Clinical Trial Results:
Open-label, Long-term, Extension Treatment using Intra-Erythrocyte Dexamethasone Sodium Phosphate (EryDex System) in Patients with Ataxia Telangiectasia Who Participated in the ATTeST-IEDAT-02-2015 Study
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Summary
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EudraCT number |
2018-000338-36 |
Trial protocol |
ES DE BE PL GB NO IT |
Global end of trial date |
02 Sep 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
10 May 2024
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First version publication date |
10 May 2024
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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 |
IEDAT-03-2018
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT03563053 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
US IND: 115929 | ||
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Sponsors
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Sponsor organisation name |
Erydel S.p.A.
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Sponsor organisation address |
Via Meucci, 3, Bresso, Italy, 20091
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Public contact |
Irene Maccabruni, Erydel S.p.A., imaccabruni@quincetx.com
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Scientific contact |
Irene Maccabruni , Erydel S.p.A., imaccabruni@quincetx.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 |
02 Sep 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Sep 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Sep 2022
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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 |
Primary Objective
To monitor and evaluate the long-term safety and tolerability of EDS-EP in AT patients.
Secondary Objective
To evaluate the long-term effect of EDS-EP on health-related Quality of Life (QoL; EQ-5D-5L scale).
Exploratory Objective:
To evaluate the long-term effect of EDS-EP in treating central nervous system (CNS) symptoms, as measured by the “Modified” International Cooperative Ataxia Rating Scale (mICARS), and Clinical Global Impression of severity and change (CGI-S/C).
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Protection of trial subjects |
The study was conducted in accordance with the Helsinki Declaration and Good Clinical Practice. Any essential documents were archived as required by Good Clinical Practice and national regulations. Independent Ethics Committee approval and written informed consent were obtained prior to starting the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Jun 2018
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
2 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 10
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Country: Number of subjects enrolled |
Spain: 11
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Country: Number of subjects enrolled |
Belgium: 3
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Country: Number of subjects enrolled |
Germany: 13
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Country: Number of subjects enrolled |
United States: 25
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Country: Number of subjects enrolled |
United Kingdom: 11
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Country: Number of subjects enrolled |
Italy: 2
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Country: Number of subjects enrolled |
Norway: 5
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Country: Number of subjects enrolled |
Tunisia: 7
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Country: Number of subjects enrolled |
India: 15
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Country: Number of subjects enrolled |
Australia: 2
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Worldwide total number of subjects |
104
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EEA total number of subjects |
44
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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) |
69
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Adolescents (12-17 years) |
6
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Adults (18-64 years) |
29
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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 |
Out of a total of 108 patients who completed the full treatment period in the ATTeST- IEDAT-02 study, 104 patients were enrolled in the IEDAT-03-2018 study and comprised the Total Set. These patients signed the ICF, completed the ATTeST study assessments, and did not present safety contraindications prior continuation with the EryDex treatment. | ||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
All patients enrolled in this study have participated in Study ATTeST-IEDAT-02-2015, and there was no de novo enrollment of new patients. Patients meeting all selection criteria received monthly infusions of EDS-EP (dose range of ~14-22 mg DSP/infusion). If this dose of EDS-EP was not tolerated, the patient was discontinued from the study. | ||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||
Blinding implementation details |
It's a open label extension study, so no blinding was applicable.
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Arms
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Arm title
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EryDex treatment | ||||||||||||||||||||||||||||||||||
Arm description |
~14-22 mg dexamethasone sodium phosphate (DSP) for 12 months. The duration of EryDex treatment could be extended further and continue until patients eventually withdrew consent, or the Investigator decided to discontinue treatment based on a risk / benefit assessment. EryDex System was a combination product that was used to load DSP into autologous erythrocytes (EDS) creating the EDS-end product. EryDex treatment consisted of a dose range correspondent to the ATTeST High Dose (obtained by loading 125 mg of DSP to the EryDex process and that, in the ATTeST, resulted in a mean of 17.4 ± 5.4 mg of DSP infused to patients) administered via ex vivo encapsulation into EDS that were infused into the patient with A-T. The dose of EryDex treatment was selected to allow collection of long-term safety data on the dose of erythrocyte encapsulated DSP that was considered more effective among the two different doses that were employed in the ATTeST study. | ||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
EryDex System treatment
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Infusion
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Dosage and administration details |
EryDex treatment consisted of a dose range correspondent to the ATTeST High Dose (obtained by loading 125 mg of DSP to the EryDex process and that, in the ATTeST, resulted in a mean of 17.4 ± 5.4 mg (mean ± standard deviation) of DSP infused to patients) administered via ex vivo encapsulation into EDS that were infused into the patient with A-T. EryDex treatment was administered monthly throughout the period of the study. The duration of EryDex treatment was planned for 12 months but could be extended further and continue until patients eventually withdrew consent, or the Investigator decided to discontinue treatment based on a risk / benefit assessment.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial (overall period)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
EryDex - FAS
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Full Analysis Set Population (FAS): the FAS comprised all patients who entered IEDAT-03-2018 study, had a Baseline Efficacy Assessment in IEDAT-03-2018 and who received at least one dose of study medication and had at least one post-Baseline Efficacy Assessment of the ICARS in this extension study.
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Subject analysis set title |
EryDex - Total Set
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
In this trial, the Total or Overall Set (N=104) numerically corresponds to the Safety set, which included all patients who provided informed consent or assent and who received any dose of study medication during ATTeST-IEDAT-03-2018 study (i.e., “Date performed” given on the “EDS-EP Infusion” eCRF page at any Visit).
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Subject analysis set title |
EryDex - SAF
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Safety Analysis Set consisted of all patients who provided informed consent or assent and who received any dose of study medication during IEDAT-03-2018 study. The Safety Analysis Set was used for all safety analyses.
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End points reporting groups
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Reporting group title |
EryDex treatment
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Reporting group description |
~14-22 mg dexamethasone sodium phosphate (DSP) for 12 months. The duration of EryDex treatment could be extended further and continue until patients eventually withdrew consent, or the Investigator decided to discontinue treatment based on a risk / benefit assessment. EryDex System was a combination product that was used to load DSP into autologous erythrocytes (EDS) creating the EDS-end product. EryDex treatment consisted of a dose range correspondent to the ATTeST High Dose (obtained by loading 125 mg of DSP to the EryDex process and that, in the ATTeST, resulted in a mean of 17.4 ± 5.4 mg of DSP infused to patients) administered via ex vivo encapsulation into EDS that were infused into the patient with A-T. The dose of EryDex treatment was selected to allow collection of long-term safety data on the dose of erythrocyte encapsulated DSP that was considered more effective among the two different doses that were employed in the ATTeST study. | ||
Subject analysis set title |
EryDex - FAS
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Full Analysis Set Population (FAS): the FAS comprised all patients who entered IEDAT-03-2018 study, had a Baseline Efficacy Assessment in IEDAT-03-2018 and who received at least one dose of study medication and had at least one post-Baseline Efficacy Assessment of the ICARS in this extension study.
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Subject analysis set title |
EryDex - Total Set
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
In this trial, the Total or Overall Set (N=104) numerically corresponds to the Safety set, which included all patients who provided informed consent or assent and who received any dose of study medication during ATTeST-IEDAT-03-2018 study (i.e., “Date performed” given on the “EDS-EP Infusion” eCRF page at any Visit).
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Subject analysis set title |
EryDex - SAF
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The Safety Analysis Set consisted of all patients who provided informed consent or assent and who received any dose of study medication during IEDAT-03-2018 study. The Safety Analysis Set was used for all safety analyses.
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End point title |
Number of Treatment-Emergent Adverse Event (TEAE), treatment-emergent serious adverse events (TESAE), and adverse events of special interest (AESI) throughout the study [1] | ||||||||||||||||||||||||||||||||||||||
End point description |
Assessment of TEAEs, treatment-emergent serious adverse events (TESAE), and adverse events of special interest (AESI) were performed throughout the study, from the time of signing of the ICF at Baseline Visit through to the Final Study Visit (Month 12 or early discontinuation). All patients were to be followed up through 30 days after the Final Visit (Month 12 or early discontinuation) or at least 60 days after the final infusion, whichever was longer.
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End point type |
Primary
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End point timeframe |
From Baseline (Visit 1 - Day 0) to Follow-up (~60 days after last infusion)
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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: Not applicable. |
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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 Using EQ-5D-5L Scale to Month 54 | ||||||||||||||||||||
End point description |
The EQ-5D included single item measures of 5 health dimensions:
- mobility,
- self-care,
- usual activities,
- pain / discomfort, and
- anxiety / depression.
In addition, EQ-5D included a global rating of current health using a visual analogue scale (VAS) ranging from 0 (worst health imaginable) to 100 (best health imaginable). The EQ VAS provided a quantitative measure of the patient’s perception of their overall health.
The EQ-5D-5L included five levels of severity (i.e., no problems, slight problems, moderate problems, severe problems, and extreme problems) for each of the five EQ-5D dimensions. These levels were scored from 1 = no problems to 5 = extreme problems: from 5, min/worst, to 25, best/max); EQ-VAS (EQ Visual Analogue scale) scoring from 0, min/worst, to 100, best/max. The efficacy data focus mainly up to Month 36 as afterwards the number of patients / assessments dropped below 20% of the initial sample size, which was required for the efficacy evaluations.
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End point type |
Secondary
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End point timeframe |
From Baseline (Visit 1- Day 0) to Month 36
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| Notes [2] - Month 6 N=73, Month 12 N=61, Month 18 N=51, Month 24 N=32, Month 30 N=22, Month 36 N= 20 |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Number of Patients With Improving, Stable or Worsening Score Using a Clinical Global Impression of Change (CGI-C) From Baseline (Visit 1- Day 0) to Month 54 | ||||||||||||||||||||||||||||||||
End point description |
The CGI-C scale assesses the change in the patient’s clinical status from baseline using a 7-point scale, ranging from 1 (very much improved) to 7 (very much worse), with a score of 4 indicating no change. Clinicians were required to conduct a full clinical interview and examination of the patient.
The interview and examination assessed various aspects of the patient’s appearance (grooming, evidence of falls, etc.), ataxia, cognition (orientation, calculation ability, language, ability to follow commands, memory, etc.), apraxia, dysarthria, extrapyramidal motor symptoms, activities of daily living, and mood. The higher the score the worse the outcome.
The efficacy data focus mainly up to Month 36 as afterwards the number of patients / assessments dropped below 20% of the initial sample size, which was required for the efficacy evaluations.
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End point type |
Secondary
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End point timeframe |
From Baseline (Visit 1- Day 0) to Month 36
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| Notes [3] - Month 6 N=80, Month 12 N=59, Month 18 N=47, Month 24 N=29, Month 30 N=19, Month 36 N= 19 |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Number of Patients With None to Severe (0 to 4) Scores in Clinical Global Impression of Severity (CGI-S)-Structured of Neurological Symptoms of AT From Baseline (Visit 1 - Day 0) to Month 54 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The CGI-S scale measures global severity of illness at a given point in time, and is usually rated on a 7-point, Likert-type scale ranging from 1 (normal, not ill at all) to 7 (among the most extremely ill patients). No version of the CGI-S exists which has been specifically adapted for use in patients with A-T; therefore, a 5-point version was developed that considered the severity of the following symptoms of A-T: ataxia (walking), dysarthria, dysmetria, extrapyramidal symptoms (chorea, myoclonus, dystonia, and tremor), and eye movements. Ratings of none (0), mild (1), moderate (2), severe (3), and very severe (4) were selected based on the level of symptomatology. The higher the score the worse the outcome.
The efficacy data focus mainly up to Month 36 as afterwards the number of patients / assessments dropped below 20% of the initial sample size, which was required for the efficacy evaluations.
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End point type |
Secondary
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End point timeframe |
From Baseline (Visit 1- Day 0) to Month 36
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| Notes [4] - Baseline N=74,Month 6 N=76, Month 12 N=59, Month 18 N=47, Month 24 N=31, Month30 N=19, Month36 N= 19 |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Change from baseline of the Modified International Cooperative Ataxia Rating Scale (mICARS) until month 54 | ||||||||||||||||||||
End point description |
The International Cooperative Ataxia Rating Scale (ICARS) was an assessment of the degree of impairment in patients with cerebellar ataxia and was administered in its entirety; however, the primary efficacy assessment was based on the modified (m)ICARS, which excluded the Oculomotor domain (items 17 to 19) and items 8 to 12 of the Kinetic Functions domain of the ICARS. The mICARS was a 54 points maximum score (min 0) questionnaire divided into 3 sections:
• Posture and Gait Disturbance section-7 items (min score 0, max score 34)
• Kinetic Function-2 items (min 0, max 12)
• Speech Disorder- 2 items (min 0, max 8).
An higher scores - both for total and subscores - indicate a higher level of disease impairment. The subscores are added to give the total score.
The efficacy data focus mainly up to Month 36 as afterwards the number of patients / assessments dropped below 20% of the initial sample size, which was required for the efficacy evaluations.
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End point type |
Secondary
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End point timeframe |
From Baseline (Visit 1- Day 0) to Month 36
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| Notes [5] - Month 6 N=78, Month 12 N=60, Month 18 N=48, Month 24 N=32, Month 30 N=21, Month 36 N= 18 |
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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 |
TEAEs were all the AEs reported from Baseline (Visit 1 - Day 0) to Follow-up (~60 days after the last infusion).
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Adverse event reporting additional description |
All AEs that occurred during this IEDAT-03-2018 study are defined as TEAEs, as all patients received EryDex treatment in the study.
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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 |
22.0
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Reporting groups
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Reporting group title |
EryDex - SAF
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Reporting group description |
The Safety Analysis Set consisted of all patients who provided informed consent or assent and who received any dose of study medication during IEDAT-03-2018 study. The Safety Analysis Set was used for all safety analyses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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29 Mar 2018 |
• Revision of the study procedures to ensure that sterility is maintained throughout the collection of autologous blood cells, processing, administration, and testing (rapid testing, gram stain and culture) of EryDex treatment.
• Addition of the reference to the document entitled “Study Procedures on Sterility Testing for Study IEDAT-03-2018 (Open Label Extension (OLE)-IEDAT)”.
• Minor editorial changes have been made and additional clarifications provided, including a modification in the study's entry criteria to allow inclusion of patients that have not worsened significantly on treatment.
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30 Apr 2018 |
• Provision of clarification explaining that the Principal Investigator, instead of the CRO, will decide if a patient is eligible to continue into the IEDAT-03-2018 study.
• The removal of requirement that the patient cannot worsen significantly during treatment (e.g., evidence of disease stabilisation or improvement as determined by the ratings of the CGI-C) to be eligible for the IEDAT-03-2018 study, to avoid doubts regarding the exclusion of the placebo patients who might not show disease stabilisation or improvement. Therefore, it has been clarified that, to be eligible for the IEDAT-03-2018 study, patients must have completed 12 months of treatment in the ATTeST study, including all its study assessments, do not present safety contraindication to continuation of treatment, and provide informed consent.
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19 Mar 2019 |
• CRO references were changed.
• Safety e-mail was changed.
• EryDel address was updated on the Sample Study Solutions and Medication Labels.
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29 Apr 2019 |
• In the study design, the treatment period was changed from 12 months of treatment to full treatment period.
• During the study, Long-term Efficacy Assessments were changed from a 6-month frequency to approximately every 6 months.
• Rapid microbial detection test (Staining test) was removed.
• The definition of the allowed treatment window was clarified: the monthly infusions should be performed every 21-28 days. A window of + 10 days was permitted for each of the scheduled Monthly Visits. Therefore, no EDS-EP infusion should be performed less than 21 days or more than 38 days after the previous infusion. The window between an infusion and the subsequent one should be kept as regular as possible throughout the study, avoiding fluctuations in administration windows. The date of an infusion is not bound to the date of the initial treatment but to the date of the previous IMP administration.
• Exclusion Criterion #4 was changed and a value in case of oral candidiasis was added. More in details:
- PREVIOUS version: CD4+ lymphocyte count < 400 / mm3 (for patients 6 years of age) or < 200 / mm3 (for patients > 6 years).
- UPDATED version:CD4+ lymphocyte count < 400 / mm3 (for patients 6 years of age) or < 150 / mm3 (for patients > 6 years). In presence of oral infections, like oral candidiasis, documented at the screening or recurrent as per medical history documentation, the limit increases to < 200 / mm3 (for patients > 6 years).
• The Microbial Staining test was removed.
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22 May 2020 |
• The planned number of patients was updated to 155.
• Timelines for the last patient in were updated.
• Appendix 13 was added: Temporary changes to the Protocol implemented / to be implemented because of COVID-19 pandemic.
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01 Dec 2020 |
• Study design and rationale were updated to allow patients who were discontinued from the ATTeST study during the COVID-19 pandemic to receive the EryDex treatment in the context of the IEDAT-03-2018 study.
• Inclusion criterion #1 was revised to include patients discontinued the ATTEST study during the COVID-19 pandemic.
• Visit assessments and schedule were amended to reflect the updated study design and inclusion criteria.
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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. | |||
| India was particularly affected by COVID-19-dependent treatment and visit interruptions.This long interruption would have resulted in insufficient long-term safety data. For this reason, EryDel decided to discontinue the IEDAT-03-2018 study in India | |||
