Clinical Trial Results:
A randomized, placebo-controlled, double-blind study to evaluate safety and dose dependent clinical efficacy of APO-2 at three different doses in patients with diabetic foot ulcer (MARSYAS II)
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Summary
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EudraCT number |
2018-001653-27 |
Trial protocol |
AT CZ DE |
Global end of trial date |
06 Dec 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Feb 2025
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First version publication date |
28 Feb 2025
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
Marsyas II
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04277598 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Aposcience AG
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Sponsor organisation address |
Dresdner Strasse 87/A 21, Wien, Austria, 1200
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Public contact |
Aposcience AG, Aposcience AG, +43 (0)664 212 05 57, info@aposcience.com
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Scientific contact |
Aposcience AG, Aposcience AG, +43 (0)664 212 05 57, info@aposcience.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 |
06 Dec 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
06 Dec 2023
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Dec 2023
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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 determine the dose-response for clinical efficacy of APO-2 multiple dose administration in patients with diabetic foot ulcer at three different dose levels compared to placebo.
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Protection of trial subjects |
The study was conducted in full conformance with the principles of the Declaration of Helsinki (as amended at the 64th World Medical Association General Assembly, Fortaleza, Brazil, October 2013) and with the laws and regulations of the country in which the clinical research was conducted. Only appropriately trained personnel were involved in the study. The study followed the International Council for Harmonisation Good Clinical Practice Guideline and the European Directive embedded in the Austrian, German, Czech and Polish drug act. Before any clinical study-related activities were performed, the investigator reviewed the informed consent form and explained the study to the patient. The investigator ensured that the patient was fully informed about the nature, significance, impact, and risks of the study.
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Background therapy |
Standard of care | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
11 Nov 2020
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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 |
Poland: 53
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Country: Number of subjects enrolled |
Austria: 22
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Country: Number of subjects enrolled |
Czechia: 46
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Country: Number of subjects enrolled |
Germany: 1
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Worldwide total number of subjects |
122
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EEA total number of subjects |
122
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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) |
67
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From 65 to 84 years |
55
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were recruited between 11-Nov-2020 and 4-Sep-2023. | |||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
The study started with a safety lead-in phase during which 15 patients were screened. In the subsequent main phase, 144 patients were screened. Of the 159 screened patients, 122 patients were treated with APO-2 or placebo. | |||||||||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (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, Assessor | |||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Site personnel, including the investigator and site personnel administering the investigational medicinal product (IMP), central assessors of wound area, and the patients were blinded to the treatment allocation. Unblinded site personnel (pharmacists) prepared the IMP for administration.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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APO-2 12.5 U/mL (FAS) | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients in the full analysis set (FAS) who were administered APO-2 12.5 U/mL hydrogel formulation. The FAS included all randomized patients who received at least 1 dose of the IMP and had a measured wound area at Baseline and at Visit 6 or later. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
APO-2
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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
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Dosage and administration details |
APO-2 was supplied as a frozen concentrate for cutaneous solution containing 100 U APOSEC(TM) dissolved in 0.5 mL of 0.9% saline solution. APOSEC(TM) is the secretome of stressed peripheral blood mononuclear cells in CellGenix Good Manufacturing Practice Dendritic Cell medium (matrix). APO-2 was diluted with 0.9% saline solution and mixed with NU-GEL up to a final volume of 4 mL at a dose of 12.5 U/mL. The reconstituted IMP was applied 3 times per week (within 7 days, at least 1 day apart) for 4 weeks topically on the wound surface area using a syringe and a spatula as an applicator. The amount of IMP applied depended on the wound area and ranged from 0.2 to 4.0 mL.
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Arm title
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APO-2 25.0 U/mL (FAS) | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients in the FAS who were administered APO-2 25.0 U/mL hydrogel formulation. The FAS included all randomized patients who received at least 1 dose of the IMP and had a measured wound area at Baseline and at Visit 6 or later. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
APO-2
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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
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Dosage and administration details |
APO-2 was supplied as a frozen concentrate for cutaneous solution containing 100 U APOSEC(TM) dissolved in 0.5 mL of 0.9% saline solution. APOSEC(TM) is the secretome of stressed peripheral blood mononuclear cells in CellGenix Good Manufacturing Practice Dendritic Cell medium (matrix). APO-2 was diluted with 0.9% saline solution and mixed with NU-GEL up to a final volume of 4 mL at a dose of 25.0 U/mL. The reconstituted IMP was applied 3 times per week (within 7 days, at least 1 day apart) for 4 weeks topically on the wound surface area using a syringe and a spatula as an applicator. The amount of IMP applied depended on the wound area and ranged from 0.2 to 4.0 mL.
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Arm title
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APO-2 50.0 U/mL (FAS) | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients in the FAS who were administered APO-2 50.0 U/mL hydrogel formulation. The FAS included all randomized patients who received at least 1 dose of the IMP and had a measured wound area at Baseline and at Visit 6 or later. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
APO-2
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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
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Dosage and administration details |
APO-2 was supplied as a frozen concentrate for cutaneous solution containing 100 U APOSEC(TM) dissolved in 0.5 mL of 0.9% saline solution. APOSEC(TM) is the secretome of stressed peripheral blood mononuclear cells in CellGenix Good Manufacturing Practice Dendritic Cell medium (matrix). APO-2 was diluted with 0.9% saline solution and mixed with NU-GEL up to a final volume of 4 mL at a dose of 50.0 U/mL. The reconstituted IMP was applied 3 times per week (within 7 days, at least 1 day apart) for 4 weeks topically on the wound surface area using a syringe and a spatula as an applicator. The amount of IMP applied depended on the wound area and ranged from 0.2 to 4.0 mL.
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Arm title
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Placebo (FAS) | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients in the FAS who were administered the placebo hydrogel formulation. The FAS included all randomized patients who received at least 1 dose of the IMP and had a measured wound area at Baseline and at Visit 6 or later. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Gel
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Routes of administration |
Topical
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Dosage and administration details |
The placebo was the processed CellGenix Good Manufacturing Practice Dendritic Cell medium (APOSEC[TM] matrix) diluted with 0.9% saline solution and mixed with NU-GEL up to a final volume of 4 mL. The reconstituted IMP was applied 3 times per week (within 7 days, at least 1 day apart) for 4 weeks topically on the wound surface area using a syringe and a spatula as an applicator. The amount of IMP applied depended on the wound area and ranged from 0.2 to 4.0 mL.
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Arm title
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APO-2 12.5 U/mL (FAS posthoc subgroup) | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients in the FAS posthoc subgroup who were administered APO-2 12.5 U/mL hydrogel formulation. The FAS subgroup included all patients in the FAS with adjudicated wound areas ≥0.8 cm2 at Visit 2. Patients were randomized based on the investigator’s assessment of wound area, which was required to be between 1 cm2 (since protocol Version 4.0: 0.8 cm2) and 8 cm2 in size. After unblinding and final data analysis, 28 patients were found to have wounds smaller than 0.8 cm2 at Randomization according to the adjudicated, centrally assessed measurements, which were used for the primary endpoint analysis. A contributing factor for this discrepancy may have been that the protocol was not clear on how to account for keratotic tissue in the measurements. For this reason, a posthoc analysis was performed, in which the 28 patients were excluded from the analysis. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
APO-2
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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
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Dosage and administration details |
APO-2 was supplied as a frozen concentrate for cutaneous solution containing 100 U APOSEC(TM) dissolved in 0.5 mL of 0.9% saline solution. APOSEC(TM) is the secretome of stressed peripheral blood mononuclear cells in CellGenix Good Manufacturing Practice Dendritic Cell medium (matrix). APO-2 was diluted with 0.9% saline solution and mixed with NU-GEL up to a final volume of 4 mL at a dose of 12.5 U/mL. The reconstituted IMP was applied 3 times per week (within 7 days, at least 1 day apart) for 4 weeks topically on the wound surface area using a syringe and a spatula as an applicator. The amount of IMP applied depended on the wound area and ranged from 0.2 to 4.0 mL.
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Arm title
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APO-2 25.0 U/mL (FAS posthoc subgroup) | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients in the FAS posthoc subgroup who were administered APO-2 25.0 U/mL hydrogel formulation. The FAS subgroup included all patients in the FAS with adjudicated wound areas ≥0.8 cm2 at Visit 2. Patients were randomized based on the investigator’s assessment of wound area, which was required to be between 1 cm2 (since protocol Version 4.0: 0.8 cm2) and 8 cm2 in size. After unblinding and final data analysis, 28 patients were found to have wounds smaller than 0.8 cm2 at Randomization according to the adjudicated, centrally assessed measurements, which were used for the primary endpoint analysis. A contributing factor for this discrepancy may have been that the protocol was not clear on how to account for keratotic tissue in the measurements. For this reason, a posthoc analysis was performed, in which the 28 patients were excluded from the analysis. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
APO-2
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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
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Dosage and administration details |
APO-2 was supplied as a frozen concentrate for cutaneous solution containing 100 U APOSEC(TM) dissolved in 0.5 mL of 0.9% saline solution. APOSEC(TM) is the secretome of stressed peripheral blood mononuclear cells in CellGenix Good Manufacturing Practice Dendritic Cell medium (matrix). APO-2 was diluted with 0.9% saline solution and mixed with NU-GEL up to a final volume of 4 mL at a dose of 25.0 U/mL. The reconstituted IMP was applied 3 times per week (within 7 days, at least 1 day apart) for 4 weeks topically on the wound surface area using a syringe and a spatula as an applicator. The amount of IMP applied depended on the wound area and ranged from 0.2 to 4.0 mL.
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Arm title
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APO-2 50.0 U/mL (FAS posthoc subgroup) | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients in the FAS posthoc subgroup who were administered APO-2 50.0 U/mL hydrogel formulation. The FAS subgroup included all patients in the FAS with adjudicated wound areas ≥0.8 cm2 at Visit 2. Patients were randomized based on the investigator’s assessment of wound area, which was required to be between 1 cm2 (since protocol Version 4.0: 0.8 cm2) and 8 cm2 in size. After unblinding and final data analysis, 28 patients were found to have wounds smaller than 0.8 cm2 at Randomization according to the adjudicated, centrally assessed measurements, which were used for the primary endpoint analysis. A contributing factor for this discrepancy may have been that the protocol was not clear on how to account for keratotic tissue in the measurements. For this reason, a posthoc analysis was performed, in which the 28 patients were excluded from the analysis. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
APO-2
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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
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Dosage and administration details |
APO-2 was supplied as a frozen concentrate for cutaneous solution containing 100 U APOSEC(TM) dissolved in 0.5 mL of 0.9% saline solution. APOSEC(TM) is the secretome of stressed peripheral blood mononuclear cells in CellGenix Good Manufacturing Practice Dendritic Cell medium (matrix). APO-2 was diluted with 0.9% saline solution and mixed with NU-GEL up to a final volume of 4 mL at a dose of 50.0 U/mL. The reconstituted IMP was applied 3 times per week (within 7 days, at least 1 day apart) for 4 weeks topically on the wound surface area using a syringe and a spatula as an applicator. The amount of IMP applied depended on the wound area and ranged from 0.2 to 4.0 mL.
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Arm title
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Placebo (FAS posthoc subgroup) | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients in the FAS posthoc subgroup who were administered the placebo hydrogel formulation. The FAS subgroup included all patients in the FAS with adjudicated wound areas ≥0.8 cm2 at Visit 2. Patients were randomized based on the investigator’s assessment of wound area, which was required to be between 1 cm2 (since protocol Version 4.0: 0.8 cm2) and 8 cm2 in size. After unblinding and final data analysis, 28 patients were found to have wounds smaller than 0.8 cm2 at Randomization according to the adjudicated, centrally assessed measurements, which were used for the primary endpoint analysis. A contributing factor for this discrepancy may have been that the protocol was not clear on how to account for keratotic tissue in the measurements. For this reason, a posthoc analysis was performed, in which the 28 patients were excluded from the analysis. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Gel
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Routes of administration |
Topical
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Dosage and administration details |
The placebo was the processed CellGenix Good Manufacturing Practice Dendritic Cell medium (APOSEC[TM] matrix) diluted with 0.9% saline solution and mixed with NU-GEL up to a final volume of 4 mL. The reconstituted IMP was applied 3 times per week (within 7 days, at least 1 day apart) for 4 weeks topically on the wound surface area using a syringe and a spatula as an applicator. The amount of IMP applied depended on the wound area and ranged from 0.2 to 4.0 mL.
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Baseline characteristics reporting groups
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Reporting group title |
APO-2 12.5 U/mL (FAS)
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Reporting group description |
Patients in the full analysis set (FAS) who were administered APO-2 12.5 U/mL hydrogel formulation. The FAS included all randomized patients who received at least 1 dose of the IMP and had a measured wound area at Baseline and at Visit 6 or later. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
APO-2 25.0 U/mL (FAS)
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Reporting group description |
Patients in the FAS who were administered APO-2 25.0 U/mL hydrogel formulation. The FAS included all randomized patients who received at least 1 dose of the IMP and had a measured wound area at Baseline and at Visit 6 or later. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
APO-2 50.0 U/mL (FAS)
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Reporting group description |
Patients in the FAS who were administered APO-2 50.0 U/mL hydrogel formulation. The FAS included all randomized patients who received at least 1 dose of the IMP and had a measured wound area at Baseline and at Visit 6 or later. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo (FAS)
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Reporting group description |
Patients in the FAS who were administered the placebo hydrogel formulation. The FAS included all randomized patients who received at least 1 dose of the IMP and had a measured wound area at Baseline and at Visit 6 or later. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
APO-2 12.5 U/mL (FAS posthoc subgroup)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients in the FAS posthoc subgroup who were administered APO-2 12.5 U/mL hydrogel formulation. The FAS subgroup included all patients in the FAS with adjudicated wound areas ≥0.8 cm2 at Visit 2. Patients were randomized based on the investigator’s assessment of wound area, which was required to be between 1 cm2 (since protocol Version 4.0: 0.8 cm2) and 8 cm2 in size. After unblinding and final data analysis, 28 patients were found to have wounds smaller than 0.8 cm2 at Randomization according to the adjudicated, centrally assessed measurements, which were used for the primary endpoint analysis. A contributing factor for this discrepancy may have been that the protocol was not clear on how to account for keratotic tissue in the measurements. For this reason, a posthoc analysis was performed, in which the 28 patients were excluded from the analysis. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
APO-2 25.0 U/mL (FAS posthoc subgroup)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients in the FAS posthoc subgroup who were administered APO-2 25.0 U/mL hydrogel formulation. The FAS subgroup included all patients in the FAS with adjudicated wound areas ≥0.8 cm2 at Visit 2. Patients were randomized based on the investigator’s assessment of wound area, which was required to be between 1 cm2 (since protocol Version 4.0: 0.8 cm2) and 8 cm2 in size. After unblinding and final data analysis, 28 patients were found to have wounds smaller than 0.8 cm2 at Randomization according to the adjudicated, centrally assessed measurements, which were used for the primary endpoint analysis. A contributing factor for this discrepancy may have been that the protocol was not clear on how to account for keratotic tissue in the measurements. For this reason, a posthoc analysis was performed, in which the 28 patients were excluded from the analysis. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
APO-2 50.0 U/mL (FAS posthoc subgroup)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients in the FAS posthoc subgroup who were administered APO-2 50.0 U/mL hydrogel formulation. The FAS subgroup included all patients in the FAS with adjudicated wound areas ≥0.8 cm2 at Visit 2. Patients were randomized based on the investigator’s assessment of wound area, which was required to be between 1 cm2 (since protocol Version 4.0: 0.8 cm2) and 8 cm2 in size. After unblinding and final data analysis, 28 patients were found to have wounds smaller than 0.8 cm2 at Randomization according to the adjudicated, centrally assessed measurements, which were used for the primary endpoint analysis. A contributing factor for this discrepancy may have been that the protocol was not clear on how to account for keratotic tissue in the measurements. For this reason, a posthoc analysis was performed, in which the 28 patients were excluded from the analysis. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo (FAS posthoc subgroup)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients in the FAS posthoc subgroup who were administered the placebo hydrogel formulation. The FAS subgroup included all patients in the FAS with adjudicated wound areas ≥0.8 cm2 at Visit 2. Patients were randomized based on the investigator’s assessment of wound area, which was required to be between 1 cm2 (since protocol Version 4.0: 0.8 cm2) and 8 cm2 in size. After unblinding and final data analysis, 28 patients were found to have wounds smaller than 0.8 cm2 at Randomization according to the adjudicated, centrally assessed measurements, which were used for the primary endpoint analysis. A contributing factor for this discrepancy may have been that the protocol was not clear on how to account for keratotic tissue in the measurements. For this reason, a posthoc analysis was performed, in which the 28 patients were excluded from the analysis. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
APO-2 12.5 U/mL (FAS)
|
||
Reporting group description |
Patients in the full analysis set (FAS) who were administered APO-2 12.5 U/mL hydrogel formulation. The FAS included all randomized patients who received at least 1 dose of the IMP and had a measured wound area at Baseline and at Visit 6 or later. | ||
Reporting group title |
APO-2 25.0 U/mL (FAS)
|
||
Reporting group description |
Patients in the FAS who were administered APO-2 25.0 U/mL hydrogel formulation. The FAS included all randomized patients who received at least 1 dose of the IMP and had a measured wound area at Baseline and at Visit 6 or later. | ||
Reporting group title |
APO-2 50.0 U/mL (FAS)
|
||
Reporting group description |
Patients in the FAS who were administered APO-2 50.0 U/mL hydrogel formulation. The FAS included all randomized patients who received at least 1 dose of the IMP and had a measured wound area at Baseline and at Visit 6 or later. | ||
Reporting group title |
Placebo (FAS)
|
||
Reporting group description |
Patients in the FAS who were administered the placebo hydrogel formulation. The FAS included all randomized patients who received at least 1 dose of the IMP and had a measured wound area at Baseline and at Visit 6 or later. | ||
Reporting group title |
APO-2 12.5 U/mL (FAS posthoc subgroup)
|
||
Reporting group description |
Patients in the FAS posthoc subgroup who were administered APO-2 12.5 U/mL hydrogel formulation. The FAS subgroup included all patients in the FAS with adjudicated wound areas ≥0.8 cm2 at Visit 2. Patients were randomized based on the investigator’s assessment of wound area, which was required to be between 1 cm2 (since protocol Version 4.0: 0.8 cm2) and 8 cm2 in size. After unblinding and final data analysis, 28 patients were found to have wounds smaller than 0.8 cm2 at Randomization according to the adjudicated, centrally assessed measurements, which were used for the primary endpoint analysis. A contributing factor for this discrepancy may have been that the protocol was not clear on how to account for keratotic tissue in the measurements. For this reason, a posthoc analysis was performed, in which the 28 patients were excluded from the analysis. | ||
Reporting group title |
APO-2 25.0 U/mL (FAS posthoc subgroup)
|
||
Reporting group description |
Patients in the FAS posthoc subgroup who were administered APO-2 25.0 U/mL hydrogel formulation. The FAS subgroup included all patients in the FAS with adjudicated wound areas ≥0.8 cm2 at Visit 2. Patients were randomized based on the investigator’s assessment of wound area, which was required to be between 1 cm2 (since protocol Version 4.0: 0.8 cm2) and 8 cm2 in size. After unblinding and final data analysis, 28 patients were found to have wounds smaller than 0.8 cm2 at Randomization according to the adjudicated, centrally assessed measurements, which were used for the primary endpoint analysis. A contributing factor for this discrepancy may have been that the protocol was not clear on how to account for keratotic tissue in the measurements. For this reason, a posthoc analysis was performed, in which the 28 patients were excluded from the analysis. | ||
Reporting group title |
APO-2 50.0 U/mL (FAS posthoc subgroup)
|
||
Reporting group description |
Patients in the FAS posthoc subgroup who were administered APO-2 50.0 U/mL hydrogel formulation. The FAS subgroup included all patients in the FAS with adjudicated wound areas ≥0.8 cm2 at Visit 2. Patients were randomized based on the investigator’s assessment of wound area, which was required to be between 1 cm2 (since protocol Version 4.0: 0.8 cm2) and 8 cm2 in size. After unblinding and final data analysis, 28 patients were found to have wounds smaller than 0.8 cm2 at Randomization according to the adjudicated, centrally assessed measurements, which were used for the primary endpoint analysis. A contributing factor for this discrepancy may have been that the protocol was not clear on how to account for keratotic tissue in the measurements. For this reason, a posthoc analysis was performed, in which the 28 patients were excluded from the analysis. | ||
Reporting group title |
Placebo (FAS posthoc subgroup)
|
||
Reporting group description |
Patients in the FAS posthoc subgroup who were administered the placebo hydrogel formulation. The FAS subgroup included all patients in the FAS with adjudicated wound areas ≥0.8 cm2 at Visit 2. Patients were randomized based on the investigator’s assessment of wound area, which was required to be between 1 cm2 (since protocol Version 4.0: 0.8 cm2) and 8 cm2 in size. After unblinding and final data analysis, 28 patients were found to have wounds smaller than 0.8 cm2 at Randomization according to the adjudicated, centrally assessed measurements, which were used for the primary endpoint analysis. A contributing factor for this discrepancy may have been that the protocol was not clear on how to account for keratotic tissue in the measurements. For this reason, a posthoc analysis was performed, in which the 28 patients were excluded from the analysis. | ||
|
|||||||||||||||||||||
End point title |
Percentage wound area reduction after 4 weeks treatment compared between groups (FAS) [1] | ||||||||||||||||||||
End point description |
Centrally adjudicated wound area measurements were used for the primary endpoint assessment. At completion of the study, photographic images of the patients' wounds, blinded to group assignment, were reviewed by 2 independent trained assessors, who acted as adjudicators in validating the wound area measurements.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Reduction from Baseline to Visit 14, ie, after 4 weeks of IMP treatment
|
||||||||||||||||||||
| Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint only reports statistics for the arms that include the patients in the FAS. Statistics for the arms that include the patients in the FAS posthoc subgroup are reported separately. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
APO-2 12.5 U/mL vs Placebo - FAS | ||||||||||||||||||||
Statistical analysis description |
Analysis of variance (ANOVA) including the stratification factors country and wound area
|
||||||||||||||||||||
Comparison groups |
APO-2 12.5 U/mL (FAS) v Placebo (FAS)
|
||||||||||||||||||||
Number of subjects included in analysis |
58
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.5938 [2] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Least squares mean difference | ||||||||||||||||||||
Point estimate |
28.57
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-36.09 | ||||||||||||||||||||
upper limit |
93.22 | ||||||||||||||||||||
| Notes [2] - 2-sided alpha = 0.05; Dunnett-adjusted |
|||||||||||||||||||||
Statistical analysis title |
APO-2 25.0 U/mL vs Placebo - FAS | ||||||||||||||||||||
Statistical analysis description |
ANOVA including the stratification factors country and wound area
|
||||||||||||||||||||
Comparison groups |
APO-2 25.0 U/mL (FAS) v Placebo (FAS)
|
||||||||||||||||||||
Number of subjects included in analysis |
69
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 1 [3] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Least squares mean difference | ||||||||||||||||||||
Point estimate |
0.85
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-58.46 | ||||||||||||||||||||
upper limit |
60.15 | ||||||||||||||||||||
| Notes [3] - 2-sided alpha = 0.05; Dunnett-adjusted |
|||||||||||||||||||||
Statistical analysis title |
APO-2 50.0 U/mL vs Placebo - FAS | ||||||||||||||||||||
Statistical analysis description |
ANOVA including the stratification factors country and wound area
|
||||||||||||||||||||
Comparison groups |
APO-2 50.0 U/mL (FAS) v Placebo (FAS)
|
||||||||||||||||||||
Number of subjects included in analysis |
57
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.8573 [4] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Least squares mean difference | ||||||||||||||||||||
Point estimate |
17.6
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-47.06 | ||||||||||||||||||||
upper limit |
82.25 | ||||||||||||||||||||
| Notes [4] - 2-sided alpha = 0.05; Dunnett-adjusted |
|||||||||||||||||||||
|
||||||||||||||||
End point title |
Proportion of patients with complete wound closure until Visit 17 (FAS) [5] | |||||||||||||||
End point description |
Complete wound closure was defined as 100% re-epithelialization of the wound surface with the absence of drainage.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Complete wound closure until Visit 17, ie, during the 12-week follow-up period
|
|||||||||||||||
| Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint only reports statistics for the arms that include the patients in the FAS. Statistics for the arms that include the patients in the FAS posthoc subgroup are reported separately. |
||||||||||||||||
|
||||||||||||||||
Statistical analysis title |
APO-2 12.5 U/mL vs Placebo - FAS | |||||||||||||||
Comparison groups |
APO-2 12.5 U/mL (FAS) v Placebo (FAS)
|
|||||||||||||||
Number of subjects included in analysis |
56
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority [6] | |||||||||||||||
P-value |
= 1 [7] | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Confidence interval |
||||||||||||||||
| Notes [6] - 2-sided Fisher's exact test [7] - 2-sided alpha = 0.05 |
||||||||||||||||
Statistical analysis title |
APO-2 25.0 U/mL vs Placebo - FAS | |||||||||||||||
Comparison groups |
APO-2 25.0 U/mL (FAS) v Placebo (FAS)
|
|||||||||||||||
Number of subjects included in analysis |
67
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority [8] | |||||||||||||||
P-value |
= 0.789 [9] | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Confidence interval |
||||||||||||||||
| Notes [8] - 2-sided Fisher's exact test [9] - 2-sided alpha = 0.05 |
||||||||||||||||
Statistical analysis title |
APO-2 50.0 U/mL vs Placebo - FAS | |||||||||||||||
Comparison groups |
APO-2 50.0 U/mL (FAS) v Placebo (FAS)
|
|||||||||||||||
Number of subjects included in analysis |
55
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority [10] | |||||||||||||||
P-value |
= 0.5616 [11] | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Confidence interval |
||||||||||||||||
| Notes [10] - 2-sided Fisher's exact test [11] - 2-sided alpha = 0.05 |
||||||||||||||||
|
|||||||||||||||||||||
End point title |
Percentage wound area reduction after 4 weeks treatment compared between groups (FAS posthoc subgroup) [12] | ||||||||||||||||||||
End point description |
Centrally adjudicated wound area measurements were used for this endpoint assessment. At completion of the study, photographic images of the patients' wounds, blinded to group assignment, were reviewed by 2 independent trained assessors, who acted as adjudicators in validating the wound area measurements.
|
||||||||||||||||||||
End point type |
Post-hoc
|
||||||||||||||||||||
End point timeframe |
Reduction from Baseline to Visit 14, ie, after 4 weeks of IMP treatment
|
||||||||||||||||||||
| Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint only reports statistics for the arms that include the patients in the FAS posthoc subgroup. Statistics for the arms that include the patients in the FAS are reported separately. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
APO-2 12.5 U/mL vs Placebo - FAS subgroup | ||||||||||||||||||||
Statistical analysis description |
ANOVA including the stratification factors country and wound area
|
||||||||||||||||||||
Comparison groups |
APO-2 12.5 U/mL (FAS posthoc subgroup) v Placebo (FAS posthoc subgroup)
|
||||||||||||||||||||
Number of subjects included in analysis |
46
|
||||||||||||||||||||
Analysis specification |
Post-hoc
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.6177 [13] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Least squares mean difference | ||||||||||||||||||||
Point estimate |
27.78
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-37.6 | ||||||||||||||||||||
upper limit |
93.17 | ||||||||||||||||||||
| Notes [13] - 2-sided alpha = 0.05; Dunnett adjusted |
|||||||||||||||||||||
Statistical analysis title |
APO-2 25.0 U/mL vs Placebo - FAS subgroup | ||||||||||||||||||||
Statistical analysis description |
ANOVA including the stratification factors country and wound area
|
||||||||||||||||||||
Comparison groups |
APO-2 25.0 U/mL (FAS posthoc subgroup) v Placebo (FAS posthoc subgroup)
|
||||||||||||||||||||
Number of subjects included in analysis |
50
|
||||||||||||||||||||
Analysis specification |
Post-hoc
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.6745 [14] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Least squares mean difference | ||||||||||||||||||||
Point estimate |
24.73
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-38.56 | ||||||||||||||||||||
upper limit |
88.03 | ||||||||||||||||||||
| Notes [14] - 2-sided alpha = 0.05; Dunnett adjusted |
|||||||||||||||||||||
Statistical analysis title |
APO-2 50.0 U/mL vs Placebo - FAS subgroup | ||||||||||||||||||||
Statistical analysis description |
ANOVA including the stratification factors country and wound area
|
||||||||||||||||||||
Comparison groups |
APO-2 50.0 U/mL (FAS posthoc subgroup) v Placebo (FAS posthoc subgroup)
|
||||||||||||||||||||
Number of subjects included in analysis |
44
|
||||||||||||||||||||
Analysis specification |
Post-hoc
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.8927 [15] | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
Least squares mean difference | ||||||||||||||||||||
Point estimate |
15.91
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-50.11 | ||||||||||||||||||||
upper limit |
81.93 | ||||||||||||||||||||
| Notes [15] - 2-sided alpha = 0.05; Dunnett adjusted |
|||||||||||||||||||||
|
||||||||||||||||
End point title |
Proportion of patients with complete wound closure until Visit 17 (FAS posthoc subgroup) [16] | |||||||||||||||
End point description |
Complete wound closure was defined as 100% re-epithelialization of the wound surface with the absence of drainage.
|
|||||||||||||||
End point type |
Post-hoc
|
|||||||||||||||
End point timeframe |
Complete wound closure until Visit 17, ie, during the 12-week follow-up period
|
|||||||||||||||
| Notes [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint only reports statistics for the arms that include the patients in the FAS posthoc subgroup. Statistics for the arms that include the patients in the FAS are reported separately. |
||||||||||||||||
|
||||||||||||||||
Statistical analysis title |
APO-2 12.5 U/mL vs Placebo - FAS subgroup | |||||||||||||||
Comparison groups |
APO-2 12.5 U/mL (FAS posthoc subgroup) v Placebo (FAS posthoc subgroup)
|
|||||||||||||||
Number of subjects included in analysis |
44
|
|||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||
Analysis type |
superiority [17] | |||||||||||||||
P-value |
= 0.7205 [18] | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Confidence interval |
||||||||||||||||
| Notes [17] - 2-sided Fisher's exact test [18] - 2-sided alpha = 0.05 |
||||||||||||||||
Statistical analysis title |
APO-2 25 U/mL vs Placebo - FAS subgroup | |||||||||||||||
Comparison groups |
APO-2 25.0 U/mL (FAS posthoc subgroup) v Placebo (FAS posthoc subgroup)
|
|||||||||||||||
Number of subjects included in analysis |
48
|
|||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||
Analysis type |
superiority [19] | |||||||||||||||
P-value |
= 0.3288 [20] | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Confidence interval |
||||||||||||||||
| Notes [19] - 2-sided Fisher's exact test [20] - 2-sided alpha = 0.05 |
||||||||||||||||
Statistical analysis title |
APO-2 50 U/mL vs Placebo - FAS subgroup | |||||||||||||||
Comparison groups |
APO-2 50.0 U/mL (FAS posthoc subgroup) v Placebo (FAS posthoc subgroup)
|
|||||||||||||||
Number of subjects included in analysis |
42
|
|||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||
Analysis type |
superiority [21] | |||||||||||||||
P-value |
= 0.4769 [22] | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Confidence interval |
||||||||||||||||
| Notes [21] - 2-sided Fisher's exact test [22] - 2-sided alpha = 0.05 |
||||||||||||||||
|
||||||||||||||||||||||||||||
End point title |
Proportion of patients with complete wound closure until Visit 14 (FAS and FAS posthoc subgroup) | |||||||||||||||||||||||||||
End point description |
Complete wound closure was defined as 100% re-epithelialization of the wound surface with the absence of drainage.
|
|||||||||||||||||||||||||||
End point type |
Post-hoc
|
|||||||||||||||||||||||||||
End point timeframe |
Complete wound closure until Visit 14, ie, during the 4-week treatment
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
Statistical analysis title |
APO-2 12.5 U/mL vs Placebo - FAS | |||||||||||||||||||||||||||
Comparison groups |
APO-2 12.5 U/mL (FAS) v Placebo (FAS)
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
57
|
|||||||||||||||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||||||||||||||
Analysis type |
superiority [23] | |||||||||||||||||||||||||||
P-value |
= 1 [24] | |||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
| Notes [23] - 2-sided Fisher's extact test [24] - 2-sided alpha = 0.05 |
||||||||||||||||||||||||||||
Statistical analysis title |
APO-2 25.0 U/mL vs Placebo - FAS | |||||||||||||||||||||||||||
Comparison groups |
APO-2 25.0 U/mL (FAS) v Placebo (FAS)
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
67
|
|||||||||||||||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||||||||||||||
Analysis type |
superiority [25] | |||||||||||||||||||||||||||
P-value |
= 0.396 [26] | |||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
| Notes [25] - 2-sided Fisher's extact test [26] - 2-sided alpha = 0.05 |
||||||||||||||||||||||||||||
Statistical analysis title |
APO-2 50.0 U/mL vs Placebo - FAS | |||||||||||||||||||||||||||
Comparison groups |
APO-2 50.0 U/mL (FAS) v Placebo (FAS)
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
53
|
|||||||||||||||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||||||||||||||
Analysis type |
superiority [27] | |||||||||||||||||||||||||||
P-value |
= 0.478 [28] | |||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
| Notes [27] - 2-sided Fisher's extact test [28] - 2-sided alpha = 0.05 |
||||||||||||||||||||||||||||
Statistical analysis title |
APO-2 12.5 U/mL vs Placebo - FAS subgroup | |||||||||||||||||||||||||||
Comparison groups |
APO-2 12.5 U/mL (FAS posthoc subgroup) v Placebo (FAS posthoc subgroup)
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
45
|
|||||||||||||||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||||||||||||||
Analysis type |
superiority [29] | |||||||||||||||||||||||||||
P-value |
= 0.6078 [30] | |||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
| Notes [29] - 2-sided Fisher's exact test [30] - 2-sided alpha = 0.05 |
||||||||||||||||||||||||||||
Statistical analysis title |
APO-2 25.0 U/mL vs Placebo - FAS subgroup | |||||||||||||||||||||||||||
Comparison groups |
APO-2 25.0 U/mL (FAS posthoc subgroup) v Placebo (FAS posthoc subgroup)
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
48
|
|||||||||||||||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||||||||||||||
Analysis type |
superiority [31] | |||||||||||||||||||||||||||
P-value |
= 1 [32] | |||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
| Notes [31] - 2-sided Fisher's exact test [32] - 2-sided alpha = 0.05 |
||||||||||||||||||||||||||||
Statistical analysis title |
APO-2 50.0 U/mL vs Placebo - FAS subgroup | |||||||||||||||||||||||||||
Comparison groups |
APO-2 50.0 U/mL (FAS posthoc subgroup) v Placebo (FAS posthoc subgroup)
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
42
|
|||||||||||||||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||||||||||||||
Analysis type |
superiority [33] | |||||||||||||||||||||||||||
P-value |
= 0.3327 [34] | |||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
| Notes [33] - 2-sided Fisher's exact test [34] - 2-sided alpha = 0.05 |
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
End point title |
Proportion of patients with a ≥80% reduction from Baseline in wound area at Visit 14 (FAS and FAS posthoc subgroup) | |||||||||||||||||||||||||||
End point description |
Proportion of patients with a ≥80% wound area reduction from Baseline at Visit 14
|
|||||||||||||||||||||||||||
End point type |
Post-hoc
|
|||||||||||||||||||||||||||
End point timeframe |
at Visit 14 (after 4 weeks of treatment)
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
Statistical analysis title |
APO-2 12.5 U/mL vs Placebo - FAS | |||||||||||||||||||||||||||
Comparison groups |
APO-2 12.5 U/mL (FAS) v Placebo (FAS)
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
57
|
|||||||||||||||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||||||||||||||
Analysis type |
superiority [35] | |||||||||||||||||||||||||||
P-value |
= 0.3675 [36] | |||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
| Notes [35] - 2-sided Fisher's exact test [36] - 2-sided alpha = 0.05 |
||||||||||||||||||||||||||||
Statistical analysis title |
APO-2 25.0 U/mL vs Placebo - FAS | |||||||||||||||||||||||||||
Comparison groups |
APO-2 25.0 U/mL (FAS) v Placebo (FAS)
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
67
|
|||||||||||||||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||||||||||||||
Analysis type |
superiority [37] | |||||||||||||||||||||||||||
P-value |
= 0.5736 [38] | |||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
| Notes [37] - 2-sided Fisher's exact test [38] - 2-sided alpha = 0.05 |
||||||||||||||||||||||||||||
Statistical analysis title |
APO-2 50.0 U/mL vs Placebo - FAS | |||||||||||||||||||||||||||
Comparison groups |
APO-2 50.0 U/mL (FAS) v Placebo (FAS)
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
53
|
|||||||||||||||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||||||||||||||
Analysis type |
superiority [39] | |||||||||||||||||||||||||||
P-value |
= 0.0412 [40] | |||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
| Notes [39] - 2-sided Fisher's exact test [40] - 2-sided alpha = 0.05 |
||||||||||||||||||||||||||||
Statistical analysis title |
APO-2 12.5 U/mL vs Placebo - FAS subgroup | |||||||||||||||||||||||||||
Comparison groups |
APO-2 12.5 U/mL (FAS posthoc subgroup) v Placebo (FAS posthoc subgroup)
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
45
|
|||||||||||||||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||||||||||||||
Analysis type |
superiority [41] | |||||||||||||||||||||||||||
P-value |
= 0.7381 [42] | |||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
| Notes [41] - 2-sided Fisher's exact test [42] - 2-sided alpha = 0.05 |
||||||||||||||||||||||||||||
Statistical analysis title |
APO-2 25.0 U/mL vs Placebo - FAS subgroup | |||||||||||||||||||||||||||
Comparison groups |
APO-2 25.0 U/mL (FAS posthoc subgroup) v Placebo (FAS posthoc subgroup)
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
48
|
|||||||||||||||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||||||||||||||
Analysis type |
superiority [43] | |||||||||||||||||||||||||||
P-value |
= 0.7456 [44] | |||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
| Notes [43] - 2-sided Fisher's exact test [44] - 2-sided alpha = 0.05 |
||||||||||||||||||||||||||||
Statistical analysis title |
APO-2 50.0 U/mL vs Placebo - FAS subgroup | |||||||||||||||||||||||||||
Comparison groups |
APO-2 50.0 U/mL (FAS posthoc subgroup) v Placebo (FAS posthoc subgroup)
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
42
|
|||||||||||||||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||||||||||||||
Analysis type |
superiority [45] | |||||||||||||||||||||||||||
P-value |
= 0.1917 [46] | |||||||||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
| Notes [45] - 2-sided Fisher's exact test [46] - 2-sided alpha = 0.05 |
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From the time of giving written informed consent until the end-of-the-study visit.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
APO-2 12.5 U/mL (SAF)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients in the safety analysis set (SAF) who were administered APO-2 12.5 U/mL hydrogel formulation. The SAF included all randomized patients who received at least 1 dose of the IMP. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
APO-2 25.0 U/mL (SAF)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients in the SAF who were administered APO-2 25.0 U/mL hydrogel formulation. The SAF included all randomized patients who received at least 1 dose of the IMP. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
APO-2 50.0 U/mL (SAF)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients in the SAF who were administered APO-2 50.0 U/mL hydrogel formulation. The SAF included all randomized patients who received at least 1 dose of the IMP. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo (SAF)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients in the SAF administered the placebo hydrogel formulation. The SAF includes all randomized patients who received at least 1 dose of the IMP. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
06 Nov 2019 |
The screening phase was extended by 7 days. It was clarified that the minimum duration of a patient in the safety lead-in phase was 93 instead of 98 days, with a maximum of about 117 instead of 116 days. The description of the IMP and the planned wound assessments were updated. For the stratification by wound area, proportions of patients for each category were added. Details about the procedures to follow in case of occurrence and reporting of pregnancies and about the reporting of serious adverse events were added. Details about the neurological assessment of the foot were added. |
||
25 Jun 2021 |
Inclusion criterion 1 was revised to add an upper age restriction of 70 years for sites in the Czech Republic. Inclusion criterion 8 was revised, ie, the ankle brachial index (ABI) at the leg with the treated wound was to be ≥0.9 (instead of between 0.7 and 1.3) with the lowest (not the highest) measured value being used as reference. The index wound duration described in exclusion criterion 3 was changed from >52 weeks to >3 years. In exclusion criterion 5, definitions for wound infection, osteomyelitis, and cellulitis were added. It was clarified that patients were to receive IMP treatment 3 times per week within 7 days. The risk benefit assessment was updated. It was added that biologically or chemically active dressings were not permitted during the study. Local adverse events (AEs) were defined. Visit windows were extended and it was clarified that treatment visits could be postponed. |
||
09 May 2022 |
The upper age limit for patients in the Czech Republic was removed in inclusion criterion 1. Inclusion criterion 5 was changed to include patients with an estimated foot ulcer surface area ≥0.8 cm2 (formerly ≥1 cm2) and ≤8 cm2. In inclusion criterion 8, the ABI at the leg with the treated wound was defined to be ≥0.5 (instead of ≥0.9) and the toe pressure was to be >40 mmHg (instead of >50 mmHg) and it was added that patients with mild to moderate peripheral arterial disease (PAD) could be included. Exclusion criterion 5 was changed to exclude patients with a history of osteomyelitis during 8 weeks (instead of 6 months) before the screening visit. In exclusion criterion 7, “or current diagnosis of claudication” was deleted. A new exclusion criterion 7a was added to exclude certain patients with PAD (eg, patients with PAD of Fontaine Stage III or IV or acute peripheral artery occlusion). The minimum APO-2 dose was changed from 6.3 U to 2.5 U per wound and treatment. The stratification proportions for wound area were revised. The sample size of patients in the main study was changed from 120 to 108 randomized patients. History of PAD was added as assessment at Visit 1. It was clarified that a positive microbiological swab test result of the target wound alone was not to be considered a wound infection. The reporting procedure for local AEs was updated to include the involvement of the target wound (yes/no). The definition of the full analysis set was changed to include all patients of the safety analysis set with a measured wound area at Baseline and at Visit 6 or later. It was clarified that if the Visit 14 measurement of wound area was missing, the last available post-baseline measurement between Visit 6 and Visit 14 was to be used. |
||
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. | |||
| The NU-GEL in the placebo had positive effects on wound healing. A treatment period of 4 weeks is too short. Unadjudicated wound assessment led to inclusion of patients with wounds <0.8cm2. Synopsis of the study report is on https://www.aposcience.at | |||
