Clinical Trial Results:
An interventional, single arm, multicenter, phase I/IIa clinical trial to investigate the efficacy and safety of allo-APZ2-ACLF for the treatment of acute-on-chronic liver failure (ACLF)
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Summary
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EudraCT number |
2018-001240-61 |
Trial protocol |
DE AT |
Global end of trial date |
26 Mar 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Mar 2022
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First version publication date |
01 Mar 2022
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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-ACLF-II-01
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT03860155 | ||
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, +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 |
05 Aug 2021
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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 |
26 Mar 2021
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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 changes in Model for End-Stage Liver Disease [MELD] score) and safety (by monitoring adverse events [AEs]) of 3 doses of allo-APZ2-ACLF administered intravenously to subjects suffering from ACLF.
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Protection of trial subjects |
Safety data were continuously reviewed by the medical monitor, with assistance from the coordinating investigator and the sponsor’s medical officer as needed, or a data safety monitoring board (DSMB) established with protocol version 04 from 06-Aug-2019. During the trial, the DSMB was renamed to data monitoring committee (DMC) and consisted of the medical monitor, sponsor's responsible medical officer, the respective representative of the clinical trial center, and an independent expert. The first 6 subjects were planned to be consecutively enrolled under safety and related data review by the DMC. To detect immediate severe adverse effects (eg, allergic reaction, systemic inflammatory response syndrome), the next subject can only be enrolled after the second infusion of the prior subject was considered to be safe by the DMC. A favourable DMC decision report on safety in this subject cohort was required before recruitment of further subjects.
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
22 Mar 2019
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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: 3
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Worldwide total number of subjects |
3
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EEA total number of subjects |
3
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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) |
3
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Men and women aged 20 to 75 years with ACLF of grade 2 or 3 as defined by the European Association for the Study of the Liver - Chronic Liver Failure (EASL-CLIF) who were not eligable for liver transplantion were recruited in 4 centers in Germany. The first subject signed the informed consent form (ICF) on 22-Mar-2019 and was a screening failure. | ||||||
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Pre-assignment
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Screening details |
In the trial, subjects were enrolled and studied under protocol versions V02 (07-Jan-2019) or V07 (13 May-2020). 5 subjects signed the ICF. 2 subjects were screening failures and not treated with allo-ALZ2-ACLF. 3 subjects were planned to be treated with allo-APZ2-ACLF (2 x 10E6 cells/kg) 3 times within 2 weeks. | ||||||
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Period 1
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Period 1 title |
Overall treatment until death (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-ACLF | ||||||
Arm description |
Subjects were to receive 3 doses of allo-APZ2-ACLF intravenously within 2 weeks and were to be followed up 24 weeks for efficacy and 24 months for safety after first allo-APZ2-ACLF application. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
allo-APZ2-ACLF
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received 3 doses of allo-APZ2-ACLF within 2 weeks (subjects treated according to protocol V02: at Days 0, 4, and 11; subjects treated according to protocol V07: at Days 0, 5, and 13) at least 3 hours after end of dialysis, if applicable. allo-APZ2-ACLF contained allogeneic skin-derived ABCB5-positive mesenchymal stem cells in Human Serum Albumin/Ringer-Lactate/Glucose solution (1 x 10E7 cells/mL) isolated from skin tissue of healthy donors. A dose of 2 x 10E6 cells/kg was given intravenously into the peripheral vein (arm) by use of a perfusor (protocol V02) or with a flow rate of 1-2 mL/min (protocol V07). To prevent allergic reactions, treatment with an antihistamine was mandatory before allo-APZ2-ACLF administration; the type of antihistamine was chosen at the discretion of the investigator.
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Baseline characteristics reporting groups
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Reporting group title |
allo-APZ2-ACLF
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Reporting group description |
Subjects were to receive 3 doses of allo-APZ2-ACLF intravenously within 2 weeks and were to be followed up 24 weeks for efficacy and 24 months for safety after first allo-APZ2-ACLF application. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
allo-APZ2-ACLF
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Reporting group description |
Subjects were to receive 3 doses of allo-APZ2-ACLF intravenously within 2 weeks and were to be followed up 24 weeks for efficacy and 24 months for safety after first allo-APZ2-ACLF application. | ||
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End point title |
Safety endpoint adverse events [1] | ||||||||||||
End point description |
The primary safety endpoint was the number of subjects with adverse events (AEs). Treatment-emergent adverse events (TEAEs) included all AEs reported from first allo-APZ2-ACLF treatment. Related TEAEs included all TEAEs with a suspected relationship to allo-APZ2-ACLF.
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End point type |
Primary
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End point timeframe |
From Screening until the end of trial.
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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: No statistical analyses for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Efficacy endpoint change of MELD score at Week 24 [2] | ||||||||
End point description |
The primary efficacy was the change from Baseline (Day 0) in MELD score at Week 24 or the last available post-baseline measurement if the Week 24 score is missing (last observation carried forward).
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End point type |
Primary
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End point timeframe |
From Baseline (Day 0, before first allo-APZ2-ACLF treatment) to Week 24.
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| Notes [2] - 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: No statistical analyses for this primary end point. |
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| Notes [3] - All subjects discontinued the trial prematurely, at the latest in Week 4. |
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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 |
From Screening until the end of trial.
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Adverse event reporting additional description |
All (3) treated subjects died before trial completion (on Day 5, in Week 3, and in Week 4, respectively) due to a TEAE (deterioration of ACLF, hypotension, and septic shock, respectively) which was not considered related to the IMP by the investigator and the medical monitor.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.0
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Reporting groups
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Reporting group title |
allo-APZ2-ACLF
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Reporting group description |
Subjects received 3 doses of allo-APZ2-ACLF intravenously within 2 weeks and were followed up 24 weeks for efficacy and 24 months for safety after first allo-APZ2-ACLF application. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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13 May 2020 |
Subjects were screened and enrolled under protocol versions V02 (07-Jan-2019) or V07 (13-May-2020).
Protocol changes to version 02 (07-Jan-2019) were:
- treatment schedule of the investigational medicinal product changed from ‘at Days 0, 4, and 11’ to at ‘Days 0, 5 (±1 day), and 13 (±1 day)’
- mandatory use of antihistamine (type at the discretion of the investigator) before IMP administration to avoid allergic reactions
- continuous monitoring of safety and related data by a DMC consisting of the medical monitor, sponsors’ responsible medical officer, and the respective representative of the clinical trial center, rather than safety monitoring by the medical monitor only (in assistance of coordinating investigator and sponsor’s medical officer, if necessary)
- change in stage-up design of enrollment and treatment of subjects: For the first 6 subjects, the next patient was to be enrolled only after the previous subject’s second infusion had been considered safe by the DMC. A safety evaluation in form of the DMC decision report planned after enrollment of 6 subjects to be submitted to the PEI for approval of further subject recruitment.
- any death should not lead to a stop of the clinical trial and an evaluation of safety after risk assessment, but to an immediate stop of treatment of all subjects and a stop of enrollment. Safety had to be discussed on a case-by-case basis in the DMC meeting. All grade 3 or 4 AEs considered related to the IMP by the investigator and any AE, event, or condition that required treatment or enrollment interruption were to be discussed by the DMC. If considered necessary by the DMC, subject treatment or enrollment were then to be stopped. |
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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 | |||||||||||||
