Clinical Trial Results:
Incidence of squamous cell carcinoma and other skin neoplasia in subjects with actinic keratosis treated with ingenol disoxate gel 0.018% or 0.037%, or vehicle.
A phase 3 trial to compare the incidence of SCC and other skin neoplasia on skin areas treated with ingenol disoxate gel or vehicle gel for actinic keratosis on face and chest or scalp.
Summary
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EudraCT number |
2017-000228-85 |
Trial protocol |
GB DE ES IT |
Global end of trial date |
12 Mar 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Apr 2019
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First version publication date |
03 Apr 2019
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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 |
LP0084-1369
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03115476 | ||
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 Trial Disclosure, LEO Pharma A/S, +45 44945888, disclosure@leo-pharma.com
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Scientific contact |
Clinical Trial 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 |
27 Aug 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Mar 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Mar 2018
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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 incidence of squamous cell carcinoma after treatment with ingenol disoxate gel and vehicle gel
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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 the amendment from Somerset West, South Africa, October 1996. All subjects received written and verbal information concerning the clinical trial. Subjects were asked to consent that their personal data were recorded, collected, processed and could be transferred to other countries in accordance with any national legislation regulating privacy and data protection.
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Background therapy |
none | ||
Evidence for comparator |
This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during the trial | ||
Actual start date of recruitment |
28 Apr 2017
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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 |
Spain: 23
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Country: Number of subjects enrolled |
United Kingdom: 37
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Country: Number of subjects enrolled |
France: 12
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Country: Number of subjects enrolled |
Germany: 61
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Country: Number of subjects enrolled |
United States: 272
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Country: Number of subjects enrolled |
Canada: 158
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Worldwide total number of subjects |
563
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EEA total number of subjects |
133
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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) |
155
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From 65 to 84 years |
391
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85 years and over |
17
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Recruitment
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Recruitment details |
Eligibility criteria: The subject has been treated in one of the trials LP0084-1193, -1194, -1195, or -1196 (main trials) and has been evaluated at Visit 11 of that trial. The following countries participated: Canada, Germany, Spain, France, UK, and US | ||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
In the main trials 1234 subjects were randomised and applied study drug. Less than half of the subjects continued into this trial: 82 from LP0084 -1193, 186 from trial -1194, 163 from -1195, and 132 from -1196. 3 subjects discontinued the trial due to death unrelated to trial treatment. The trial was terminated by sponsor decision. | ||||||||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
From V2 (Day1) in main trial
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Assessor | ||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ingenol disoxate gel 0.018% | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects who had been treated with ingenol disoxate gel 0.018% on face or chest in the main trial | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Ingenol disoxate gel 0.018%
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Gel
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Routes of administration |
Topical use
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Dosage and administration details |
This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during this trial
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Arm title
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Ingenol disoxate gel 0.037% | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects who had been treated with ingenol disoxate 0.037% on the scalp in the main trial | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Ingenol disoxate gel 0.037%
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Gel
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Routes of administration |
Topical use
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Dosage and administration details |
This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during this trial
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Arm title
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Vehicle gel | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
vehicle gel (to ingenol disoxate gel) that contained no active ingredients | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Vehicle gel
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Gel
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Routes of administration |
Topical use
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Dosage and administration details |
This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during this trial
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Period 2
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Period 2 title |
LP0084-1369 trial period
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Is this the baseline period? |
Yes [1] | ||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ingenol disoxate gel 0.018% | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Ingenol disoxate gel 0.018%
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Gel
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Routes of administration |
Topical use
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Dosage and administration details |
This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during the trial
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Arm title
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Ingenol disoxate gel 0.037% | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Ingenol disoxate gel 0.037%
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Gel
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Routes of administration |
Topical use
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Dosage and administration details |
This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during the trial
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Arm title
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Vehicle gel | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Vehicle gel
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Gel
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Routes of administration |
Topical use
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Dosage and administration details |
This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during the trial
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Notes [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: The full analysis set comprise 1234 randomised subjects from the 4 main trials (LP0084-1193, -1194, -1195, or - 1196) who applied investigational medicinal product (This is period 1). Of these subjects, 563 subjects continued into trial LP0084-1369. This would be period 2 i.e the LP0084-1369 trial period which is the baseline period for the present trial |
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Notes [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: The full analysis set comprise 1234 randomised subjects from the 4 main trials (LP0084-1193, -1194, -1195, or - 1196) who applied investigational medicinal product. Of these subjects, 563 subjects continued into trial LP0084-1369 |
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Baseline characteristics reporting groups
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Reporting group title |
LP0084-1369 trial period
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Trial period
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Subject analysis set type |
Safety analysis | |||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The trial period is from the first visit in trial LP0084-1369 until the end of the trial.
1234 subjects where randomised and applied investigational medicinal product in the 4 main trials and were included in the full analysis set. All subjects in the full analysis set were included in the safety analysis set.
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End points reporting groups
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Reporting group title |
Ingenol disoxate gel 0.018%
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Reporting group description |
Subjects who had been treated with ingenol disoxate gel 0.018% on face or chest in the main trial | ||
Reporting group title |
Ingenol disoxate gel 0.037%
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Reporting group description |
Subjects who had been treated with ingenol disoxate 0.037% on the scalp in the main trial | ||
Reporting group title |
Vehicle gel
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Reporting group description |
vehicle gel (to ingenol disoxate gel) that contained no active ingredients | ||
Reporting group title |
Ingenol disoxate gel 0.018%
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Reporting group description |
- | ||
Reporting group title |
Ingenol disoxate gel 0.037%
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Reporting group description |
- | ||
Reporting group title |
Vehicle gel
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Reporting group description |
- | ||
Subject analysis set title |
Trial period
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The trial period is from the first visit in trial LP0084-1369 until the end of the trial.
1234 subjects where randomised and applied investigational medicinal product in the 4 main trials and were included in the full analysis set. All subjects in the full analysis set were included in the safety analysis set.
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End point title |
Time to first squamous cell carcinoma (SCC) in the treatment area | ||||||||||||||||
End point description |
Time to first squamous cell carcinoma (SCC) in the treatment area. Relative difference between groups (ingenol disoxate vs vehicle) expressed as hazard ratio.
The indicated measured values are the observed incidence rates of the SCC in the treatment area which form the basis of the statistical analysis of the time to event analysis
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End point type |
Primary
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End point timeframe |
From Visit 2 to first SCC in the treatment area, up to 24 months
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Notes [1] - actual number of subjects analysed is 407: subjects in the period from Visit 2 in the main trial [2] - actual number of subjects analysed is 418: subjects in the period from Visit 2 in the main trial [3] - actual number of subjects analysed is 409: subjects in the period from Visit 2 in the main trial |
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Statistical analysis title |
likelihood ratio test | ||||||||||||||||
Statistical analysis description |
Relative difference between groups (ingenol disoxate vs vehicle) expressed as hazard ratio
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Comparison groups |
Ingenol disoxate gel 0.018% v Ingenol disoxate gel 0.037% v Vehicle gel
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Number of subjects included in analysis |
563
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.43 [4] | ||||||||||||||||
Method |
likelyhood ratio test | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
1.43
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.61 | ||||||||||||||||
upper limit |
3.9 | ||||||||||||||||
Notes [4] - ingenol disoxate vs vehicle |
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End point title |
Time to first SCC or other skin neoplasia in the treatment area | ||||||||||||||||
End point description |
To compare the incidence of SCC or other skin neoplasia after treatment with ingenol disoxate gel and vehicle gel.
The indicated measured values are the observed incidence rates of the SCC in the treatment area which form the basis of the statistical analysis of the time to event analysis
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End point type |
Secondary
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End point timeframe |
From Visit 2 to first SCC or other skin neoplasia in the treatment area, up to 24 months
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Notes [5] - actual number of subjects analysed is 407: subjects in the period from Visit 2 in the main trial [6] - actual number of subjects analysed is 418: subjects in the period from Visit 2 in the main trial [7] - actual number of subjects analysed is 409: subjects in the period from Visit 2 in the main trial |
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Statistical analysis title |
likelihood ratio test | ||||||||||||||||
Statistical analysis description |
relative difference between treatment groups (ingenol disoxate gel vs vehicle) expressed as hazard ratio, full analysis set
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Comparison groups |
Ingenol disoxate gel 0.037% v Ingenol disoxate gel 0.018% v Vehicle gel
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Number of subjects included in analysis |
534
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.01 [8] | ||||||||||||||||
Method |
likelyhood ratio test | ||||||||||||||||
Parameter type |
Hazard ratio | ||||||||||||||||
Point estimate |
1.99
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
1.17 | ||||||||||||||||
upper limit |
3.62 | ||||||||||||||||
Notes [8] - Ingenol disoxate vs vehicle |
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Adverse events information
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Timeframe for reporting adverse events |
The trial period: from first visit in this trial until the end of the trial
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Adverse event reporting additional description |
Safety information is based on actual treatment' i.e. the treatment that was administered to the patient. This differed from 'planned treatment' (wich was used for the Participant Flow). Only events in the treatment area were collected (SAEs outside treatment area only collected if deemed related by the investigator to the study drug)
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Ingenol disoxate gel 0.018%
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Reporting group description |
Subjects who had been treated with ingenol disoxate gel 0.018% on face or chest in the main trial | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Ingenol disoxate gel 0.037%
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Reporting group description |
Subjects who had been treated with ingenol disoxate 0.037% on the scalp in the main trial | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Vehicle gel
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Reporting group description |
vehicle gel to ingenol disoxate gel | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 Jul 2017 |
The reason for the amendment is to change the definition of the full analysis set to include all randomised subjects from the main trials |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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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 |