Clinical Trial Results:
A RANDOMISED, PLACEBO-CONTROLLED, DOUBLE-BLIND, INTERVENTIONAL, MULTICENTER, PHASE I/IIA CLINICAL TRIAL TO INVESTIGATE THE EFFICACY AND SAFETY OF ALLO-APZ2-PAOD FOR THE TREATMENT OF PERIPHERAL ARTERIAL OCCLUSIVE DISEASE (PAOD)
Summary
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EudraCT number |
2017-000235-14 |
Trial protocol |
DE GB CZ AT PL |
Global end of trial date |
15 May 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Jul 2021
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First version publication date |
30 Jul 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
allo-APZ2-PAOD-II-01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03339973 | ||
WHO universal trial number (UTN) |
- | ||
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, +49 6221718330, office@rheacell.com
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Scientific contact |
Information Office, 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 |
31 Jul 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
15 May 2020
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The aim of this clinical trial is to investigate the efficacy (by monitoring the wound size reduction of PAOD-related clinically relevant ulcers) and safety (by monitoring adverse events) of one dose of allo-APZ2-PAOD administered intramuscularly into an affected lower leg of subjects with PAOD.
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Protection of trial subjects |
Optional wound debridement and clearance of necrotic tissue at relevant ulcers was performed and the subject was treated with local anesthetic cream (e.g., Lidocain/Prilocain) if necessary, before the investigational product (IMP) was injected. Local anesthetics intravenously or strong analgesics, e.g., Piritramide (Dipidolor®) were to be given at subject's request or in case of severe pain. After application of the IMP (last injection), the subject was requested to stay in the hospital for 2 hours. If strong analgesics were used, safety monitoring may be extended at the discretion of the investigator.
The first 3 subjects were treated at least 2 weeks apart. The Medical Monitor continuously reviewed the safety data and requested assistance from the Independent Data Monitoring Committee (IDMC) as needed. In addition, safety data were reviewed monthly by the IDMC, and a recommendation was made to the sponsor and investigator as to whether administration to patients could be continued or the trial should be discontinued. After 10 subjects completed Week 2, the treatment was temporarily interrupted for a safety analysis by the IDMC. Because of premature termination of the trial due to insufficient patient recruitment, the planned second safety analysis by the IDMC was not performed after 30 subjects completed Week 2.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Mar 2018
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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 |
Austria: 2
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Country: Number of subjects enrolled |
Czechia: 3
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Country: Number of subjects enrolled |
Germany: 19
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Worldwide total number of subjects |
24
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EEA total number of subjects |
24
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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) |
5
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From 65 to 84 years |
19
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85 years and over |
0
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Recruitment
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Recruitment details |
Male and female subjects aged 45 to 85 years (to 75 years only in Czech Republic) with PAOD (Rutherford category 5) in at least one lower extremity were recruited in 9 centers in Germany and 1 center each in the Czech Republic and Austria. The first subject signed the informed consent form on 05-Mar-2018 and the last subject on 10-Mar-2020. | ||||||||||||||||||
Pre-assignment
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Screening details |
24 subjects signed the informed consent. 10 subjects were screening failures and not treated with IMP. 7 subjects each were randomized to allo-APZ2-PAOD treatment (7.5 x 10E6 cells per injection site) or to placebo treatment. 2 subjects randomized to allo-APZ2-PAOD were not treated because of an AE or an other reason of premature discontinuation. | ||||||||||||||||||
Period 1
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Period 1 title |
12-week follow-up
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||
Roles blinded |
Investigator, Subject | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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allo-APZ2-PAOD | ||||||||||||||||||
Arm description |
Subjects received 1 dose of allo-APZ2-PAOD per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for efficacy for 12 weeks. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
allo-APZ2-PAOD
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Subjects received 1 dose of allo-APZ2-PAOD per injection site intramuscularly into the lower leg. allo-APZ2-PAOD contains 7.5 x 10E6 allogeneic skin-derived ABCB5-positive mesenchymal stem cells isolated from skin tissue of healthy donors in 750 µL Human Serum Albumin/Ringer-Lactate/Glucose solution. The used cell amount depended on the number of injection sites (N=20-30), which depended on length of the lower leg. Injection sites were to be started about 6-9 cm below the popliteal space. 3 injections were placed in 1 row horizontally along the vessel axes of the posterior tibial artery, anterior tibial artery and fibular artery. Next horizontal row was 3 cm distal to the last one. In the distal last third of the lower leg only 2 injections were placed in 1 row, 1 on the inner and 1 on the outer leg side, with a row distances of 3 cm. Optional wound debridement and clearance of necrotic tissue at relevant ulcers was performed and the subject was treated with local anesthetic before.
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
Subjects received 1 dose of placebo per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for efficacy for 12 weeks. | ||||||||||||||||||
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 |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Subjects received 1 dose of placebo (750 µL Human Serum Albumin/Ringer-Lactate/Glucose solution) per injection site intramuscularly into the lower leg. The number of injection sites (N=20-30) depended on the length of the lower leg. Injection sites were to be started about 6-9 cm below the popliteal space. 3 injections were placed in 1 row horizontally along the vessel axes of the posterior tibial artery, anterior tibial artery and fibular artery. Next horizontal row was 3 cm distal to the last one. In the distal last third of the lower leg only 2 injections were placed in 1 row, 1 on the inner and 1 on the outer leg side, with a row distances of 3 cm. Optional wound debridement and clearance of necrotic tissue at relevant ulcers was performed and the subject was treated with local anesthetic before.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Twenty-four patients signed the informed consent. Ten patients were defined as screening failures and not treated with IMP. Two patients were randomized to allo-APZ2-PAOD but not treated: 1 patient had an AE and 1 patient discontinued the trial before treatment by other reason. Twelve patients were included in the full- and the safety-anlysis set for final analysis after early clinical trial termination. |
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Period 2
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Period 2 title |
12-month safety follow-up
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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allo-APZ2-PAOD | ||||||||||||||||||
Arm description |
Subjects received 1 dose of allo-APZ2-PAOD per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for safety for 12 months. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
allo-APZ2-PAOD
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Subjects received 1 dose of allo-APZ2-PAOD per injection site intramuscularly into the lower leg. allo-APZ2-PAOD contains 7.5 x 10E6 allogeneic skin-derived ABCB5-positive mesenchymal stem cells isolated from skin tissue of healthy donors in 750 µL Human Serum Albumin/Ringer-Lactate/Glucose solution. The used cell amount depended on the number of injection sites (N=20-30), which depended on length of the lower leg. Injection sites were to be started about 6-9 cm below the popliteal space. 3 injections were placed in 1 row horizontally along the vessel axes of the posterior tibial artery, anterior tibial artery and fibular artery. Next horizontal row was 3 cm distal to the last one. In the distal last third of the lower leg only 2 injections were placed in 1 row, 1 on the inner and 1 on the outer leg side, with a row distances of 3 cm. Optional wound debridement and clearance of necrotic tissue at relevant ulcers was performed and the subject was treated with local anesthetic before.
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
Subjects received 1 dose of placebo per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for safety for 12 months. | ||||||||||||||||||
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 |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Subjects received 1 dose of placebo (750 µL Human Serum Albumin/Ringer-Lactate/Glucose solution) per injection site intramuscularly into the lower leg. The number of injection sites (N=20-30) depended on the length of the lower leg. Injection sites were to be started about 6-9 cm below the popliteal space. 3 injections were placed in 1 row horizontally along the vessel axes of the posterior tibial artery, anterior tibial artery and fibular artery. Next horizontal row was 3 cm distal to the last one. In the distal last third of the lower leg only 2 injections were placed in 1 row, 1 on the inner and 1 on the outer leg side, with a row distances of 3 cm. Optional wound debridement and clearance of necrotic tissue at relevant ulcers was performed and the subject was treated with local anesthetic before.
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Baseline characteristics reporting groups
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Reporting group title |
allo-APZ2-PAOD
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Reporting group description |
Subjects received 1 dose of allo-APZ2-PAOD per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for efficacy for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received 1 dose of placebo per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for efficacy for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
allo-APZ2-PAOD
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Reporting group description |
Subjects received 1 dose of allo-APZ2-PAOD per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for efficacy for 12 weeks. | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects received 1 dose of placebo per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for efficacy for 12 weeks. | ||
Reporting group title |
allo-APZ2-PAOD
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Reporting group description |
Subjects received 1 dose of allo-APZ2-PAOD per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for safety for 12 months. | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects received 1 dose of placebo per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for safety for 12 months. |
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End point title |
Percent change in total wound size from Baseline at Week 12 | |||||||||||||||||||||
End point description |
The primary efficacy endpoint was the percent change from Baseline to Week 12 in total wound size of the target leg. The total wound size of the target leg was calculated as sum of the wound sizes of all relevant ulcers of the target leg.
The last observation carried forward (LOCF) approach was applied for 1 patient in the allo-APZ2-PAOD group. The measurement at Week 12 was missing, therefore the last available post-baseline measurement (in this case the value at Week 2) was used for the primary endpoint analysis.
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End point type |
Primary
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End point timeframe |
From Baseline (Day 0, pre-dose) until the end of 12-week follow-up (Week 12).
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Notes [1] - Diabetics are N=4 and non-diabetics are N=1. [2] - Diabetis are N=4 and non-diabetics are N=3. |
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Statistical analysis title |
Change in total wound size from Baseline (t-test) | |||||||||||||||||||||
Statistical analysis description |
The 95% confidence interval for the mean change of total wound size from Baseline (pre-dose) at Week 12 was calculated. LOCF for missing data was applied.
The primary efficacy endpoint was analyzed with a t-test with treatment as independent variable. The significance level was 0.05 (2-sided). Stratification by diabetes was not possible because the diabetic stratum sizes were too small (e.g., less than 3 subjects within the stratum). The data were previously tested for normal distribution.
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Comparison groups |
allo-APZ2-PAOD v Placebo
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Number of subjects included in analysis |
12
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | |||||||||||||||||||||
P-value |
= 0.4036 | |||||||||||||||||||||
Method |
t-test, 2-sided | |||||||||||||||||||||
Parameter type |
Mean difference (final values) | |||||||||||||||||||||
Point estimate |
37.29
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
-57.99 | |||||||||||||||||||||
upper limit |
132.57 | |||||||||||||||||||||
Variability estimate |
Standard deviation
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Dispersion value |
73.03
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Notes [3] - The primary efficacy variable was subjected to confirmatory statistical analysis in a two-stage group sequential study design. The primary null hypothesis to be tested was H0: µallo-APZ2-PAOD = µPlacebo vs H1: µallo-APZ2-PAOD ≠ µPlacebo where µ is the mean percent change from Baseline to Week 12 in total wound size of the target leg. |
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Adverse events information
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Timeframe for reporting adverse events |
From administration of the IMP until the end of 12-month follow-up (Month 12).
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Adverse event reporting additional description |
In 4 subjects (2 per treatment group), adverse event reporting ended before Month 12 due to early trial termination by the Sponsor.
Two subjects died (1 per treatment group) before Month 12.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.01
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Reporting groups
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Reporting group title |
allo-APZ2-PAOD
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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16 Apr 2018 |
Protocol v5.0 with the following changes to v4.0:
- Inclusion criterion 3 was specified in more detail; inclusion criterion 4 was changed (maximum wound size of 20 cm² instead of 10 cm²), wording of inclusion criterion 9 was changed (from “Patients with hypertension, if they are treated…” to “If patients are hypertensive, they have to be treated…”)
- Exclusion criterion 6 was changed (from “…with bone exposure” to “…with exposure of destructive bone lesion”), exclusion criterion 7 was split into 2 criteria and specifying details were added; the numbering of subsequent exclusion criteria was changed accordingly
- The option to use intravenous injections of strong analgesics upon subject request and longer safety observation time in case of strong analgesics use at the discretion of the investigator was added
- The use of vitamin K and direct oral anticoagulants as concomitant medications was specified in more detail
- The visit window for screening was changed (from “14 days to 7 days before treatment” to “21 days to 7 days before treatment”). |
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19 Apr 2018 |
Protocol v6.0 with the following changes to v5.0:
- Exclusion criterion 6 was rephrased (from “… with ulcers with exposure of destructive bone lesions” to “…with osteomyelitis at ulceration”). |
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27 Aug 2018 |
Protocol v7.0 with the following changes to v6.0:
- The trial was changed from a national (Germany) to an international trial with additional sites in the United Kingdom, Austria, Czech Republic, and Poland
- Inclusion criterion 3 was changed to allow angiography results not older than 6 months (formerly 3 months)
- The safety observation time after IMP injection was specified to be at least 2 hours; accordingly, vital signs were to be assessed the earliest 2 hours after the IMP administration
- Unblinding via randomization envelopes was changed to unblinding via the electronic case report form system. |
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07 Feb 2019 |
Protocol v8.0 with the following changes to v7.0:
- The specification that no minimal number of subjects with diabetes or without diabetes was added
- Inclusion criterion 7 was changed (from “No evidence of change of wound size of more than 25% for at least 6 weeks before screening” to “No evidence of wound healing after standard of care treatment for at least 1 week before screening”)
- Exclusion criterion 1, the origin of skin lesions was rephrased (from “mixed anterior-venous” to “leading venous”)
- Exclusion criterion 9 was changed to include subjects with surgical/interventional reconstruction more than 1 week before screening or with not successful revascularization
- Exclusion criterion 10 was changed to include subjects with major amputations of lower extremities within 12 months before screening
- Exclusion criterion 22 was changed to allow previous use of glucocorticoid-medication above the cushing threshold dose. Medications that might influence wound healing, hyperbaric oxygen therapy, spinal cord stimulation and sympathectomy, as well as vasoactive substances other than the test drug, haemodilution or rheological therapy were not allowed from screening until Week 12
- Octenisept for wound care was only to be used in subjects without a history of allergic reactions to the product
- The visit window for screening was changed (from “21 days to 7 days before treatment” to “21 days to 2 days before treatment”)
- The examination of injection sites was added for Visits 2-9
- Relationship assessment of adverse events to the procedure was added
- Suspected unexpected serious adverse reaction reporting was expanded from German legislation to include applicable European and other applicable national regulatory requirements. |
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05 Apr 2019 |
In Czech Republic, subjects were studied on protocol version CZE 3.0, dated 05-Apr-2019, which corresponds to Version 8.0, dated 07-Feb-2019, except that only subjects aged 45 to 75 years were to be included. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
None reported |