Extension Treatment Using EryDex System in Patients With AT Who Participated in the ATTeST-IEDAT-02-2015 Study (OLE-IEDAT)

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

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).

Study Overview

• Status: Terminated
• Conditions: Genetic Syndrome; Ataxia Telangiectasia
• Intervention / Treatment: Combination product: EryDex System

Detailed Description

This was an international (North America, Europe, Africa, Asia and Australia), multi-center, prospective, open-label treatment study, designed to continue to provide the study medication to all patients who completed 12 months of treatment (including those treated with placebo) in the ATTeST-IEDAT-02-2015 trial, completed the study assessments, do not present safety contraindication to continuation of treatment, and provided informed consent.

The study aimed to collect information on the long-term safety and efficacy of the trial treatment.

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.

During the study, long-term efficacy assessments were performed every 6 months, while safety parameters were assessed at each monthly visit. The Schedule of Visits and assessments for the first 12 months were replicated for the second year onwards for patients who continued EryDex treatment beyond 12 months.

The analysis of the EryDex long-term safety and tolerability was based on the occurrence of Treatment-Emergent Adverse Events (TEAEs), including Serious AEs and discontinuations due to AEs. The long-term effect was measured by the "Modified" International Cooperative Ataxia Rating Scale, (mICARS), Rescored mICARS, Clinical Global Impression of severity and change (CGI-S/C) and health-related Quality of Life (QoL; EQ-5D-5L scale).

The ICARS, EQ-5D-5L and the CGI-C / S were administered by a properly qualified rater identified at each site who performed the ratings on the efficacy measures. The ICARS rater remained blinded to other assessments and did not have access to the safety data. The CGI rater did not have access to the ICARS ratings or safety data but was able to refer to other scales in scoring the CGI.

All patients enrolled in this study have participated in Study ATTeST-IEDAT-02-2015, and there was no de novo enrollment of new patients.

EryDel S.p.A (now Quince Therapeutics) decided to discontinue the IEDAT-03-2018 study in India due to the COVID-19 pandemic. On 13 Apr 2022, after the last patient completed one year of EryDex treatment, EryDel S.p.A. communicated the end of the open label extension study IEDAT-03-2018 and the stop of the EryDex treatment for patients in the context of this study.

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Department of Neurology Royal Children's Hospital
• Belgium
  • Leuven, Belgium, 3000
    • Laboratory of Pediatric Immunology UZ Leuven
• Germany
  • Frankfurt, Germany, 60590
    • Klinik für Kinder- und Jugendmedizin, Allergologie, pneumologie und Mukoviszidose, Universitätsklinikum Frankfurt
• India
  • Bangalore, India, 560 029
    • National Institute of Mental Health and Neurosciences (NIMHANS) Department of Neurology
  • Hyderabad, India, 500 082
    • Nizam's Institute of Medical Sciences Department of Neurology
  • Mumbai, India, 400 026
    • Jaslok Hospital and Research Center Department of Pediatric Neurology
  • Tamil Nadu
    • Chennai, Tamil Nadu, India
      • Vijaya Health Centre, Department of Neurology
• Italy
  • Roma, Italy
    • Dipartimento Neuroscienze umane e salute mentale, Policlinico Umberto I Università La Sapienza
• Norway
  • Oslo, Norway
    • Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital
• Poland
  • Warsaw, Poland, 04-730
    • Department of Clinical Immunology - The Children's Memorial Health Institute
• Spain
  • Madrid, Spain, 28046
    • Servicio de Neurolgia Pediatrica, Hospital Materno-Infantil La Paz
• Tunisia
  • Tunis, Tunisia
    • Razi Hospital, Clinical Investigation Center-Neuroscience
• United Kingdom
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom
      • Nottingham University Hospitals NHS Trust - Queen's Medical Centre
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Ataxia Center and HD Center of Excellence - UCLA
  • Maryland
    • Baltimore, Maryland, United States, 21287-3923
      • Division of Pediatric Allergy and Immunology - Johns Hopkins Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Department of Pediatrics Division of Child and Adolescent Neurology Mitochondrial Clinic - University of Texas Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient completed the double-blind period in the ATTeST study and completed the final (Visit 15 / Month 12) Efficacy Assessments of ATTeST or discontinued the study during the COVID-19 pandemic.
2. Patient tolerated the study medication, without any evidence of steroid adverse events, or treatment-related severe events / serious adverse events.
3. Body weight > 15 kg.
4. The patient and his / her parent / caregiver (if below the age of consent), or a legal representative, provided written informed consent to participate. If consent was provided solely by the caregiver in accordance with local regulations, the patient also was asked to provide their assent to participate in the study.
5. Patient did not present safety contraindication for continuation of treatment, as determined by the Principal Investigator (PI) according to the procedures described below.

Moreover, patients who were discontinued from the ATTeST study during the COVID-19 pandemic were eligible to receive the EryDex treatment in the IEDAT-03-2018 study, in the absence of safety contraindications to continuation of the treatment, and after signing the informed consent.

There were no de novo enrolled patients.

Exclusion Criteria:

Patients who met one or more of the following criteria were not considered to be eligible to participate in the study:

General

1. Females that were:

   1. Pregnant, or were breast-feeding (for EU countries only)
   2. Of childbearing potential, pregnant, or were breast-feeding (for US and Rest of World countries).

   Females of childbearing potential using adequate birth control, as determined by their Health Care Provider, were eligible.

2. A disability that may prevent the patient from completing all study requirements.

3. Current participation in another clinical study with another investigational drug.

   Medical History and Current Status

4. Cluster differential 4 positive (CD4+) lymphocytes 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).
5. Current neoplastic disease.
6. Severe impairment of the immunological system.
7. Severe or unstable pulmonary disease.
8. Uncontrolled diabetes. Patients with diabetes that had been stabilized (i.e., no hypoglycemic or hyperglycemic episodes in the past 3 months) were eligible.
9. Any other severe, unstable, or serious disease or condition that in the Investigator's opinion would put the patient at risk for imminent life-threatening morbidity, need for hospitalization, or mortality.
10. Eligibility of patients with abnormal laboratory test values were determined by the Investigator.
11. Confirmed haemoglobinopathies, e.g., haemoglobin C disease, sickle cell anaemia, or thalassemia.
12. Moderate or severe renal and / or hepatic impairment.

13. Patients who experienced moderate / severe steroid side effects, or moderate / severe adverse events associated with the EryDex treatment administered in the ATTeST study.

    Prior / Concomitant Medication

14. Requires treatment with an oral or parenteral steroid. Treatment with inhaled or intranasal steroids for asthma or allergies, as well as use of topical steroids were permitted.
15. Requires any other concomitant medication prohibited by the protocol.
16. Use of any drug that is a strong inducer / inhibitor of Cytochrome P450 3A4 (CYP3A4).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: active drug; ~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.

Combination product: EryDex System; EryDex System was a combination product that was used to load dexamethasone sodium phosphate (DSP) into autologous erythrocytes (EDS) creating the EDS-end product which was infused into the patients. 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. 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, based on the analysis of the ATTeST blinded, Phase 3 study data.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Treatment-Emergent Adverse Event (TEAE), Treatment-emergent Serious Adverse Events (TESAE), and Adverse Events of Special Interest (AESI) Throughout the Study	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.	From Baseline (Visit 1 - Day 0) to Follow-up (~60 days after last infusion, i.e. up to 50.5 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Quality of Life Using EQ-5D-5L Scale to Month 36	The EQ-5D included single item measures of 5 health dimensions: mobility,; self-care,; usual activities,; pain / discomfort, and; anxiety / depression. 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).The EQ-5D results were converted into a continuous index score: as for this index score, the closer the value is to 1, the better is the health status. 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.	From Baseline (Visit 1- Day 0) to Month 36
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 36	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.	From Baseline (Visit 1- Day 0) to Month 36
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 36	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.	From Baseline (Visit 1- Day 0) to Month 36
Change From Baseline of the Modified International Cooperative Ataxia Rating Scale (mICARS) Until Month 36	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.	From Baseline (Visit 1- Day 0) to Month 36

Collaborators and Investigators

• Sponsor: Quince Therapeutics S.p.A.
• Investigators: Study Director: Guenter R Janhofer, MD, PhD, EryDel S.p.A.

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2018
• Primary Completion (Actual): September 2, 2022
• Study Completion (Actual): September 2, 2022

Study Registration Dates

• First Submitted: May 23, 2018
• First Submitted That Met QC Criteria: June 8, 2018
• First Posted (Actual): June 20, 2018

Study Record Updates

• Last Update Posted (Actual): October 8, 2024
• Last Update Submitted That Met QC Criteria: September 12, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Dexamethasone; Ataxia Telangiectasia; AT; EryDex system; Dexamethasone sodium phosphate
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Neurologic Manifestations; Genetic Diseases, Inborn; Dyskinesias; DNA Repair-Deficiency Disorders; Neurocutaneous Syndromes; Cerebellar Diseases; Primary Immunodeficiency Diseases; Spinocerebellar Ataxias; Ataxia; Telangiectasis; Cerebellar Ataxia; Ataxia Telangiectasia
• Other Study ID Numbers: IEDAT-03-2018; 2018-000338-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No