Clinical Trial Results:
An interventional, multicenter, single arm, phase I/IIa clinical trial to investigate the efficacy and safety of allo-APZ2-DFU on wound healing of diabetic neuropathic ulcer (DFU)
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Summary
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EudraCT number |
2017-000234-57 |
Trial protocol |
DE |
Global end of trial date |
29 Jun 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Jul 2021
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First version publication date |
01 Jul 2021
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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 |
allo-APZ2-DFU-II-01
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Additional study identifiers
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ISRCTN number |
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US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
RHEACELL GmbH & Co. KG
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Sponsor organisation address |
Im Neuenheimer Feld 517, Heidelberg, Germany, 69120
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Public contact |
Information Office, RHEACELL GmbH & Co. KG, RHEACELL GmbH & Co. KG, +49 6221718330, office@rheacell.com
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Scientific contact |
Information Office, RHEACELL GmbH & Co. KG, RHEACELL GmbH & Co. KG, +49 6221718330, office@rheacell.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 |
29 Jun 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
29 Jun 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
29 Jun 2020
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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 investigate the efficacy (by monitoring the wound surface area reduction of diabetic foot ulcers [DFUs]) and safety (by monitoring adverse events [AEs]) of 2 doses of the investigational medicinal product (IMP) allo-APZ2-DFU topically administered to the wound matrix of patients with DFU.
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation (of Technical Requirements for Pharmaceuticals for Human Use) Good Clinical Practice (GCP, CPMP/ICH/135/95). All national and local regulatory requirements were followed. The investigator ensured that the patient was fully informed about the objectives, procedures, potential risks, any discomforts, and expected benefits of the trial.
Based on the available data, a starting dose of 2x10^6 allogeneic skin-derived ATP-binding cassette sub-family B member 5 (ABCB5)-positive cells/cm², if administered topically on DFU wounds (1 to 50 cm²), was considered to be safe (196-fold safety margin) and expected to be beneficial for patients with DFU.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 Aug 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 23
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Worldwide total number of subjects |
23
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EEA total number of subjects |
23
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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) |
13
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From 65 to 84 years |
10
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85 years and over |
0
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Recruitment
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Recruitment details |
Of the 63 patients screened at 8 centers, 40 patients were screening failures; 23 patients met the eligibility criteria, were treated with allo-APZ2-DFU, and were included in the safety analysis set (SAF). | ||||||||||
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Pre-assignment
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Screening details |
Patients who met all inclusion and none of the exclusion criteria were eligible to participate in the trial. | ||||||||||
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Period 1
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Period 1 title |
Treatment and follow-up (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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allo-APZ2-DFU | ||||||||||
Arm description |
Patients treated with the IMP, allo-APZ2-DFU | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
allo-APZ2-DFU
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Investigational medicinal product code |
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Other name |
ABCB5-positive mesenchymal stem cells
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Pharmaceutical forms |
Cutaneous suspension
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Routes of administration |
Topical use
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Dosage and administration details |
Up to 2 topical applications of 2x10^6 cells/cm², applied in 200 μL Human Serum Albumin/Ringer-Lactate/Glucose solution with a syringe on the wound surface of patients with DFU and optionally covered with fibrin gel after 15-30 minutes.
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Baseline characteristics reporting groups
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Reporting group title |
Treatment and follow-up
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Reporting group description |
Patients treated with allo-APZ2-DFU | |||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
allo-APZ2-DFU
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Reporting group description |
Patients treated with the IMP, allo-APZ2-DFU | ||
Subject analysis set title |
Safety analysis set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The SAF included all patients who were treated with allo-APZ2-DFU at least once.
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Subject analysis set title |
Full analysis set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The full analysis set (FAS) included all patients of the SAF with wound surface area assessments at Day 0 (Baseline) and at least one post-baseline visit.
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Subject analysis set title |
Modified full analysis set
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
The modified FAS (mFAS) included all patients of the FAS except for 3 patients with major protocol deviations affecting efficacy assessments.
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End point title |
Percentage of wound surface area reduction at Week 12 [1] | ||||||||||||
End point description |
The wound surface area was assessed using digital photographs and digital planimetry software.
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End point type |
Primary
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End point timeframe |
From Baseline to Week 12
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: In a posthoc analysis the precent reduction in wound surface area was evaluated with a Wilcoxon signed rank test. H0 tested was median = 0. The 2-sided p was <0.0001 in both the FAS and mFAS. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of wound surface area reduction at Weeks 2, 4, 6, 8 and 12 (without last observation carried forward [LOCF]) | |||||||||||||||||||||||||||
End point description |
The wound surface area was assessed using digital photographs and digital planimetry software.
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| Notes [2] - At some visits, less than 23 patients were investigated. [3] - At some visits, less than 20 patients were investigated. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Percentage of visible wound surface area reduction at Weeks 2, 4, 6, 8 and 12 (without LOCF) | |||||||||||||||||||||||||||
End point description |
The wound surface area was assessed using digital photographs and digital planimetry software.
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| Notes [4] - At some visits, less than 23 patients were investigated. [5] - At some visits, less than 20 patients were investigated. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Absolute target wound surface area reduction at Weeks 2, 4, 6, 8 and 12 (without LOCF) | |||||||||||||||||||||||||||
End point description |
The wound surface area was assessed using digital photographs and digital planimetry software.
At Baseline, the median size of the wound was 2.58 cm² (range: 1.03 - 15.20) in the FAS and 3.08 cm² (range: 1.13 - 15.20) in the mFAS.
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| Notes [6] - At some visits, less than 23 patients were investigated. [7] - At some visits, less than 20 patients were investigated. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Median time to first complete target wound closure | |||||||||
End point description |
The wound surface area was assessed using digital photographs and digital planimetry software. Complete wound closure was defined as 95% to 100% epithelialization of the wound.
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End point type |
Secondary
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End point timeframe |
From Baseline to Week 12.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of patients achieving complete target wound closure at Weeks 2, 4, 6, 8 and 12, and at any timepoint | ||||||||||||||||||||||||||||||
End point description |
The wound surface area was assessed using digital photographs and digital planimetry software. Complete wound closure was defined as 95% to 100% epithelialization of the wound.
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| Notes [8] - At some visits, less than 23 patients were investigated. [9] - At some visits, less than 20 patients were investigated. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Time to first 30% reduction of target wound surface area | ||||||||||||
End point description |
The wound surface area was assessed using digital photographs and digital planimetry software.
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End point type |
Secondary
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End point timeframe |
From Baseline to Week 12.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of patients achieving at least 30% reduction of target wound surface area at Weeks 2, 4, 6, 8 and 12, and at any timepoint | |||||||||||||||||||||||||||
End point description |
The wound surface area was assessed using digital photographs and digital planimetry software.
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| Notes [10] - At some visits, less than 23 patients were investigated. [11] - At some visits, less than 20 patients were investigated. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Number of patients whose target wound reopened after wound closure within the 12-week efficacy follow-up | |||||||||
End point description |
The wound surface area was assessed using digital photographs and digital planimetry software. Complete wound closure was defined as 95% to 100% epithelialization of the wound.
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Assessment of target wound exudation at Day 0 and Week 6.1 prior to IMP application, and at Week 12 | ||||||||||||||||||||||||||||||||||||
End point description |
Wound exudation was classified by the investigator using the following scores:
High: small amounts of fluid or free fluids are visible when the dressing is removed; dressing is extensively marked or wet.
Moderate: Small amounts of fluid are visible when dressing is removed; wound bed may appear glossy; primary dressing may be lightly marked.
Low: Wound bed is dry; there is no visible moisture; primary dressing is unmarked; dressing may be adherent to wound.
Wound exudation was assessed at all visits, representative results for 3 visits are reported below.
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| Notes [12] - At Week 6.1, 16 patients were investigated. [13] - At Week 6.1, 13 patients were investigated. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Assessment of target wound epithelialization at Day 0 and Week 6.1 prior to IMP application, and at Week 12 | |||||||||||||||||||||
End point description |
Epithelialization (in % of wound area) was assessed by the investigator based on image analysis and is shown here for 3 selected visits.
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| Notes [14] - At Week 6.1, 9 patients were analyzed. [15] - At Week 6.1, 6 patients were analyzed. |
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Assessment of target wound formation of granulation tissue at Day 0 and Week 6.1 prior to IMP application, and at Week 12 | |||||||||||||||||||||
End point description |
Formation of granulation tissue was assessed by the investigator based on image analysis and is shown here for 3 seleted visits.
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| Notes [16] - At Week 6.1, 9 patients were investigated. [17] - At Week 6.1, 6 patients were investigated. |
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Time to amputation at target leg until Week 12 | ||||||||||||
End point description |
An amputation at the target leg until Week 12 was reported in only one patient.
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Pain assessment as per numerical rating scale (NRS) at Day 0, Week 6.1, and Week 12 | ||||||||||||||
End point description |
Pain was assessed by the patient using an NRS ranging between no pain (0) and worst imaginable pain (10) and is shown here for 3 seleted visits.
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| Notes [18] - At Week 6.1, 16 patients were investigated. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change from Baseline in Quality of life (QoL) as assessed with the short form 36 (SF-36) questionnaire at Week 12 | ||||||||||||||||||||||||||
End point description |
Quality of life was assessed using the short form 36 (SF-36) questionnaire. Changes from Baseline in the scores of 9 subscales were measured. A higher score corresponds to a more positive health status.
Median (full range) values at Baseline were:
Limitations in physical functioning: 50.00 (5.0 - 100.0)
Limitations in role activities due to problems in physical health: 25.00 (0.0 - 100.0)
Limitations in usual role due to emotional problems: 100.00 (0.0 - 100.0)
Limitations in social functioning due to physical or emotional problems: 87.50 (0.0 - 100.0)
Mental health (depressed or happy): 76.00 (0.0 - 100.0)
Bodily pain: 74.00 (12.0 - 100.0)
Vitality (fatigue and energy): 55.00 (0.0 - 85.0)
General health: 55.00 (10.0 - 92.0)
Health transition: 3.00 (2.0 - 5.0)
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
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End point title |
Change from Baseline in Dermatology-specific QoL as assessed with the Dermatology Life Quality Index (DLQI) questionnaire at Weeks 4 and 12 | ||||||||||||
End point description |
The DLQI consists of 10 questions concerning symptoms and feelings, daily activities, leisure, work, school, personal relationships, and treatment. Each question is answered by a tick box: ‘not at all’, ‘a little’, ‘a lot’, or ‘very much’. Each question is scored from 0 to 3 and the scores are summed, giving a range from 0 (no impairment of life quality) to 30 (maximum impairment). All questions relate to the previous week.
At Baseline, the median DLQI summary score was 6.0 (range: 0 - 28).
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End point type |
Secondary
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End point timeframe |
As indicated in the end point title.
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Treatment-emergent AEs were reported from the application of allo-APZ2-DFU (Day 0) until the end of the safety follow-up (Month 12).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
Safety analysis set
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 3% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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07 Jul 2017 |
o Inclusion criterion 3: ‘If the ABI is >1.3, an additional doppler ultrasonography must be performed to exclude a PAOD masked by media sclerosis’ was added
o Wound debridement can also be carried out at Visit 1
o Definition of “best standard of care management” of the diabetic foot ulcer was added
o New Inclusion Criterion 4 added: At Screening Visit (Visit 1) the target ulcer should exist for at least six weeks without complete wound healing despite receiving standard of care treatment as described in the study protocol, and the wound surface area should be between 1 and 50 cm² measured by using a scaled measuring sensor in combination with digital image analysis
o New Inclusion Criterion 6 added: Patients suffering from two or more ulcers at the same extremity, as long as these ulcers are separated by a minimum bridge of 1 cm of healthy tissue
o New Exclusion Criterion 8 added: Ulcers due to non-diabetic etiology. |
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17 Aug 2017 |
o Change of Inclusion Criterion 4: ‘At Screening visit (Visit 1) the target ulcer should exist for at least six weeks without complete wound healing despite receiving standard of care treatment as described in the study protocol, and the wound surface area should be between 1 and 50 cm² measured by using a scaled measuring sensor in combination with digital image analysis’ was changed to ‘At Screening Visit 1 and 2 the wound surface area should be between 1 and 50 cm² measured by using a scaled measuring sensor in combination with digital image analysis’
o Change of Exclusion Criterion 2: presence of osteomyelitis was changed to clinical signs of active osteomyelitis in the last three months
o Change of Exclusion Criterion 14: ‘History of tumour disease or active tumour disease, systemic or local neoplasia or suspicion of any carcinomas or malignant tumour’ was changed to ‘Any malignancy within the past 5 years, excluding successfully treated carcinoma in situ, basal cell carcinoma or squamous cell carcinoma of the skin without evidence of metastases’
o Secondary efficacy endpoint ‘Percentage of invisible and visible wound surface area reduction at Weeks 2, 4, 8 and 12 (without LOCF)’ was added
o Secondary efficacy endpoint ‘Absolute invisible and visible wound surface area reduction at Weeks 2, 4, 8 and 12 (without LOCF)’ was added
o Secondary efficacy endpoints: assessments of QoL using the SF-36 questionnaire and of dermatology-specific QoL based on the DLQI were additionally to be done at Visit 3
o Visit 1 was moved from 1-7 days before Visit 2 to at least 6 weeks before Visit 2
o Wound debridement can also be carried out at Visit 3. |
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09 Apr 2018 |
o Change of Inclusion Criterion 8: allowed BMI was extended from a range between 20 and 40 kg/m² to a range of 20 and 45 kg/m²
o Clarified that Tisseel application after IMP application is optional and should occur 15-30 minutes after IMP application
o Specified that determination of the wound surface will be done at Visit 1 and Visit 2 (instead of only Visit 2)
o Appendix 1, wound surface area calculation was updated. |
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28 May 2018 |
o A second IMP application was introduced (adding Visit 10, Week 6.1), including 1 additional visit before and 2 additional visits after the 2nd IMP application
(Visit 9, Visit 11 and Visit 12 to be performed at Week 6, Week 6.2, and Week 6.3, respectively).
Visit 9 was added to measure the wound size 1 to 3 days before the 2nd IMP application to calculate the required cell amount. All treatments and procedures related to the IMP application were to be repeated at Visit 10 (physical examination and vital signs, and optional wound debridement).
The risk/benefit assessment was adapted for the inclusion of a 2nd IMP application.
o Due to the inclusion of 4 new visits for the 2nd IMP application, new time points, i.e. Week 6, Week 6.1, Week 6.2, and Week 6.3, were added to the following
secondary efficacy endpoints:
− Percentage wound surface area reduction (Week 6 only)
− Percentage of invisible and visible wound surface area reduction (Week 6 only)
− Absolute wound surface area reduction (Week 6 only)
− Absolute invisible and visible wound surface area reduction (Week 6 only)
− Assessment of wound infection
− Proportion of patients achieving 30% and complete wound closure (Week 6 only)
− Wound exudation, epithelialization and formation of granulation tissue (Week 6 and Week 6.1), and
− Pain assessment as per NRS.
o Primary efficacy endpoint: Week 6 was added as an LOCF measurement in case of a missing wound surface area measurement at Week 12.
o Safety endpoints: Week 6.1 was added to analyze data obtained by physical examination and the assessment of vital signs.
o For Inclusion Criterion 4 clarified that the required wound surface area between 1 and 50 cm² applies for the target ulcer.
o Inclusion Criterion 6 wording changes. |
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07 Mar 2019 |
o In Inclusion Criterion 2 the following: ‘…..The HbA1c value at Visit 1 should not vary more than 1.5% (absolute range) compared to a HbA1c value that was
previously measured 1 to 3 months before visit 1’ changed to ‘….The HbA1c value at Visit 1 should not vary more than 1.5% (absolute range) compared to a HbA1c
value that was previously measured 1 to 6 months before visit 1.’
o In Inclusion Criterion 3 the following: ‘…..The presence of diabetic neuropathic ulcers “malum perforans” not involving subcutis (Grade I according to Wagner)
at plantar side of the foot diagnosed by ABI ≥0.8, without claudication, or TcPO2 >40 mmHg…’ changed to ‘….The presence of diabetic neuropathic ulcers “malum
perforans” (Grade I and II according to Wagner) at plantar side of the foot diagnosed by ABI ≥0.7, without claudication, or TcPO2 >40 mmHg.’
o Exclusion Criterion 1 clarified that acute Charot foot is meant. |
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12 Dec 2019 |
o The procedure to transfer wound photographs to the sponsor added.
o New SOP references added. |
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27 Apr 2020 |
o Specified that due to the COVID-19 pandemic and the already reached target of responders, it was planned to complete the trial on 30-Jun-2020. References to the respective trial stop were added and adjusted.
o The possibility to treat non-target wounds was removed. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The trial was completed on 29-June-2020 (last patient last visit) due to the coronavirus disease-2019 (COVID-19) pandemic and the efficacy of allo-APZ2-DFU as specified in a protocol amendment. | |||
