Clinical Trial Results:
A randomized, double-blind, intra-individual, multi-center Phase III study to evaluate the safety and efficacy of BF 200 ALA (Ameluz®) versus placebo in the treatment of mild to severe actinic keratosis on extremities, trunk/ neck with photodynamic therapy (PDT) when using the BF-RhodoLED® lamp
Summary
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EudraCT number |
2017-000486-72 |
Trial protocol |
DE |
Global end of trial date |
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Jul 2019
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First version publication date |
03 Jul 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 |
ALA-AK-CT010
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Biofrontera Bioscience GmbH
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Sponsor organisation address |
Hemmelrather Weg 201, Leverkusen, Germany, 51377
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Public contact |
Clinical Trial Management, Biofrontera Bioscience GmbH, +49 2148763210, clintrialCT010@biofrontera.com
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Scientific contact |
Clinical Trial Management, Biofrontera Bioscience GmbH, +49 2148763210, clintrialCT010@biofrontera.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 |
Interim
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Date of interim/final analysis |
09 Jan 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
09 Jan 2019
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Global end of trial reached? |
No
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General information about the trial
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Main objective of the trial |
Primary objective: To compare the efficacy of BF-200 ALA (also referred to as Ameluz®) with placebo for treatment of mild to severe actinic keratosis (AK) located on extremities and trunk/neck with PDT when using the BF RhodoLED® lamp.
Secondary objective: To evaluate the safety and secondary efficacy parameters related to BF 200 ALA for treatment of AK on extremities and trunk/neck with PDT when using the BF-RhodoLED® lamp.
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Protection of trial subjects |
Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 Sep 2017
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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 |
9 Months | ||
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: 56
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Worldwide total number of subjects |
56
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EEA total number of subjects |
56
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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) |
10
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From 65 to 84 years |
45
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85 years and over |
1
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Recruitment
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Recruitment details |
Trial was conducted in Germany with a total of 6 sites that recruited subjects. Recruitment of subjects started on 18 September 2017. | |||||||||||||||
Pre-assignment
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Screening details |
Subjects were screened at Visit 1 for eligibility which was approx. 2 weeks prior to assignment to treatment (PDT-1). Of the 56 subjects screened in the study, 50 subjects were randomized, and 48 subjects completed the study regularly. | |||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
56 | |||||||||||||||
Number of subjects completed |
50 | |||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Adverse event, non-fatal prior to treatment: 1 | |||||||||||||||
Reason: Number of subjects |
Consent withdrawn by subject prior to treatment: 1 | |||||||||||||||
Reason: Number of subjects |
Screening failure: 4 | |||||||||||||||
Period 1
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Period 1 title |
Clinical observation 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 |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||||||||
Blinding implementation details |
Although verum and placebo are indistinguishable by appearance, the intensity of adverse events (AEs) is likely to differ. To guarantee the blind status of the investigator assessing the efficacy of the treatment in this intra-individual study, PDT and all safety assessments were to be performed by a second investigator. Patients were to be instructed to report AEs during the illumination(s) and the coming days only to the second investigator.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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BF-200 ALA (Verum) | |||||||||||||||
Arm description |
A nanoemulsion containing 7.8% 5-aminolevulinic acid (5-ALA) | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
BF-200 ALA
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Investigational medicinal product code |
BF-200 ALA
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Other name |
Ameluz®
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Pharmaceutical forms |
Gel
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Routes of administration |
Topical use
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Dosage and administration details |
• BF-200 ALA gel (2g) was administered (about 1 mm thickness) according to randomization schedule, covering lesions and surroundings
• Treatment field on one side did not have to be continuous, but had to cover a total area of approx. 20 cm² and had to be within the 6x16 cm² illumination field to allow illumination in a single step
• Treatment field on each patient’s side could be located on all parts of extremities or trunk/neck, but treatment fields on both sides had to be located in comparable locations (treatment subareas)
• Treatment subareas included back of the hands, lower arms, upper arms, lower legs, upper legs, décolleté, neck or other comparable parts of the trunk
• Application near genitalia was to be avoided
• IMP dried for approx. 10 min
• Lesions were occluded with a light-tight dressing
• Subjects had to stay in a well-tempered environment during 3h incubation
• Dressing was removed; remnant gel wiped off
• Illumination with BF-RhodoLED®(10 min; 37 J/cm²)
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Arm title
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Placebo | |||||||||||||||
Arm description |
A nanoemulsion formulation similar to BF-200 ALA but without the active ingredient ALA. | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
Vehicle
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Pharmaceutical forms |
Gel
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Routes of administration |
Topical use
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Dosage and administration details |
• Placebo gel (2g) was administered (about 1 mm thickness) according to randomization schedule, covering lesions and surroundings
• Treatment field on one side did not have to be continuous, but had to cover a total area of approx. 20 cm² and had to be within the 6x16 cm² illumination field to allow illumination in a single step
• Treatment field on each patient’s side could be located on all parts of extremities or trunk/neck, but treatment fields on both sides had to be located in comparable locations (treatment subareas)
• Treatment subareas included back of the hands, lower arms, upper arms, lower legs, upper legs, décolleté, neck or other comparable parts of the trunk
• Application near genitalia was to be avoided
• IMP dried for approx. 10 min
• Lesions were occluded with a light-tight dressing
• Subjects had to stay in a well-tempered environment during 3h incubation
• Dressing was removed; remnant gel wiped off
• Illumination with BF-RhodoLED®(10 min; 37 J/cm²)
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Baseline characteristics reporting groups [1]
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Reporting group title |
Clinical observation period
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same. Justification: 56 patients were screened, but only 50 patients were randomized. Due to non-randomized subjects, the number of enrolled subjects is not equal to the number of subjects in the clinical observation period (subjects reported in baseline period). |
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End points reporting groups
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Reporting group title |
BF-200 ALA (Verum)
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Reporting group description |
A nanoemulsion containing 7.8% 5-aminolevulinic acid (5-ALA) | ||
Reporting group title |
Placebo
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Reporting group description |
A nanoemulsion formulation similar to BF-200 ALA but without the active ingredient ALA. |
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End point title |
Total lesion clearance rate in percent per patient’s side 12 weeks after last PDT (FAS) | ||||||||||||
End point description |
Total lesion clearance rate in percent per patient’s side, defined as the percentage of individual lesions with complete remission on the respective side of the patient assessed 12 weeks after the last PDT.
The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups will be as randomized.
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End point type |
Primary
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End point timeframe |
12 weeks after last PDT
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Statistical analysis title |
One-sided Wilcoxon signed rank test (FAS) | ||||||||||||
Statistical analysis description |
The Wilcoxon signed rank test (one-sided, alpha=0.025) was applied (using the location parameter mu0 of 0%).
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
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Comparison groups |
BF-200 ALA (Verum) v Placebo
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Number of subjects included in analysis |
98
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
One-sided Wilcoxon signed rank test | ||||||||||||
Confidence interval |
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Statistical analysis title |
Non-parametric, one-sided 97.5% CI (FAS) | ||||||||||||
Statistical analysis description |
Additionally, a non-parametric, one-sided 97.5% confidence interval (CI) for the median difference in response rates rALA - rPla was calculated. If the lower bound of this CI is greater than 0, it indicates superiority of BF-200 ALA PDT to placebo PDT. The application of the non-parametric CI was subordinate.
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
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Comparison groups |
BF-200 ALA (Verum) v Placebo
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Number of subjects included in analysis |
98
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Median difference (final values) | ||||||||||||
Point estimate |
60
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Confidence interval |
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level |
97.5% | ||||||||||||
sides |
1-sided
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lower limit |
33.3 | ||||||||||||
upper limit |
- |
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End point title |
Patient complete clearance per patient’s side 12 weeks after the last PDT (FAS) | ||||||||||||
End point description |
Confirmatory hypothesis testing of secondary variables measured during the clinical study period was to be done only after the test of the primary efficacy variable was passed (superiority of BF-200 ALA PDT over placebo PDT confirmed for FAS), and was to be done strictly in the given order to ensure the family wise error rate. Confirmatory hypothesis testing in the pre-defined order would have stopped once the first non-significant test result had been obtained.
The first secondary efficacy variable in the hierarchic test procedure was the patient complete clearance per patient’s side, defined as the percentage of patients with all lesions cleared at the respective patient’s side.
The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
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End point type |
Secondary
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End point timeframe |
12 weeks after the last PDT
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Statistical analysis title |
McNemar’s test (FAS) | ||||||||||||
Statistical analysis description |
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
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Comparison groups |
BF-200 ALA (Verum) v Placebo
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Number of subjects included in analysis |
98
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mcnemar | ||||||||||||
Confidence interval |
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End point title |
Total lesion clearance rate of moderate (according to Olsen) lesions in percent per patient’s side 12 weeks after the last PDT (FAS) | ||||||||||||
End point description |
The second secondary efficacy variable in the hierarchic test procedure was the total lesion clearance rate of moderate lesions in percent per patient’s side, defined as the percentage of moderate lesions at baseline with complete remission on the respective side of the patient 12 weeks after the last PDT.
The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
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End point type |
Secondary
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End point timeframe |
12 weeks after the last PDT
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Statistical analysis title |
One-sided Wilcoxon signed rank test (FAS) | ||||||||||||
Statistical analysis description |
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
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Comparison groups |
BF-200 ALA (Verum) v Placebo
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Number of subjects included in analysis |
87
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
One-sided Wilcoxon signed rank test | ||||||||||||
Confidence interval |
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Statistical analysis title |
Non-parametric, one-sided 97.5% CI (FAS) | ||||||||||||
Statistical analysis description |
The application of the non-parametric CI was subordinate.
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
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Comparison groups |
BF-200 ALA (Verum) v Placebo
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Number of subjects included in analysis |
87
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Median difference (final values) | ||||||||||||
Point estimate |
75
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Confidence interval |
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level |
97.5% | ||||||||||||
sides |
1-sided
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lower limit |
33.3 | ||||||||||||
upper limit |
- |
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End point title |
Total lesion clearance rate in percent per patient’s side in the treatment area extremities 12 weeks after the last PDT (FAS) | ||||||||||||
End point description |
The third secondary efficacy variable in the hierarchic test procedure was the total lesion clearance rate in percent per patient’s side in the treatment area extremities, defined as the percentage of individual lesions in the treatment area extremities with complete remission on the respective side of the patient.
The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
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End point type |
Secondary
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End point timeframe |
12 weeks after the last PDT
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Statistical analysis title |
One-sided Wilcoxon signed rank test (FAS) | ||||||||||||
Statistical analysis description |
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
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Comparison groups |
BF-200 ALA (Verum) v Placebo
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
One-sided Wilcoxon signed rank test | ||||||||||||
Confidence interval |
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Statistical analysis title |
Non-parametric, one-sided 97.5% CI (FAS) | ||||||||||||
Statistical analysis description |
The application of the non-parametric CI was subordinate.
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
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Comparison groups |
Placebo v BF-200 ALA (Verum)
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Median difference (final values) | ||||||||||||
Point estimate |
66.7
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Confidence interval |
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level |
97.5% | ||||||||||||
sides |
1-sided
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lower limit |
35 | ||||||||||||
upper limit |
- |
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End point title |
Total lesion clearance rate in percent per patient’s side in the treatment area trunk/neck 12 weeks after the last PDT (FAS) | ||||||||||||
End point description |
The fourth secondary efficacy variable in the hierarchic test procedure was the total lesion clearance rate in percent per patient’s side in the treatment area trunk/neck, defined as the percentage of individual lesions in the treatment area trunk/neck with complete remission on the respective side of the patient.
The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
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End point type |
Secondary
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End point timeframe |
12 weeks after the last PDT
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Statistical analysis title |
One-sided Wilcoxon signed rank test (FAS) | ||||||||||||
Statistical analysis description |
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
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Comparison groups |
Placebo v BF-200 ALA (Verum)
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Number of subjects included in analysis |
20
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0156 | ||||||||||||
Method |
One-sided Wilcoxon signed rank test | ||||||||||||
Confidence interval |
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Statistical analysis title |
Non-parametric, one-sided 97.5% CI (FAS) | ||||||||||||
Statistical analysis description |
The application of the non-parametric CI was subordinate.
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
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Comparison groups |
BF-200 ALA (Verum) v Placebo
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Number of subjects included in analysis |
20
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Median difference (final values) | ||||||||||||
Point estimate |
18.3
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Confidence interval |
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level |
97.5% | ||||||||||||
sides |
1-sided
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lower limit |
0 | ||||||||||||
upper limit |
- |
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End point title |
Histopathologically confirmed lesion response (HCR) rate 12 weeks after the last PDT per patient’s side (FAS) | ||||||||||||
End point description |
The fifth secondary efficacy variable in the hierarchic test procedure was the histopathologically confirmed lesion response (HCR) rate per patient’s side 12 weeks after the last PDT.
The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
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End point type |
Secondary
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End point timeframe |
12 weeks after the last PDT
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Statistical analysis title |
McNemar’s test (FAS) | ||||||||||||
Statistical analysis description |
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
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Comparison groups |
BF-200 ALA (Verum) v Placebo
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Number of subjects included in analysis |
94
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0032 | ||||||||||||
Method |
Mcnemar | ||||||||||||
Confidence interval |
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End point title |
Total lesion clearance rate in percent per patient’s side 12 weeks after PDT-1 (FAS) | ||||||||||||
End point description |
The sixth secondary efficacy variable in the hierarchic test procedure was the total lesion clearance rate in percent per patient’s side, defined as the percentage of individual lesions with complete remission on the respective side of the patient at Visit 4 (12 weeks after PDT-1), irrespective if patient received re-treatment or not.
The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
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End point type |
Secondary
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End point timeframe |
12 weeks after PDT-1
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Statistical analysis title |
One-sided Wilcoxon signed rank test (FAS) | ||||||||||||
Statistical analysis description |
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
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Comparison groups |
Placebo v BF-200 ALA (Verum)
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Number of subjects included in analysis |
98
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
One-sided Wilcoxon signed rank test | ||||||||||||
Confidence interval |
|||||||||||||
Statistical analysis title |
Non-parametric, one-sided 97.5% CI (FAS) | ||||||||||||
Statistical analysis description |
The application of the non-parametric CI was subordinate.
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
|
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Comparison groups |
BF-200 ALA (Verum) v Placebo
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||||||||||||
Number of subjects included in analysis |
98
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||
Point estimate |
50
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Confidence interval |
|||||||||||||
level |
97.5% | ||||||||||||
sides |
1-sided
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lower limit |
25 | ||||||||||||
upper limit |
- |
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End point title |
Patient complete clearance per patient’s side, 12 weeks after PDT-1 (FAS) | ||||||||||||
End point description |
The seventh secondary efficacy variable in the hierarchic test procedure was the patient complete clearance per patient’s side, defined as the percentage of patients with all lesions cleared at the respective patient’s side at Visit 4 (12 weeks after PDT-1), irrespective if patient received re-treatment or not.
The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
12 weeks after PDT-1
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
McNemar’s test (FAS) | ||||||||||||
Statistical analysis description |
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
|
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Comparison groups |
BF-200 ALA (Verum) v Placebo
|
||||||||||||
Number of subjects included in analysis |
98
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0003 | ||||||||||||
Method |
Mcnemar | ||||||||||||
Confidence interval |
|
||||||||||||||||||||||||||||
End point title |
The overall cosmetic outcome per patient’s side 12 weeks after the last PDT (FAS) | |||||||||||||||||||||||||||
End point description |
The eighth secondary efficacy variable in the hierarchic test procedure was the overall cosmetic outcome per patient's side 12 weeks after the last PDT as assessed by the investigator.
The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
|
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End point type |
Secondary
|
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End point timeframe |
12 weeks after the last PDT
|
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|
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Statistical analysis title |
One-sided Wilcoxon signed rank test (FAS) | |||||||||||||||||||||||||||
Statistical analysis description |
A Wilcoxon signed rank test was applied to compare patient’s sides 12 weeks after the last PDT. Each 'very good' was counted as 0, each 'good' as 1, each 'satisfactory' as 2, each 'unsatisfactory' as 3, and each 'impaired' as 4.
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
|
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Comparison groups |
BF-200 ALA (Verum) v Placebo
|
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Number of subjects included in analysis |
98
|
|||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||||||||
P-value |
< 0.0001 | |||||||||||||||||||||||||||
Method |
One-sided Wilcoxon signed rank test | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
Statistical analysis title |
Non-parametric, one-sided 97.5% CI (FAS) | |||||||||||||||||||||||||||
Statistical analysis description |
The application of the non-parametric CI was subordinate.
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
|
|||||||||||||||||||||||||||
Comparison groups |
BF-200 ALA (Verum) v Placebo
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
98
|
|||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||
Parameter type |
Median difference (final values) | |||||||||||||||||||||||||||
Point estimate |
0
|
|||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
level |
97.5% | |||||||||||||||||||||||||||
sides |
1-sided
|
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lower limit |
0 | |||||||||||||||||||||||||||
upper limit |
- |
|
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End point title |
Lesion complete response per treatment arm (percentage of completely cleared individual lesions, in relation to number of lesions at baseline [Visit 2]) assessed 12 weeks after the last PDT (FAS) | ||||||||||||
End point description |
A tertiary efficacy variable was the lesion complete response per treatment arm (percentage of completely cleared individual lesions, in relation to number of lesions at baseline [Visit 2]) assessed 12 weeks after the last PDT.
The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
To realistically reflect the result, the number of subjects (shown below) was replaced by the number of lesions for this analysis.
|
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End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
12 weeks after the last PDT
|
||||||||||||
|
|||||||||||||
Notes [1] - This is the number of patients that received BF-200 ALA. They had 258 lesions in total. [2] - This is the number of patients that received placebo. They had 268 lesions in total. |
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Patient’s satisfaction with treatment applied to his/her respective side (FAS) | |||||||||||||||
End point description |
A tertiary efficacy variable was the patient’s satisfaction with treatment applied to his/her respective side.
The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
|
|||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||
End point timeframe |
12 weeks after last PDT
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Application site pain during PDT-1 reported by the patients per patient’s side (SAF) | ||||||||||||
End point description |
Safety endpoint:
Patient's pain intensity during PDT is assessed at the end of each illumination period using a numeric rating pain scale ranging from no pain at all (0) to worst possible pain (10).
If the patient could not indicate the specific side of pain sensation, the worst pain experienced for patient’s both (left and right) side (and treatment areas) was documented equally.
One patient was treated incorrectly at PDT-2, but with the correct treatment at PDT-1. Within the Safety Analysis Set (SAF), this patient is allocated to BF-200 ALA for both sides.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
During PDT-1
|
||||||||||||
|
|||||||||||||
Notes [3] - Subj. analysed: 51 (in SAF 1 pat. was allocated to verum for both sides -> incorrect IMP administr.) |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Application site pain during PDT-2 reported by the patients per patient’s side (SAF) | ||||||||||||
End point description |
Safety endpoint:
Patient's pain intensity during PDT is assessed at the end of each illumination period using a numeric rating pain scale ranging from no pain at all (0) to worst possible pain (10).
If the patient could not indicate the specific side of pain sensation, the worst pain experienced for patient’s both (left and right) side (and treatment areas) was documented equally.
One patient was treated incorrectly at PDT-2, but with the correct treatment at PDT-1. Within the Safety Analysis Set (SAF), this patient is allocated to BF-200 ALA for both sides.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
During PDT-2
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Total lesion clearance rate in percent per patient’s side 12 weeks after last PDT (PPS) | ||||||||||||
End point description |
Sensitivity analysis of primary endpoint.
Total lesion clearance rate in percent per patient’s side, defined as the percentage of individual lesions with complete remission on the respective side of the patient assessed 12 weeks after the last PDT.
The per protocol set (PPS) consists of all patients of the FAS without any major protocol deviations.
Patients will be included in the PPS if they fulfill all of the following criteria:
• Treated with investigational products and PDT mode according to the randomization plan.
• The 2 patient sides (R & L) are comparable and the number of AK lesions varies not more than 50%.
• At least one AK lesion assessment after the first, and if retreated after the second PDT, is available.
• No forbidden concomitant medications or therapies.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
12 weeks after last PDT
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
One-sided Wilcoxon signed rank test (PPS) | ||||||||||||
Statistical analysis description |
The Wilcoxon signed rank test (one-sided, alpha=0.025) was applied (using the location parameter mu0 of 0%).
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
|
||||||||||||
Comparison groups |
BF-200 ALA (Verum) v Placebo
|
||||||||||||
Number of subjects included in analysis |
86
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
One-sided Wilcoxon signed rank test | ||||||||||||
Confidence interval |
|||||||||||||
Statistical analysis title |
Non-parametric, one-sided 97.5% CI (PPS) | ||||||||||||
Statistical analysis description |
Additionally, a non-parametric, one-sided 97.5% confidence interval (CI) for the median difference in response rates rALA - rPla was calculated. If the lower bound of this CI is greater than 0, it indicates superiority of BF-200 ALA PDT to placebo PDT. The application of the non-parametric CI was subordinate.
Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
|
||||||||||||
Comparison groups |
Placebo v BF-200 ALA (Verum)
|
||||||||||||
Number of subjects included in analysis |
86
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||
Point estimate |
66.7
|
||||||||||||
Confidence interval |
|||||||||||||
level |
97.5% | ||||||||||||
sides |
1-sided
|
||||||||||||
lower limit |
50 | ||||||||||||
upper limit |
- |
|
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Adverse events information
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Timeframe for reporting adverse events |
18 September 2017 (study initiation date/first patient signed informed consent) until 09 January 2019 (study completion date for observer blind part).
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Adverse event reporting additional description |
TEAEs (treatment emergent adverse events) are defined as all AEs or SAEs with time of onset or worsening on or after the time of first IMP application. All safety analyses are based on the safety analysis set, which consists of all subjects treated at least with one IMP application. The assignment of subjects' sides was as actually treated.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.0
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Reporting groups
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Reporting group title |
TEAEs related to side treated with BF-200 ALA
|
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TEAEs related to side treated with Placebo
|
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TEAEs with relation to side not applicable
|
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TEAEs with relation to side unknown
|
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 4% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
28 Jul 2017 |
Substantial Protocol Amendment resulting in Clinical Study Protocol (CSP) 2.0 dated 20-Jul-2017 to further define the extent of adverse events that had to be documented during the follow-up period. Approved by German Competent Authority (CA) on 28-Jul-2017. Recruitment of patients started after the approval of CSP V2.0 by CA and Ethics Committee.
|
||
06 Aug 2018 |
Substantial Protocol Amendment resulting in CSP 3.0 dated 23-Jul-2018 to change the order of two secondary endpoints. Approved by German Competent Authority on 06-Aug-2018.
|
||
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 |