Jan 2009
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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 |
Israel: 1
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Country: Number of subjects enrolled |
Netherlands: 5
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Country: Number of subjects enrolled |
Poland: 2
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Country: Number of subjects enrolled |
Spain: 4
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Country: Number of subjects enrolled |
Sweden: 7
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Country: Number of subjects enrolled |
Austria: 2
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Country: Number of subjects enrolled |
Denmark: 9
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Country: Number of subjects enrolled |
Finland: 4
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Country: Number of subjects enrolled |
France: 1
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Country: Number of subjects enrolled |
Germany: 13
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Country: Number of subjects enrolled |
Hungary: 1
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Country: Number of subjects enrolled |
Italy: 1
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Country: Number of subjects enrolled |
Lithuania: 12
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Worldwide total number of subjects |
62
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EEA total number of subjects |
61
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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) |
0
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Adults (18-64 years) |
54
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From 65 to 84 years |
8
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 90 patients were enrolled into the study in Austria, Denmark, Finland, France, Germany, Hungary, Israel, Italy, Lithuania, Netherlands, Poland, Spain and Sweden from February 2009 to Oct 2014. | |||||||||
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Pre-assignment
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Screening details |
Screening Criteria: 1. Signed Informed Consent 2. Age ≥ 18 years 3. UDCA treatment for at least 6 months prior to baseline exam. 4. Liver biopsy performed. In total, 90 patients were screened. Thereof 62 patients were randomised and received at least one dose of study medication and were included in the safety set and full analysis set (FAS) . | |||||||||
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Pre-assignment period milestones
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Number of subjects started |
62 | |||||||||
Number of subjects completed |
62 | |||||||||
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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 |
Conducted with the double-blind design.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Arm A | |||||||||
Arm description |
9 mg Budesonide (3 mg capsules TD). 6 mg Budesonide (3 mg capsules BD) are allowed if adjustment according to disease activity is necessary plus 12-16 mg/kg BW/d ursodeoxycholic acid | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Budesonide plus ursodeoxycholic acid
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
9 mg Budesonide (3 mg capsules TD). 6 mg Budesonide (3 mg capsules BD) if adjustment according to disease plus 12-16 mg/kg BW/d ursodeoxycholic acid.
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Arm title
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Arm B | |||||||||
Arm description |
Budesonide Placebo (one Placebo capsule TD) or BD depending on AST values plus 12-16 mg/kg BW/d ursodeoxycholic acid . | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Budesonide Placebo (one capsule TD) or BD depending on AST values plus 12-16 mg/kg BW/d ursodeoxycholic acid.
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Budesonide Placebo (one capsule TD) or BD depending on AST values plus 12-16 mg/kg BW/d ursodeoxycholic acid.
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Baseline characteristics reporting groups
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Reporting group title |
Treatment Phase (overall period)
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Reporting group description |
90 patients have signed an Informed Consent at Screening. 62 patients were finally randomised in one of the two treatment groups. 28 patients were Screening failures. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Arm A
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Reporting group description |
9 mg Budesonide (3 mg capsules TD). 6 mg Budesonide (3 mg capsules BD) are allowed if adjustment according to disease activity is necessary plus 12-16 mg/kg BW/d ursodeoxycholic acid | ||
Reporting group title |
Arm B
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Reporting group description |
Budesonide Placebo (one Placebo capsule TD) or BD depending on AST values plus 12-16 mg/kg BW/d ursodeoxycholic acid . | ||
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End point title |
Number of patients with Improvement of liver histology | |||||||||
End point description |
Number of patients with improvement of liver histology with respect to inflammation and no progression of fibrosis.
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End point type |
Primary
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End point timeframe |
From Baseline to the last individual patient visit
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Statistical analysis title |
Cochran-Mantel-Haenszel test | |||||||||
Statistical analysis description |
For confirmatory hypothesis testing the Cochran-Mantel-Haenszel test for comparing two rates
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Comparison groups |
Arm A v Arm B
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Number of subjects included in analysis |
62
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.025 | |||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||
Confidence interval |
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End point title |
Number of patients presenting with cirrhosis or esophageal varices and/or ascites | |||||||||
End point description |
Number of patients presenting with cirrhosis or esophageal varices and/or ascites at the end of the treatment.
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End point type |
Secondary
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End point timeframe |
At the end of the treatment (from Baseline to the last individual patient visit).
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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 |
Adverse Events were assessed at all interim visits (Week 2, Week 4, Month 3, Month 6, Month 9, starting from Month 12 (every 6 months) to final study visit of individual patient or Month 36 respectively.
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Adverse event reporting additional description |
Treatment-Emergent Adverse Events
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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 |
12.0
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Reporting groups
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Reporting group title |
Arm A
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Reporting group description |
9 mg Budesonide (3 mg capsules TD). 6 mg Budesonide (3 mg capsules BD) are allowed if adjustment according to disease activity is necessary plus 12-16 mg/kg BW/d ursodeoxycholic acid. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm B
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Reporting group description |
Budesonide Placebo (one Placebo capsule TD) or BD depending on AST values plus 12-16 mg/kg BW/d ursodeoxycholic acid | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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23 Sep 2011 |
Amendment was issued based on an advice from the German competent authority and containing the following elements:
• Modification of trial population from "patients at risk of disease progression" to "patients with an incomplete response to UDCA treatment"
• Modification of the primary endpoint
• Modification of the secondary endpoints
• Adjustment of sample size due to modified primary endpoint and trial population
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12 Feb 2015 |
Termination of recruitment into the study following a recommendation of the Independent Data Monitoring Committee. Patients had to leave the study after at least 1 year of study treatment. The last visit of the last patient who completed the study after at least 1 year of treatment was estimated to occur in August 2015. As a consequence, the number of patient enrolled into the study was 62. |
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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. | |||
| Early termination of the trial by the sponsor based on the recommendation of the IDMC. IDMC recommendation was to observe the blinded patients recruited until now for one year more was respected. | |||
