Clinical Trial Results:
A phase 4 trial comparing the efficacy of subcutaneous injections of brodalumab to oral administrations of fumaric acid esters in adults with moderate to severe plaque psoriasis
Summary
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EudraCT number |
2016-003867-21 |
Trial protocol |
DE |
Global end of trial date |
21 Mar 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Feb 2020
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First version publication date |
13 Feb 2020
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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 |
LP0160-1327
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03331835 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
LEO Pharma A/S
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Sponsor organisation address |
Industriparken 55, Ballerup, Denmark, 2750
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Public contact |
Clinical Disclosure, LEO Pharma A/S, +45 44945888, disclosure@leo-pharma.com
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Scientific contact |
Clinical Disclosure, LEO Pharma A/S, +45 44945888, disclosure@leo-pharma.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 Aug 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
24 Jan 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Mar 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To compare the efficacy of subcutaneous injections of brodalumab to oral administration of fumaric acid esters in subjects with moderate to severe plaque psoriasis who are naive to systemic treatment.
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Protection of trial subjects |
This clinical trial was conducted to conform to the principles of the Declaration of Helsinki as adopted by the 18th World Medical Association General Assembly, 1964, and subsequent amendments.
All subjects or their legally acceptable representative received written and verbal information concerning the clinical trial.
Subjects or their legally acceptable representative were asked to consent that their personal data were recorded, collected, processed and could be transferred to EU and non-EU countries in accordance with any national legislation regulating privacy and data protection.
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Background therapy |
- | ||
Evidence for comparator |
An oral preparation containing fumaric acid esters (dimethyl fumarate and monoethyl fumarate salts; Fumaderm®) was selected as comparator, because it is a well-established and widely used systemic treatment in Germany for patients with moderate to severe plaque psoriasis in whom topical therapy is not effective (Nast et al. J Dtsch Dermatol Ges. 2018;165]:645-669). Fumaric acid esters were recommended in 2017 as appropriate comparator for this patient population by the Federal Joint Committee (G-BA), a German decision-making body (Scientific Advice [2016-B-165] of the Gemeinsamer Bundesausschuss (G-BA) according to § 8 Abs.1 AM-NutzenV. 2017). | ||
Actual start date of recruitment |
01 Oct 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 210
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Worldwide total number of subjects |
210
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EEA total number of subjects |
210
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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) |
193
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From 65 to 84 years |
17
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Number of subjects screened: 325 Screening failures: 101 Withdrawn before randomisation: 14 | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
Open-label treatment (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||
Blinding implementation details |
The risk of bias related to open-label treatment was mitigated by blinded investigator assessments and detailed precautions were taken to avoid unblinding assessors. Due to potential dose adjustments needed for subjects randomised to fumaric acid esters, the investigator and subject needed to know the treatment allocated. The sponsor was also blinded.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Brodalumab | |||||||||||||||||||||||||||
Arm description |
Brodalumab 210 mg s.c. injection Q2W | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Brodalumab
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Investigational medicinal product code |
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Other name |
Kyntheum (R)
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Dosage: 210 mg in 1.5 mL solution for subcutaneous injection (140 mg/mL). Weekly administration for the first 3 weeks (Weeks 0, 1, and 2) followed by administration every 2 weeks (Q2W) up to Week 24.
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Arm title
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Fumaric acid esters | |||||||||||||||||||||||||||
Arm description |
Oral fumaric acid esters up to 240 mg 3 times daily (TID) | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
fumaric acid esters
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Investigational medicinal product code |
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Other name |
Fumaderm (R), Fumaderm (R) initial
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Administration by participant 3 times daily in doses ranging from 30 to 240 mg dimethyl fumarate per oral administration.
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Baseline characteristics reporting groups
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Reporting group title |
Brodalumab
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Reporting group description |
Brodalumab 210 mg s.c. injection Q2W | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fumaric acid esters
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Reporting group description |
Oral fumaric acid esters up to 240 mg 3 times daily (TID) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Brodalumab
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Reporting group description |
Brodalumab 210 mg s.c. injection Q2W | ||
Reporting group title |
Fumaric acid esters
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Reporting group description |
Oral fumaric acid esters up to 240 mg 3 times daily (TID) |
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End point title |
Having Least 75% Lower Psoriasis Area and Severity Index (PASI) Score Relative to Baseline (PASI 75 Response) From Baseline at Week 24 | ||||||||||||
End point description |
Co-primary endpoint
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End point type |
Primary
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End point timeframe |
Week 24
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Statistical analysis title |
Analysis of co-primary endpoint PASI75 | ||||||||||||
Statistical analysis description |
The difference in response rate between treatment groups was analysed using the Cochran-Mantel-Haenszel test with stratification by weight group (≥100 kg or <100 kg). The null hypotheses of no difference in response rates between brodalumab and fumaric acid esters was tested against the two-sided alternative that there was a difference on a 5% level. Subjects who drop-out of the trial before Week 24 (end of treatment visit) were regarded as non-responders.
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Comparison groups |
Brodalumab v Fumaric acid esters
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Number of subjects included in analysis |
210
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||
Point estimate |
42.86
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
30.93 | ||||||||||||
upper limit |
54.79 |
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End point title |
Static Physician’s Global Assessment (sPGA) scale score of 0 or 1 at Week 24 | ||||||||||||
End point description |
Co-primary endpoint
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End point type |
Primary
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End point timeframe |
24 weeks
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Statistical analysis title |
Analysis of co-primary endpoint sPGA 0 or 1 | ||||||||||||
Statistical analysis description |
The difference in response rate between treatment groups was analysed using the Cochran-Mantel-Haenszel test with stratification by weight group (≥100 kg or <100 kg). The null hypotheses of no difference in response rates between brodalumab and fumaric acid esters was tested against the two-sided alternative that there was a difference on a 5% level. Subjects who drop-out of the trial before Week 24 (end of treatment visit) were regarded as non-responders.
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Comparison groups |
Brodalumab v Fumaric acid esters
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Number of subjects included in analysis |
210
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||
Point estimate |
44.76
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
32.81 | ||||||||||||
upper limit |
56.71 |
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End point title |
Having Least 90% Lower Psoriasis Area and Severity Index (PASI) Score Relative to Baseline (PASI 90 Response) From Baseline at Week 24 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24 weeks
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Statistical analysis title |
Analysis of secondary endpoint PASI90 | ||||||||||||
Statistical analysis description |
The difference in response rate between treatment groups was analysed using the Cochran-Mantel-Haenszel test with stratification by weight group (≥100 kg or <100 kg). The null hypotheses of no difference in response rates between brodalumab and fumaric acid esters was tested against the two-sided alternative that there was a difference on a 5% level. Subjects who drop-out of the trial before Week 24 (end of treatment visit) were regarded as non-responders.
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Comparison groups |
Brodalumab v Fumaric acid esters
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Number of subjects included in analysis |
210
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||
Point estimate |
43.81
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
31.78 | ||||||||||||
upper limit |
55.84 |
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End point title |
Having 100% Lower Psoriasis Area and Severity Index (PASI) Score Relative to Baseline (PASI 100 Response) From Baseline at Week 24 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24 weeks
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Statistical analysis title |
Analysis of secondary endpoint PASI100 | ||||||||||||
Statistical analysis description |
The difference in response rate between treatment groups was analysed using the Cochran-Mantel-Haenszel test with stratification by weight group (≥100 kg or <100 kg). The null hypotheses of no difference in response rates between brodalumab and fumaric acid esters was tested against the two-sided alternative that there was a difference on a 5% level. Subjects who drop-out of the trial before Week 24 (end of treatment visit) were regarded as non-responders.
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Comparison groups |
Brodalumab v Fumaric acid esters
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Number of subjects included in analysis |
210
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||
Point estimate |
31.43
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
20.76 | ||||||||||||
upper limit |
42.1 |
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End point title |
Change from baseline at Week 24 in PASI score | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24 weeks
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Statistical analysis title |
Mean change from baseline in PASI score | ||||||||||||
Statistical analysis description |
The endpoint was analysed by using mixed model for repeated measures (MMRM) model including treatment group, week, interaction between treatment and time, baseline value, and baseline weight group as fixed factors. Within subject covariance was estimated by an unstructured covariance matrix.
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Comparison groups |
Brodalumab v Fumaric acid esters
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Number of subjects included in analysis |
196
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-3.08
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-4.83 | ||||||||||||
upper limit |
-1.33 |
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End point title |
PASI improvement (%) from baseline at Week 24 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24 weeks
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Statistical analysis title |
PASI improvement (%) from baseline to Week 24 | ||||||||||||
Statistical analysis description |
The endpoint was analysed using mixed model for repeated measures (MMRM) model including treatment group, week, interaction between treatment and time, baseline value, and baseline weight group as fixed factors. Within subject covariance was estimated by an unstructured covariance matrix. Treatment groups were defined as randomised treatment.
Number of randomised and analysed paticipants differs, as those with missing data in all visits for a given endpoint are not included in the analysis.
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Comparison groups |
Brodalumab v Fumaric acid esters
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Number of subjects included in analysis |
196
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Median difference (net) | ||||||||||||
Point estimate |
-16.36
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-23.03 | ||||||||||||
upper limit |
-9.68 |
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End point title |
Change from baseline at Week 24 in affected BSA | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24 weeks
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Statistical analysis title |
Change from baseline at Week 24 in affected BSA | ||||||||||||
Statistical analysis description |
The endpoint was analysed using mixed model for repeated measures (MMRM) model including treatment group, week, interaction between treatment and time, baseline value, and baseline weight group as fixed factors. Within subject covariance was estimated by an unstructured covariance matrix. Treatment groups were defined as randomised treatment.
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Comparison groups |
Brodalumab v Fumaric acid esters
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Number of subjects included in analysis |
210
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-8.91
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-13 | ||||||||||||
upper limit |
-4.81 |
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End point title |
Psoriasis Symptom Inventory (PSI) responder at Week 24 | |||||||||
End point description |
A PSI responder is defined as having a total score ≤8 and no item score >1. No statistical analysis of this data was performed due to missing data at both baseline and Week 24. This was due to operational challenges with the eDiaries handed out to subjects.
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End point type |
Secondary
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End point timeframe |
24 weeks
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Notes [1] - Less than 105 subjects had data at Week 24. [2] - Less than 105 subjects had data at Week 24. |
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No statistical analyses for this end point |
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End point title |
PSI total score of 0 at Week 24 | |||||||||
End point description |
No statistical analysis of this data was performed due to missing data at baseline and Week 24. This was due to operational challenges with the eDiary devices handed out to subjects.
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End point type |
Secondary
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End point timeframe |
24 weeks
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Notes [3] - Less than 105 subjects had data at Week 24. [4] - Less than 105 subjects had data at Week 24. |
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No statistical analyses for this end point |
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End point title |
Number of symptom-free days from randomisation to Week 24 | ||||||||||||
End point description |
A symptom-free day was defined as a total PSI of 0 on that day. No statistical analysis of this data was performed due to missing data at baseline and Week 24. This was due to operational challenges with the eDiary devices handed out to subjects.
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End point type |
Secondary
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End point timeframe |
24 weeks
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Notes [5] - Less than 105 subjects had data at Week 24 [6] - Less than 105 subjects had data at Week 24 |
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No statistical analyses for this end point |
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End point title |
Burden of symptoms shown as area under curve (AUC) of PSI total score | ||||||||||||
End point description |
Burden of symptoms was assessed as the normalised AUC of PSI total score from baseline to the last available assessment. The AUC for the PSI total score was calculated for each subject using the standard trapezoidal rule. The AUC was then normalised by dividing it with the time from baseline to the last available assessment of the PSI total score.
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End point type |
Secondary
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End point timeframe |
24 weeks
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Notes [7] - Not all 105 subjects had data available for analysis for this endpoint [8] - Not all 105 subjects had data available for analysis for this endpoint |
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Statistical analysis title |
AUC of PSI total score | ||||||||||||
Statistical analysis description |
The AUC was analysed using an analysis of covariance (ANCOVA) with treatment group, baseline weight group, and the baseline PSI total score as explanatory variables. Treatment groups are defined as randomised treatment.
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Comparison groups |
Brodalumab v Fumaric acid esters
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Number of subjects included in analysis |
161
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-4.92
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-6.31 | ||||||||||||
upper limit |
-3.53 |
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End point title |
Change from baseline at Week 24 DLQI total score | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24 weeks
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Statistical analysis title |
Change from baseline in DLQI total score at Week24 | ||||||||||||
Statistical analysis description |
The endpoint was analysed by using mixed model for repeated measures (MMRM) model including treatment group, week, interaction between treatment and time, baseline value, and baseline weight group as fixed factors. Within subject covariance was estimated by an unstructured covariance matrix.
|
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Comparison groups |
Brodalumab v Fumaric acid esters
|
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Number of subjects included in analysis |
185
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.004 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-2.57
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
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lower limit |
-4.32 | ||||||||||||
upper limit |
-0.82 |
|
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End point title |
DLQI total score of 0 or 1 at Week 24 | |||||||||
End point description |
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End point type |
Secondary
|
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End point timeframe |
24 weeks
|
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Statistical analysis title |
DLQI total score of 0 or 1 at Week 24 | |||||||||
Statistical analysis description |
Estimated risk difference, 95% CI and p-value were derived from CMH analysis stratified by weight group at baseline (≤100 kg, > 100 kg). Non-responder imputation (NRI) was used to impute missing data. Treatment groups were defined as randomised treatment.
|
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Comparison groups |
Brodalumab v Fumaric acid esters
|
|||||||||
Number of subjects included in analysis |
210
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
40.95
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
28.75 | |||||||||
upper limit |
53.16 |
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End point title |
Change from baseline at Week 24 in NAPSI total score | ||||||||||||
End point description |
|||||||||||||
End point type |
Other pre-specified
|
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End point timeframe |
24 weeks
|
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|
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Notes [9] - Only subjects with nail psoriasis at baseline were included in this end point. [10] - Only subjects with nail psoriasis at baseline were included in this end point. |
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Statistical analysis title |
Change from baseline in NAPSI score at Week 24 | ||||||||||||
Statistical analysis description |
The endpoint was analysed by using mixed model for repeated measures (MMRM) model including treatment group, week, interaction between treatment and time, baseline value, and baseline weight group as fixed factors. Within subject covariance was estimated by an unstructured covariance matrix. Treatment groups were defined as randomised treatment.
|
||||||||||||
Comparison groups |
Brodalumab v Fumaric acid esters
|
||||||||||||
Number of subjects included in analysis |
81
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.028 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-1.72
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.24 | ||||||||||||
upper limit |
-0.19 |
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Adverse events information
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Timeframe for reporting adverse events |
Timeframe for AE
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Adverse event reporting additional description |
AE additional description
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20
|
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Reporting groups
|
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Reporting group title |
Fumaric Acid Ester
|
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Brodalumab 210 mg Q2W
|
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
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Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
12 Oct 2017 |
The reason for the amendment is to implement requirements from the health authorities in Germany. |
||
17 Aug 2018 |
The reason for Amendment 2 is to clarify that exclusion criteria related to the PROs eC-SSRS and PHQ-8 pertain to both the screening and the baseline visit. Also, the wording for the eC-SSRS criteria, and the described assessment hereof, has been updated to reflect the report from the eC-SSRS. The wording in version 3.0 of the protocol was based on the paper version of the C-SSRS. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |