Clinical Trial Results:
A multi-center, randomized, double-blind, three-arm, 16 week, adaptive phase III clinical study to investigate the efficacy and safety of LAS41008 vs LASW1835 and vs placebo in patients with moderate to severe plaque psoriasis
Summary
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EudraCT number |
2012-000055-13 |
Trial protocol |
DE AT NL 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 |
11 Dec 2016
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First version publication date |
11 Dec 2016
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Other versions |
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 |
M41008-1102
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
ALMIRALL S.A.
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Sponsor organisation address |
Laureà Miró 408-410, Sant Feliu de Llobregat (Barcelona), Spain, 08980
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Public contact |
Disclosure Central Team, ALMIRALL S.A., R&D@almirall.com
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Scientific contact |
Disclosure Central Team, ALMIRALL S.A., R&D@almirall.com
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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 |
19 Oct 2015
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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? |
No
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General information about the trial
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Main objective of the trial |
The primary objectives of the study are:
Superiority of LAS41008 versus placebo based on the proportion of subjects achieving PASI 75 (a reduction of at least 75% in the Psoriasis Area and Severity Index) at Week 16
Superiority of LAS41008 versus placebo based on the proportion of subjects achieving a score of 'clear' or 'almost clear' in the Physician’s Global Assessment (PGA) at Week 16
Non-inferiority of LAS41008 compared to LASW1835 (internal code for Fumaderm®) regarding PASI 75 at Week 16
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Protection of trial subjects |
This study was conducted in accordance with the protocol, Good Clinical Practice (GCP), ICH (International Conference on Harmonization) guidelines, and the ethical principles set forth in the Declaration of Helsinki and its amendments (October 2008)
A favourable opinion of the relevant independent ethics committees was obtained prior to the start of the study and written informed consent was obtained from all patients prior to entry into the study. The investigator explained to each patient, orally and in writing (patient information sheet), the nature, significance, risks and implications of the trial
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Background therapy |
- | ||
Evidence for comparator |
Fumaderm® is a prescription only medicine currently approved only in Germany, where it is the most commonly prescribed oral therapy for the treatment of psoriasis Several publications and other prescribing evidence indicate that Fumaderm® is used by specialist dermatology centers under local legal arrangements in a number of other countries throughout Europe | ||
Actual start date of recruitment |
07 Jan 2013
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
12 Months | ||
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 |
Netherlands: 11
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Country: Number of subjects enrolled |
Poland: 321
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Country: Number of subjects enrolled |
Austria: 65
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Country: Number of subjects enrolled |
Germany: 302
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Worldwide total number of subjects |
699
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EEA total number of subjects |
699
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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) |
637
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From 65 to 84 years |
61
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85 years and over |
1
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Recruitment
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Recruitment details |
This study was conducted in a total of 57 sites, 7 in Austria, 36 in Germany, 12 in Poland, and 2 in the Netherlands The first patient visit was in January 2013 and the last patient visit was October 2015 | ||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 839 patients were screened and 704 patients were randomised Wash-out periods were 2 weeks (corticosteroids, vitamin A or D analogues, anthracene derivatives, tar and salicylic acid preparations), 1 month (conventional systemic antipsoriatic drugs and phototherapy), 3 months (antipsoriatic biologics) or 6 months (cytostatics) | ||||||||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Treatment period (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 |
Investigator, Subject | ||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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LAS41008 | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
LAS41008
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Investigational medicinal product code |
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Other name |
Dimethyl fumarate
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
During the first three weeks of the treatment period, patients received up to 3 x 1 tablet containing 30 mg LAS41008 (30 mg/day in Week 1, 60 mg/day in Week 2 and 90 mg/day in Week 3)
During the subsequent 13 weeks (Week 4 until Week 16), patients received up to 3 x 2 tablets each containing 120 mg LAS41008 leading to a maximum of 720 mg/day (120 mg/day in Week 4, 240 mg/day in Week 5, 360 mg/day in Week 6, 480 mg/day in Week 7, 600 mg/day in Week 8, 720 mg/day in Week 9 onwards)
In case of individual intolerability of the increased dosage, the patient was to receive the last tolerated dose, which was then to be maintained until the end of the treatment period
If treatment success (patient achieved a score of 'clear' or 'almost clear' in the PGA or >90% improvement in PASI from baseline) was reached before administration of the maximum dose of 720 mg/day, no further dose increase was necessary and the dosage was to be steadily reduced to an individual maintenance dose
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Arm title
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Fumaderm® | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fumaderm®
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Investigational medicinal product code |
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Other name |
Dimethyl fumarate
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
During the first three weeks of the treatment period, patients received up to 3 x 1 tablet containing 30 mg Fumaderm® (30 mg/day in Week 1, 60 mg/day in Week 2 and 90 mg/day in Week 3)
During the subsequent 13 weeks (Week 4 until Week 16), patients received up to 3 x 2 tablets each containing 120 mg Fumaderm® leading to a maximum of 720 mg/day (120 mg/day in Week 4, 240 mg/day in Week 5, 360 mg/day in Week 6, 480 mg/day in Week 7, 600 mg/day in Week 8, 720 mg/day in Week 9 onwards)
In case of individual intolerability of the increased dosage, the patient was to receive the last tolerated dose, which was then to be maintained until the end of the treatment period
If treatment success (patient achieved a score of 'clear' or 'almost clear' in the PGA or >90% improvement in PASI from baseline) was reached before administration of the maximum dose of 720 mg/day, no further dose increase was necessary and the dosage was to be steadily reduced to an individual maintenance dose
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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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 |
During the first three weeks of the treatment period, patients received up to 3 x 1 placebo and during the subsequent 13 weeks (Week 4 until Week 16), patients received up to 3 x 2 placebo tablets
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Baseline characteristics reporting groups
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Reporting group title |
LAS41008
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fumaderm®
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
LAS41008
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Reporting group description |
- | ||
Reporting group title |
Fumaderm®
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Reporting group description |
- | ||
Reporting group title |
Placebo
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Reporting group description |
- |
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End point title |
Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 at Week 16 | ||||||||||||||||
End point description |
PASI 75 is a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI)
The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities
Degree of severity (per body region) for each variable:
0 = no symptom
1 = slight
2 = moderate
3 = marked
4 = very marked
Surface area involved (per body region):
1 = <10%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
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End point type |
Primary
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End point timeframe |
Week 16 of treatment
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Statistical analysis title |
LAS41008 vs Placebo | ||||||||||||||||
Statistical analysis description |
P values are derived from the Wald test for risk differences and a combination (p value Stage 1 x p value Stage 2) of the p-values from Stage 1 (from study start to the time of the interim analysis) and Stage 2 (period comprising the remaining treatment period and the first 2 months of follow up for all subjects continuing in the study) according to the Bauer & Köhne procedure
Co-primary endpoints were non-adjusted
The last observation carried forward (LOCF) method was used for missing data
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Comparison groups |
Placebo v LAS41008
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Number of subjects included in analysis |
398
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [1] | ||||||||||||||||
Method |
Wald test | ||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||
Point estimate |
0.222
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Confidence interval |
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level |
99.24% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.107 | ||||||||||||||||
upper limit |
0.337 | ||||||||||||||||
Notes [1] - p value is significant if <0.0038 |
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Statistical analysis title |
LAS-41008 vs Fumaderm® | ||||||||||||||||
Statistical analysis description |
P values are derived from the Wald test for risk differences and a combination (p value Stage 1 x p value Stage 2) of the p-values from Stage 1 (from study start to the time of the interim analysis) and Stage 2 (period comprising the remaining treatment period and the first 2 months of follow up for all subjects continuing in the study) according to the Bauer & Köhne procedure
Co-primary endpoints were non-adjusted
The last observation carried forward (LOCF) method was used for missing data
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Comparison groups |
Fumaderm® v LAS41008
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Number of subjects included in analysis |
540
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||
P-value |
= 0.0003 [2] | ||||||||||||||||
Method |
Wald test | ||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||
Point estimate |
-0.028
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Confidence interval |
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level |
99.24% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.14 | ||||||||||||||||
upper limit |
0.084 | ||||||||||||||||
Notes [2] - p value is significant if <0.0038 |
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End point title |
Proportion of patients achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment at Week 16 | ||||||||||||||||
End point description |
The Physician's Global Assessment (PGA) is scored as:
0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present))
1 = almost clear (intermediate between mild and clear)
2 = mild (slight plaque elevation, scaling and/or erythema)
3 = moderate (moderate plaque elevation, scaling and/or erythema)
4 = moderate to severe (marked plaque elevation, scaling and/or erythema)
5 = severe (very marked plaque elevation, scaling and/or erythema)
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End point type |
Primary
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End point timeframe |
Week 16 of treatment
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Statistical analysis title |
LAS41008 vs Placebo | ||||||||||||||||
Statistical analysis description |
P values are derived from the Wald test for risk differences and a combination (p value Stage 1 x p value Stage 2) of p-values from Stage 1 (from study start to the time of the interim analysis) and Stage 2 (period comprising the remaining treatment period and the first 2 months of follow up for all subjects continuing in the study) according to the Bauer & Köhne procedure
Co-primary endpoints were non-adjusted
The last observation carried forward (LOCF) method was used for missing data
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Comparison groups |
Placebo v LAS41008
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Number of subjects included in analysis |
398
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [3] | ||||||||||||||||
Method |
Wald test | ||||||||||||||||
Parameter type |
Median difference (net) | ||||||||||||||||
Point estimate |
0.2
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Confidence interval |
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level |
99.24% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.09 | ||||||||||||||||
upper limit |
0.31 | ||||||||||||||||
Notes [3] - p value is significant if <0.0038 |
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End point title |
Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 at Week 3 and 8 | ||||||||||||||||||||||||
End point description |
PASI 75 is a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI)
The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities
Degree of severity (per body region) for each variable:
0 = no symptom
1 = slight
2 = moderate
3 = marked
4 = very marked
Surface area involved (per body region):
1 = <10%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
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End point type |
Secondary
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End point timeframe |
Week 3 and 8 of treatment
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No statistical analyses for this end point |
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End point title |
Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 50 and PASI 90 at Week 3, 8, and 16 | ||||||||||||||||||||||||||||||||||||||||
End point description |
PASI 50 is a reduction of at least 50% in the Psoriasis Area and Severity Index (PASI); PASI 90 is a reduction of at least 90% in the PASI
The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities
Degree of severity (per body region) for each variable:
0 = no symptom
1 = slight
2 = moderate
3 = marked
4 = very marked
Surface area involved (per body region):
1 = <10%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
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End point type |
Secondary
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End point timeframe |
Week 3, 8, and 16 of treatment
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No statistical analyses for this end point |
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End point title |
Proportion of patients achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment at Week 3 and 8 | ||||||||||||||||||||||||
End point description |
The Physician's Global Assessment (PGA) is scored as:
0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present))
1 = almost clear (intermediate between mild and clear)
2 = mild (slight plaque elevation, scaling and/or erythema)
3 = moderate (moderate plaque elevation, scaling and/or erythema)
4 = moderate to severe (marked plaque elevation, scaling and/or erythema)
5 = severe (very marked plaque elevation, scaling and/or erythema)
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End point type |
Secondary
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End point timeframe |
Week 3 and 8 of treatment
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No statistical analyses for this end point |
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End point title |
Absolute values and percent change from baseline in Psoriasis Area and Severity Index (PASI) at Week 3, 8, 16, and 2 months treatment-free | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities
Degree of severity (per body region) for each variable:
0 = no symptom
1 = slight
2 = moderate
3 = marked
4 = very marked
Surface area involved (per body region):
1 = <10%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
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End point type |
Secondary
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End point timeframe |
Week 3, 8 and 16 of treatment and 2 months treatment-free
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No statistical analyses for this end point |
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End point title |
Physician's Global Assessment score at Week 3 | ||||||||||||||||||||||||||||||||||||||||
End point description |
The Physician's Global Assessment (PGA) is scored as:
0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present))
1 = almost clear (intermediate between mild and clear)
2 = mild (slight plaque elevation, scaling and/or erythema)
3 = moderate (moderate plaque elevation, scaling and/or erythema)
4 = moderate to severe (marked plaque elevation, scaling and/or erythema)
5 = severe (very marked plaque elevation, scaling and/or erythema)
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End point type |
Secondary
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End point timeframe |
Week 3 of treatment
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No statistical analyses for this end point |
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End point title |
Physician's Global Assessment score at Week 8 | ||||||||||||||||||||||||||||||||||||||||
End point description |
The Physician's Global Assessment (PGA) is scored as:
0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present))
1 = almost clear (intermediate between mild and clear)
2 = mild (slight plaque elevation, scaling and/or erythema)
3 = moderate (moderate plaque elevation, scaling and/or erythema)
4 = moderate to severe (marked plaque elevation, scaling and/or erythema)
5 = severe (very marked plaque elevation, scaling and/or erythema)
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End point type |
Secondary
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End point timeframe |
Week 8 of treatment
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No statistical analyses for this end point |
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|||||||||||||||||||||||||||||||||||||||||
End point title |
Physician's Global Assessment score at Week 16 | ||||||||||||||||||||||||||||||||||||||||
End point description |
The Physician's Global Assessment (PGA) is scored as:
0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present))
1 = almost clear (intermediate between mild and clear)
2 = mild (slight plaque elevation, scaling and/or erythema)
3 = moderate (moderate plaque elevation, scaling and/or erythema)
4 = moderate to severe (marked plaque elevation, scaling and/or erythema)
5 = severe (very marked plaque elevation, scaling and/or erythema)
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Week 16 of treatment
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Physician's Global Assessment score 2 months treatment-free | ||||||||||||||||||||||||||||||||||||||||
End point description |
The Physician's Global Assessment (PGA) is scored as:
0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present))
1 = almost clear (intermediate between mild and clear)
2 = mild (slight plaque elevation, scaling and/or erythema)
3 = moderate (moderate plaque elevation, scaling and/or erythema)
4 = moderate to severe (marked plaque elevation, scaling and/or erythema)
5 = severe (very marked plaque elevation, scaling and/or erythema)
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
2 months treatment-free
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||
End point title |
Mean % change from baseline in % body surface area (BSA) affected | ||||||||||||||||||||||||||||||||
End point description |
|||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Week 3, 8, 16 of treatment and 2 months treatment-free
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||
End point title |
Treatment success rate | ||||||||||||||||||||||||||||||||
End point description |
Treatment success was defined as patients achieving either a 'clear' or 'almost clear score in the Physician's Global Assessment (PGA) score and/or Psoriasis Area and Severity Index (PASI) 90
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Week 3, 8, 16 of treatment and 2 months treatment-free
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||
End point title |
Remission rate | ||||||||||||||||||||||||||||||||
End point description |
The remission rate was defined as a score of 'clear' in the Physician's Global Assessment (PGA) score
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Week 3, Week 8, Week 16 of treatment and 2 months treatment-free
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Mean time to relapse within 2 months of stopping therapy | ||||||||||||||||
End point description |
Relapse was defined as the event when the achieved maximal improvement from baseline was subsequently reduced by ≥50% based on the Psoriasis Area and Severity Index (PASI)
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 2 months after stopping therapy
|
||||||||||||||||
|
|||||||||||||||||
Notes [4] - 16/175 patients in the LAS41008 group had a relapse [5] - 17/179 patients in the Fumaderm® group had a relapse [6] - 16/68 patients in the placebo group had a relapse |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Time to rebound within 2 months of stopping therapy | ||||||||||||||||
End point description |
Rebound was defined as worsening of psoriasis over baseline value (Psoriasis Area and Severity Index [PASI]≥125%) or new pustular, erythrodermic or more inflammatory psoriasis occurring within 2 months of stopping therapy
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 2 months after stopping therapy
|
||||||||||||||||
|
|||||||||||||||||
Notes [7] - 2/177 patients in the LAS41008 group had a rebound [8] - 4/183 patients in the Fumaderm® group had a rebound [9] - 7/75 patients in the placebo group had a rebound |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Patient Benefit Index (PBI) at Week 16 and 2 months treatment-free | ||||||||||||||||||||||||
End point description |
The Patient Benefit Index (PBI) was calculated based on the Patient Need Questionnaire (PNQ) assessed at the start of treatment and on the Patient Benefit Questionnaire (PBQ) assessed after 16 weeks of treatment and during the follow-up period
In the PNQ, patients were asked to indicate how important they considered 25 different treatment goals on a five-point scale from 'not at all' to 'very'
In the PBQ, patients were asked if the study treatment had helped them to achieve these goals
The PBI was calculated by averaging the preference-weighed results of all items
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Week 16 of treatment and 2 months treatment-free
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||
End point title |
Absolute values and percent change from baseline in Psoriasis Area and Severity Index (PASI) at 6 and 12 months treatment-free | ||||||||||||||||||||||||||||||||
End point description |
The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities
Degree of severity (per body region) for each variable:
0 = no symptom
1 = slight
2 = moderate
3 = marked
4 = very marked
Surface area involved (per body region):
1 = <10%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
6 and 12 months treatment-free
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Physician's Global Assessment score 6 months treatment-free | ||||||||||||||||||||||||||||||||||||||||
End point description |
The Physician's Global Assessment (PGA) is scored as:
0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present))
1 = almost clear (intermediate between mild and clear)
2 = mild (slight plaque elevation, scaling and/or erythema)
3 = moderate (moderate plaque elevation, scaling and/or erythema)
4 = moderate to severe (marked plaque elevation, scaling and/or erythema)
5 = severe (very marked plaque elevation, scaling and/or erythema)
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
6 months treatment-free
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Physician's Global Assessment score 12 months treatment-free | ||||||||||||||||||||||||||||||||||||||||
End point description |
The Physician's Global Assessment (PGA) is scored as:
0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present))
1 = almost clear (intermediate between mild and clear)
2 = mild (slight plaque elevation, scaling and/or erythema)
3 = moderate (moderate plaque elevation, scaling and/or erythema)
4 = moderate to severe (marked plaque elevation, scaling and/or erythema)
5 = severe (very marked plaque elevation, scaling and/or erythema)
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
12 months treatment-free
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Mean % change from baseline in % body surface area (BSA) affected at 6 and 12 months treatment-free | ||||||||||||||||||||||||
End point description |
|||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
6 and 12 months treatment-free
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Mean time to relapse including data up to 12 months treatment-free | ||||||||||||||||
End point description |
Relapse was defined as the event when the achieved maximal improvement from baseline was subsequently reduced by ≥50% based on PASI
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 12 months treatment-free
|
||||||||||||||||
|
|||||||||||||||||
Notes [10] - 54/267 patients in the LAS41008 group had a relapse [11] - 66/273 patients in the Fumaderm® group had a relapse [12] - 40/131 patients in the placebo group had a relapse |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||
End point title |
Dermatology Life Quality Index (DLQI) score | ||||||||||||||||||||||||||||||||
End point description |
The Dermatology Life Quality Index (DLQI) is a patient-reported outcome that also includes assessment of improvement in symptoms such as pruritus
The questionnaire comprises 10 questions (eg, over the last week, how itchy, sore, painful or stinging has your skin been?) relating to symptoms and feelings, daily activities, leisure, work and school, personal relationships and treatment
The scoring of each question was as follows:
0 = not at all
1 = a little
2 = a lot
3 = very much
The DLQI was calculated by summing the score for each question, resulting in a maximum of 30 and a minimum of 0
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Week 16 of treatment and 2, 6 and 12 months treatment-free
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 at Week 16 by intake of potentially nephrotoxic medicines | ||||||||||||||||||||||||
End point description |
PASI 75 is a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI)
The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities
Degree of severity (per body region) for each variable:
0 = no symptom
1 = slight
2 = moderate
3 = marked
4 = very marked
Surface area involved (per body region):
1 = <10%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Week 16 of treatment
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
End point title |
Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 at Week 16 by age group | ||||||||||||||||||||||||||||
End point description |
PASI 75 is a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI)
The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities
Degree of severity (per body region) for each variable:
0 = no symptom
1 = slight
2 = moderate
3 = marked
4 = very marked
Surface area involved (per body region):
1 = <10%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Week 16 of treatment
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Proportion of patients achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment at Week 16 by intake of potentially nephrotoxic medicines | ||||||||||||||||||||||||
End point description |
The Physician's Global Assessment (PGA) is scored as:
0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present))
1 = almost clear (intermediate between mild and clear)
2 = mild (slight plaque elevation, scaling and/or erythema)
3 = moderate (moderate plaque elevation, scaling and/or erythema)
4 = moderate to severe (marked plaque elevation, scaling and/or erythema)
5 = severe (very marked plaque elevation, scaling and/or erythema)
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Week 16 of treatment
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
End point title |
Proportion of patients achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment at Week 16 by age group | ||||||||||||||||||||||||||||
End point description |
The Physician's Global Assessment (PGA) is scored as:
0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present))
1 = almost clear (intermediate between mild and clear)
2 = mild (slight plaque elevation, scaling and/or erythema)
3 = moderate (moderate plaque elevation, scaling and/or erythema)
4 = moderate to severe (marked plaque elevation, scaling and/or erythema)
5 = severe (very marked plaque elevation, scaling and/or erythema)
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Week 16 of treatment
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
During the 16 week (± 3 days) treatment period and 12 months (± 10 days) follow-up period
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Serious adverse events with onset >30 days after end of treatment were not classified as serious treatment-emergent adverse events
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
LAS41008
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Safety analysis set (SAS) defined as all patients who were randomised and received at least one dose of the investigational medicinal product | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fumaderm®
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Safety analysis set (SAS) defined as all patients who were randomised and received at least one dose of the investigational medicinal product | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Safety analysis set (SAS) defined as all patients who were randomised and received at least one dose of the investigational medicinal product | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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08 Oct 2012 |
Concomitant therapy with cytostatics and medications with known harmful influences on the kidneys was prohibited
A severe decline in the leukocyte (WBC) count – particularly with parameters below 3000/μL, or other pathological blood count changes or a creatinine increase above normal, were added as examples of adverse events that would constitute possible reasons for premature withdrawal of subjects
It was added that during the first three weeks of treatment no dose reductions were possible |
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07 Feb 2013 |
It was clarified that patients could be included with prior therapy with systemic drugs for psoriasis that was discontinued due to an adverse event or insufficient effect
It was clarified that male patients except vasectomized males (instead of previously including vasectomized males) had to use contraceptive measures
BSA assessments at each follow-up visit were added
PGA assessment at screening was added
It was clarified that during the first week of treatment with the maintenance dose (week 4) no dose reduction was possible
It was clarified that the sponsor reserved the right to modify or terminate the study at any time in agreement with the involved Ethics Committees and Competent Authorities |
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15 May 2013 |
Patients taking medications with known harmful influence on the kidneys were now to be included (and not, as previously described, excluded from the study) and a new secondary objective was added to assess safety and efficacy of LAS41008 and Fumaderm® in this subgroup of patients
An analysis of the safety and efficacy of LAS41008 and Fumaderm® when administered concomitantly with medicines known to have potential nephrotoxic effects, e.g. angiotensin-converting enzyme, angiotensin II inhibitors and statins was added
A more detailed definition of severe renal impairment was added and a more detailed definition of abnormal liver enzymes was added
The risk benefit assessment was updated |
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03 Nov 2014 |
Clarification that a full integrated clinical study report was to be written after all patients had completed the 2 month follow up examination and that the 6 month and 12 month follow-up data was to be included in an updated study report after all patients had completed the 12 month follow-up |
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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 |