Clinical Trial Results:
Multicenter Phase II Safety and Preliminary Efficacy Study of 2 dose regimens of HepaStem in Patients with Acute on Chronic Liver Failure
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Summary
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EudraCT number |
2016-001177-32 |
Trial protocol |
BE FR ES BG |
Global end of trial date |
21 Aug 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Jun 2022
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First version publication date |
01 Jun 2022
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Other versions |
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Summary report(s) |
Safety Efficacy |
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 |
HEP101
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02946554 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Promethera Therapeutics (formerly Promethera Biosciences)
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Sponsor organisation address |
Rue Granbonpré 11, Mont-Saint-Guibert, Belgium, 1435
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Public contact |
Welcome Desk, Promethera Therapeutics (formerly Promethera Biosciences), 32 10394300, regulatory@promethera.com
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Scientific contact |
Welcome Desk, Promethera Therapeutics (formerly Promethera Biosciences), 32 10394300, regulatory@promethera.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 |
15 Sep 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
27 Aug 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Aug 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 assess the safety of different dose regimens of HepaStem in cirrhotic patients presenting with acute-on-chronic liver failure (ACLF) or with acute decompensation (AD) at risk of developing ACLF up to Day 28 of the active study period.
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Protection of trial subjects |
The study was conducted in accordance with the ICH Guideline for GCP (specific to ATMP), the guiding principles of the "Declaration of Helsinki", the local data protection and all other applicable regulatory requirements.
Several study procedures were added or updated during the study conduct through amendments to protect trial subjects.
•Participants were hospitalized during the screening and treatment periods to allow continuous monitoring; vital signs were continuously monitored
•Hepatic ultrasonography and US Doppler of the portal vein were performed before and/or during and after each HepaStem, as well as at during the last study visit
•Infusion criteria were updated in order to ensure that participants with a significant pre-existing coagulation imbalance would not receive HepaStem and specify the action to be taken in case of major changes in the coagulation factors
•Additional monitoring blood tests were performed to ensure a close follow-up of the participants before, during and after the infusions
•The volume of HepaStem to be administered and the frequency of administration were reduced in the amended protocols
•In order to prevent transfusion-like reaction, a bolus of 100 mg hydrocortisone or equivalent glucocorticoid was given 15 to 30 minutes before each HepaStem infusion.
•The frequency of SMC meetings was increased
•The sample size was updated
•Adequate medical care was provided to the study participants in case of an adverse event (AE) or a serious AE, which were to be followed up by the investigator until resolution or until the degree of persistent disability could be assessed.
Some procedures, such as the optional transjugular biopsy, were no longer required to limit any further risk of bleeding for the participant.
After completion of the study, all participants who received at least 1 infusion of HepaStem were invited to participate in the long-term follow-up PROLONGSTEM study for 5 additional years (EudraCT: 2017-003989-27)
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Background therapy |
All participants were recruited at hospitals with specialized hepatology and intensive care units. Cirrhotic patients with ACLF/AD at risk of developing ACLF at first evaluation post-admission and/or developing ACLF during hospitalization were assessed for inclusion. The study was designed to administer HepaStem in subsequent cohorts of participants hospitalized for ACLF/AD and/or who developed ACLF during hospitalization. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
05 Dec 2016
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
1 Years | ||
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 |
Spain: 4
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Country: Number of subjects enrolled |
Belgium: 15
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Country: Number of subjects enrolled |
Bulgaria: 5
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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) |
24
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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 |
21 centers in hospitals with specialized hepatology and intensive care units opened in 4 countries; 10 centers were active in 3 countries (Spain, Belgium and Bulgaria). Date of first patient screened: 05-DEC-2016; date of first patient enrolled: 16-DEC-2016. | ||||||||||||
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Pre-assignment
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Screening details |
The screening period lasted up to 7 days following informed consent signature and allowed assessing participant’s eligibility. Participants were hospitalized during the screening period. 34 patients were screened, 25 were eligible and included in the FAS, 24 received HepaStem infusion and were included in the SAF. | ||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
24 | ||||||||||||
Number of subjects completed |
24 | ||||||||||||
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Period 1
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Period 1 title |
Screening period
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Is this the baseline period? |
No | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
Blinding implementation details |
All participants included in the study were adults suffering from cirrhosis as diagnosed by liver histology or clinical and imaging examination.
There was no blinding in this study.
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Arms
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Arm title
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Single arm - Screening period | ||||||||||||
Arm description |
- | ||||||||||||
Arm type |
No intervention | ||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Period 2
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Period 2 title |
Infusion day (Day 1)
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Is this the baseline period? |
Yes [1] | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
Blinding implementation details |
All participants enrolled in the study were administered 1 or 2 doses (one week apart) of HepaStem. There was no blinding in this study.
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Arms
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Arm title
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Single arm - Infusion day (Day 1) | ||||||||||||
Arm description |
- | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
HepaStem
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Dispersion for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
• Cohort 1, first participants enrolled (4.2x10^6 cells/kg BW/infusion, twice or 5.3x10^6 cells/kg BW/infusion, once): N=3, initial Cohort 1a.
• Cohort 2 (0.6-0.8x10^6 cells/kg BW/infusion): N=6, all participants from initial Cohort 1b and 2a.
• Cohort 3 (0.6x10^6 cells/kg BW/infusion, twice): N=3, 3 participants from initial Cohort 2b.
• Cohort 4 (1.2x10^6 cells/kg BW/infusion): N=4, all 3 participants from initial Cohort 2c plus one participant from initial Cohort 2b.
• Cohort 5 (1.2x10^6 cells/kg BW/infusion, twice): N=8, all 5 participants from initial Cohort 2d plus 3 participants from initial Cohort 2b.
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| Notes [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: Baseline characteristics included the assessments performed on Day 1 prior to the first infusion when data were available (vital signs, blood tests). Changes from screening to Day 1 prior to infusion or shift tables are provided for quantitative and qualitative parameters, respectively. |
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Period 3
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Period 3 title |
Active treatment period D14
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Is this the baseline period? |
No | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
Blinding implementation details |
All participants enrolled in the study were administered 1 or 2 doses (one week apart) of HepaStem. There was no blinding in this study.
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Arms
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Arm title
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Single arm - Active treatment period D14 | ||||||||||||
Arm description |
- | ||||||||||||
Arm type |
No intervention | ||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Period 4
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Period 4 title |
Active surveillance period D28
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Is this the baseline period? |
No | ||||||||||||
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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Single arm - Active surveillance period D28 | ||||||||||||
Arm description |
- | ||||||||||||
Arm type |
No intervention | ||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Period 5
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Period 5 title |
Long-term follow-up period M3
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Is this the baseline period? |
No | ||||||||||||
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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Single arm - Long-term follow-up period M3 | ||||||||||||
Arm description |
- | ||||||||||||
Arm type |
No intervention | ||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Period 6
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Period 6 title |
Long-term follow-up period Y1
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Is this the baseline period? |
No | ||||||||||||
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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Single arm - Long-term follow-up period Y1 | ||||||||||||
Arm description |
- | ||||||||||||
Arm type |
No intervention | ||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Infusion day (Day 1)
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Reporting group description |
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Subject analysis sets
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Subject analysis set title |
SAF
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Of the 25 participants who were eligible and included in the FAS, only 24 who received 1 or 2 doses of HepaStem infusion were included in the SAF. Six participants for whom a major protocol deviation was recorded were excluded from the PP, which was constituted of 18 participants.
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End points reporting groups
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Reporting group title |
Single arm - Screening period
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Reporting group description |
- | ||
Reporting group title |
Single arm - Infusion day (Day 1)
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Reporting group description |
- | ||
Reporting group title |
Single arm - Active treatment period D14
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Reporting group description |
- | ||
Reporting group title |
Single arm - Active surveillance period D28
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Reporting group description |
- | ||
Reporting group title |
Single arm - Long-term follow-up period M3
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Reporting group description |
- | ||
Reporting group title |
Single arm - Long-term follow-up period Y1
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Reporting group description |
- | ||
Subject analysis set title |
SAF
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Of the 25 participants who were eligible and included in the FAS, only 24 who received 1 or 2 doses of HepaStem infusion were included in the SAF. Six participants for whom a major protocol deviation was recorded were excluded from the PP, which was constituted of 18 participants.
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End point title |
Adverse events reported up to Day 28 of the active study period [1] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Adverse events (AEs) assessed for seriousness, severity, relationship to HepaStem and/or HepaStem administration procedure (including clinically significant changes in clinical examinations, vital signs, laboratory tests, abdominal echography and Doppler).
The relationship will be assessed based on investigator assessment and in addition by the SMC and the sponsor’s pharmacovigilance in line with the ATMP guideline.
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End point type |
Primary
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End point timeframe |
Up to Day 28 (end of active study period)
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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 formal statistical hypotheses were assessed. Standard descriptive statistics were used for quantitative and categorical variables. |
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| Notes [2] - The number/percentage of participants having at least one adverse event were measured from D1 to D28 |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Clinical efficacy parameters assessed on Day 28, Month 3 and Year 1 - Mortality and liver transplantation | |||||||||||||||||||||||||
End point description |
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
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End point type |
Secondary
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End point timeframe |
On Day 28 (end of the active study period), Month3, and Year 1 (end of the long-term follow-up and of the study)
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| No statistical analyses for this end point | ||||||||||||||||||||||||||
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End point title |
Clinical efficacy parameter assessed on Day 28, Month 3 and Year 1 - CLIF-OF score | ||||||||||||||||||||
End point description |
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
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End point type |
Secondary
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End point timeframe |
On Day 28 (end of the active study period), Month3, and Year 1 (end of the long-term follow-up and of the study)
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Biological efficacy parameter at Day 28, Month 3 and Year 1 – Bilirubin | ||||||||||||||||||||
End point description |
Serum total bilirubin.
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
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End point type |
Secondary
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End point timeframe |
On Day 28 (end of the active study period), Month3, and Year 1 (end of the long-term follow-up and of the study)
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Biological efficacy parameter at Day 28, Month 3 and Year 1 - Creatinine | ||||||||||||||||||||
End point description |
Serum creatinine.
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
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End point type |
Secondary
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End point timeframe |
On Day 28 (end of the active study period), Month3, and Year 1 (end of the long-term follow-up and of the study)
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Biological efficacy parameter at Day 28, Month 3 and Year 1 - INR | ||||||||||||||||||||
End point description |
Prothrombin International Normalized Ratio.
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
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End point type |
Secondary
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End point timeframe |
On Day 28 (end of the active study period), Month3, and Year 1 (end of the long-term follow-up and of the study)
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Biological efficacy parameter at Day 28, Month 3 and Year 1 - Albumin | ||||||||||||||||||||
End point description |
Serum Albumin.
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
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End point type |
Secondary
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End point timeframe |
On Day 28 (end of the active study period), Month3, and Year 1 (end of the long-term follow-up and of the study)
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Adverse Events of Special Interest | |||||||||||||||||||||
End point description |
Serious adverse event with fatal outcome, malignancies, adverse events assessed by the investigator as possibly related to HepaStem, liver transplantation and outcome of liver transplantation.
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
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End point type |
Secondary
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End point timeframe |
Between Day 28 and Month 3, and between Month 3 and Year 1
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
New ACLF episode | ||||||||||||
End point description |
New ACLF episode.
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Between Day 28 and Month 3, and between Month 3 and Year 1
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||
End point title |
Clinical efficacy parameter assessed up to Day 28 - CLIF-C ACLF score | ||||||||||
End point description |
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
On Day 28 (end of the active study period)
|
||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||||||||||||||||||||
End point title |
Clinical efficacy parameter assessed on Day 28, Month 3 and Year 1 - CLIF ACLF grade | ||||||||||||||||||||||||||||
End point description |
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
On Day 28 (end of the active study period), Month3, and Year 1 (end of the long-term follow-up and of the study)
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Clinical efficacy parameter assessed on Day 28, Month 3 and Year 1 - CLIF-C AD | ||||||||||||||||||||
End point description |
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
On Day 28 (end of the active study period), Month3, and Year 1 (end of the long-term follow-up and of the study)
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Clinical efficacy parameter assessed on Day 28, Month 3 and Year 1 - MELD score | ||||||||||||||||||||
End point description |
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
On Day 28 (end of the active study period), Month3, and Year 1 (end of the long-term follow-up and of the study)
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Clinical efficacy parameter assessed on Day 28, Month 3 and Year 1 - Child Pugh score | ||||||||||||||||||||
End point description |
No formal statistical hypotheses were assessed.
Standard descriptive statistics were used for quantitative and categorical variables.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
On Day 28 (end of the active study period), Month3, and Year 1 (end of the long-term follow-up and of the study)
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||
|
Adverse events information [1]
|
|||
Timeframe for reporting adverse events |
AEs up to Day 28, AESIs between Day 28 and Year 1
|
||
Adverse event reporting additional description |
Up to Day 28, all AEs were collected and assessed for seriousness, severity, relationship to HepaStem and/or HepaStem administration procedure (including clinically significant changes in clinical examinations, vital signs, laboratory tests, abdominal echography and Doppler).
Between Day 28 and Year 1, only AESIs were collected.
|
||
Assessment type |
Systematic | ||
|
Dictionary used for adverse event reporting
|
|||
Dictionary name |
MedDRA | ||
Dictionary version |
18.1
|
||
| Frequency threshold for reporting non-serious adverse events: 0% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Information relative to non-serious adverse events is provided in the endpoint section: Primary endpoint (Adverse events reported up to Day 28) and secondary endpoint (Adverse Events of Special Interest reported between Day 28 and Year 1) |
|||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
13 Dec 2016 |
v2.0
• Inclusion/exclusion criteria were updated:
o as HepaStem might have a procoagulant effect, inclusion and treatment discontinuation criteria were further specified
o the delay between corticosteroid treatment and screening visit was updated
• The organ failure criteria were clarified to take into account patients treated with terlipressin.
|
||
21 Mar 2017 |
v3.0 (only submitted to Belgian competent authorities; not approved) dated 21 Mar-2017
v3.2 (submitted to Belgium IEC) dated 11-May-2017, v 3.1 and v3.3 (approved) submitted to the French competent authorities
Following the occurrence for the 2 severe SAEs of bleeding and the temporary halt of the study, the study protocol was amended:
• To decrease the dose and their frequency of administration (refer to Sections 9.1.1 and 9.4 for further details). Consequently, the volume to be administered was also adapted
• To enroll participants who were at a less severe stage of ACLF, i.e., patients with AD and INR < 2
• To increase the safety monitoring of the participants before, during and after HepaStem infusion:
o by increasing the monitoring of coagulation parameters (addition of monitoring parameters and repetition of some assessments during and after the treatment period)
o by allowing the collection of a sample for TEG/TGT to be analyzed centrally
o by repeating the imagery examination at the last participant visit to have a complete status of the participant at the end of study comparable to the evaluations done at screening
o in addition, to limit any further risk of bleeding for the participant, transjugular liver biopsy was no longer required and an exclusion criterion (if performed, sufficient time in-between procedure and dosing was to be allowed)
• To update criteria for infusion in order to ensure that participants with a significant pre-existing coagulation imbalance would not receive HepaStem and specify the action to be taken in case of major changes in the coagulation factors (refer to Section 9.3.1 for further details)
• To increase the frequency of SMC meetings
• To update the sample size
• For participants who underwent a major surgery, at least 4 weeks have to pass before cells infusion
• To ensure the independency of the SMC, all members are to be external and independent to PROMETHERA THERAPEUTICS |
||
15 Feb 2018 |
v 4.0 (only submitted in Spain and Bulgaria)
• The screening period was extended to ensure the delivery of HepaStem on site within the screening period. |
||
26 Jun 2018 |
v 5.0 and v5.1
• Two additional cohorts (2c and 2d), including each 3 participants, were planned in order to assess the safety of higher dose (1.0x10^6 cells/kg BW/infusion).
• The recruitment of 3 additional participants (more severe ACLF) to be included in the cohort considered as safe by the SMC (Cohort 2b) has been added.
• To be in line with the inclusion of patients at a more severe stage of the disease, exclusion criteria were redefined to exclude participants with circulatory and/or respiratory failure according to the CLIF C OF consortium.
• Following the conclusion raised by the SMC members on 25-Jun-2018, the patients with a suspicion of hepatocellular carcinoma were to be excluded. All exams were to be performed to confirm or not the diagnosis.
• Screening procedures were revised in order to include the monitoring of fibrinogen.
|
||
14 Dec 2018 |
v 6.0 and v6.1
• The total sample size was revised based upon SMC’s recommendations to approximately 21 evaluable participants.
• A third and fourth analyses were planned on Day 28 and Month 3, respectively, on all participants, including enrolled participants in Cohort 2b having an INR > 2 and participants enrolled in Cohorts 2c and 2d.
• Before HepaStem infusion, an equivalent of hydrocortisone (in equivalent dose) could be given instead of hydrocortisone.
|
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
|||
| http://www.ncbi.nlm.nih.gov/pubmed/34169246 |
|||
